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Notes sur conférence 06
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Facteurs de vulnérabilité génétique

(Premiére conférence analysée  Jeudi 27 novembre 2003 , Maj Notes 09/07/07)

  Notes   Références  

   Les principaux documents de référence sont indiqués en fin. Il n'est pas question d'être exhaustif sur un tel sujet, aussi a-t-on privilégie les documents récents faisant autorité (rapports de recherche) et les rares documents en français.  La presse de vulgarisation médicale a été volontairement écartée. 

  Le trouble bipolaire est une maladie à très forte composante génétique (80-90%), mais ce n'est pas une hérédité mendélienne simple. Il y a intervention au minimun d'une dizaine de génes différents. La situation  commence, en 2007,à pouvoir être analysée d'un point de vue global en faisant des analyses comparatives complétes de génomes de malades et de génomes de population témoin à l'aide de puces à ADN couvrant le génome entier et de bibliothèques de SNP.

La première étude génétique portant sur l’ensemble du génome et visant à déterminer le génes impliqués dans la prédisition du trouble bipolaire vient de révéler ses premiers résultats dans la revue Molecular Psychiatry le 8 mai 2007. Un enzyme, le DGKH issu d’un gène du chromosome 13q, impliqué dans le cycle de l’insotil phosphatase, représente une nouvelle cible prometteuse pour un futur médicament.

L’intérêt principal de cette étude n’est pas dans la découverte d’une nouvelle liaison génétique. Il en parait une par trimestre et bien peu sont confirmées sur des échantillons différents. L’intérêt réside dans la méthode employé. Pour la première fois, les méthodes "bulldozer" d’analyse de la génétique moléculaire sur l’ensemble du génome (wide scan genome) ont été mises en oeuvre pour déterminer les gènes les plus "liés" au trouble bipolaire type 1. Les changement du génome portant sur un seul nucleotide sont appelés des SNP (prononcer SNIP) et servent souvent de marqueurs génétiques. 550 000 SNP ont été examinés, 2000 SNP "candidats" ont fait l’objet d’une étude approfondie, 88 retenus et 37 ont fait l’objet d’un génotypage individuel. Le géne le plus lié au TB-1 est le DGKH avec 3 SNP montrant un fort facteur d’association. Mais chaque SNP retenu n’a qu’un faible coefficient de corrélation (le DGKH a un odds ratio de 1,59 alors qu’un OD de 3,0 minimum est la norme habituelle pour les publications).

Baum et col concluent : Le trouble bipolaire ne peut être qu’une affection polygénique pour laquelle la modification d’un seul géne n’est ni nécessaire, ni suffisante pour son développement.

Qu’en conclure, pratiquement pour l’avenir du traitement des personnes atteintes de trouble bipolaire ?

1). Constatons d’abord que la génétique moléculaire n’est à l’origine, pour l’instant, d’aucun médicament thymorégulateur. Ceux-ci ont été découvert, soit par le hasard d’observations cliniques (lithium), soit en testant pour cet usage des médicaments d’abord utilisés dans d’autres troubles psychiatriques (anti-épileptiques et neuroleptiques).

2). Les techniques de génétique moléculaire sont en croissance exponentielle, et les progrès viendront certainement par cette voie.

3). La première étape sera la découverte du mécanisme (de l’étiologie) du trouble. C’est infiniment plus complexe pour les mécanismes cérébraux, où les voies de régulation sont nombreuses et corrélées, que pour les maladies vasculaires ou musculaires.

4). Une fois les mécanismes moléculaires déterminés, comme pour la chorée de Huntington (1993, huntingtine) ou la myopathie de Duchenne (1986, dystrophine), ce n’est pas pour autant qu’un traitement sera disponible à court terme. Dans les deux maladies citées, il n’y a toujours pas de traitement efficace en 2007.

Les avancées scientifiques sont porteuses d’espoir pour le futur, mais sans qu’il soit possible de fixer une date pour la disposition d’un traitement efficace.


NOTES

Anecdote : le chef de clinique demande à une consultante "votre frère est un vrai ou un faux jumeau ? "

I. ETUDES SUR LES JUMEAUX.   Les vrais jumeaux, ceux issus d'un même oeuf les homozygotes, ont les mêmes génes. Si le facteur génétique était  primordial,  deux vrais jumeaux devraient avoir le même destin. Or si l'un est bipolaire, l'autre n'a que 65% de chance de l'être.

II. STATISTIQUES.
  Pére ou mére bipo : 5% des enfants seront bipolaires 
Frère ou soeur bipo : 10% de "chance" d'être bipolaire
Pére (ou Mére) et oncle(ou tante) : 14%
Pére et mère (rare) : 30%
  Quand deux jumeaux ne sont pas atteints, leurs enfants ont la même "chance" d'être bipolaire, bien qu'élevés dans des familles différentes.   Il ne s'agit pas d'une affection monogénique, mais de multiples gènes de prédisposition.

III. PENETRANCE ET AGGREGATION..
  Le poids d'aggrégation exprime la part de prédisposition génétique.
  Les maladies dépendant d'un seul géne et strictement génétiques (par exemple chorée de Huntington, myopathie de Duchesne, muscoviscidose) ont un poids d'aggrégation de 10000. 
Pour beaucoup de maladies on parle de génes de fragilisation ou de vulnérabilité.

   Autisme            50
   Schizophrénie    10
   Bipolarité         10
    Psoriasis            8
   Diabéte                6
   Asthme                6
   Hypertension artérielle   2

  • IV.LOCALISATION DES GENES.
  •   Les études génétiques ont abouti à de multiples localisations au surplus différentes suivant les populations .
  •  Le génes de prédisposition sont parfois les mêmes que ceux observés pour la schizophrénie.
    •   Il s'agit d'un facteur d'hérédite complexe, multi-génes et dépendant de l'environnement.
  •   Les études du professeur Marion Leboyer ont trouvé trois regroupements dont le plus significatif est celui des atteintes précoces (moins de 18 ans). Le poids génétique ici semble beaucoup plus important que dans le cas général.

    • (à compléter)
       Une page d'analyse reprend les fondements scientifiques de l'hérédite et donne beaucoup de références dont, ô surprise, certaines en français :
     organisation des systèmes biologiques

    Références.
    (disponibles sur le web-pdf, html - ou en document papier)

    Blog univ. Edinburgh

    Ce blog sur la génétique  analyse les articles de recherches récents sur la génétique des troubles psychiatriques complexes (schizophrénie et troubles bipolaires). La signification -o combien délicate - des recherches et leurs perpectives sont intelligemment commentés et avec mesure. C'est suffisamment rare pour être souligné.  Beaucoup trop de scientifiques, quand ils veulent se muer en penseurs, brossent de vastes fresques allant de la cellule à l'homme  en accumulant les hypothèses ad hoc.  Autant vaudrait écrire de la science-fiction, il n'y aurait, au moins, pas tromperie sur la marchandise.

    Analyses des jumeaux bipolaires à partir du registre national finlandais. Am. J. Psy oct 2004 p 1814 Kiessepa et col
    Quand un jumeau monozygote est bipolaire l'autre à 43% de l'être au sens strict (BP1) contre 6% pour un jumeau dizygote. Le taux monte à 50% avec une définition intermédiaire (BP1 ou schizo-affectif) et même à 75% si l'on prend l'ensemble du spectre bipolaire : BP1,BP2, BNOS, Cyclothymie, Dépressions récurrentes.

    http://www.neurotransmitter.net/bipolar.html
    Abstracts (résumés) de tous les articles de recherche récents (2002-2003) parus sur le sujet, en particulier les pages suivantes dont le titre donne une idée des pistes de recherche actuelles :

    Synthéses.

    Molecular genetics of schizophrenia : a critical review Berry,N, Vaidehi,J,Pal,H - J Psychiatry Neurosciences 2003;28(6).
    "     Survol des progrès en cours et des orientations futures en génétique moléculaire de la schizophrénie."
    En conclusion "Il est apparent qu'aucune localisation unique ne peut causer qu'un effet modeste., malgré qu'elle puisse être la première à être identifiée et que des  efforts intensifs seront requis pour identifier les multiples gènes ayant un effet mineur. De même, il est difficile d'ignorer la possibilité que de multiples interactions non-linéaires entre gènes et facteurs environnementaux peuvent entraîner un tel désordre hétérogène."
    Note : les gènes de fragilité pour les troubles bipolaires sont souvent les mêmes que ceux pour la schizophrénie.(cf exposé ci-dessous)

    Shared Genetic Susceptibility for Bipolar and Schizophrenic Disorders

    Video  |  Audio (Length:  31 min.)

    W. Berrettini
    University of Pennsylvania School of Medicine, Philadelphia, PA, USA
    Vth pittburgh conference on bipolar disorder  June 2003

    Abstract
    Schizophrenic and bipolar disorders are similar in several epidemiologic respects, including age-at-onset, lifetime risk, course of illness, worldwide distribution, risk for suicide, gender influence (men and women at equal risk for both groups of disorders) and genetic susceptibility. Despite these similarities, schizophrenia and bipolar disorders are typically considered to be separate entities, with distinguishing clinical characteristics, non-overlapping etiologies and distinct treatment regimens. Over the past three decades, multiple family studies are consistent with greater nosologic overlap than previously acknowledged. First degree relatives of bipolar probands are at increased risk for bipolar, schizoaffective and unipolar disorders. First degree relatives of schizophrenic probands are at increased risk for schizophrenic, schizoaffective and unipolar disorders. Molecular linkage studies (conducted during the past decade) reveal that some susceptibility loci may be common to both nosologic classes, including those located at 18p11.2, 22q11-13, 13q32, 8p22 and 10p14. This indicates that our nosology will require substantial revision during the next decade, to reflect this shared genetic susceptibility, as specific genes are identified.


    Neuroplasticity and Cellular Resilience in Bipolar Disorder

    Video  |  Audio (Length:  35 min.)

    H.K. Manji
    National Institute of Mental Health, Bethesda, MD, USA
    Vth pittburgh conference on bipolar disorder  June 2003

    Abstract
    Attempts to comprehend the brain's role in mania and depression began in earnest as clinically effective mood altering drugs began to appear in the late 1950s and early 1960s. Over the next three decades, clinical studies attempted to uncover the biological factors mediating the pathophysiology of manic-depressive illness utilizing a variety of biochemical strategies. Studies were, by and large, designed to detect relative excess or deficiency associated with pathological states; not surprisingly, progress in unraveling the unique neurobiology of this disorder was slow using such strategies in isolation. However, the last decade of the 20th century has truly been a remarkable one for biomedical research. The “molecular medicine revolution” has brought to bear the power of sophisticated cellular and molecular biologic methodologies to tackle many of society’s most devastating illnesses. The rate of progress has been exciting indeed, and hundreds of G protein coupled receptors and over a dozen G proteins and effectors have now been identified and characterized at the molecular and cellular level. This has allowed the study of a variety of human diseases which are caused by abnormalities in cell to cell communication; studies of such diseases are offering unique insights into the physiologic and pathophysiologic functioning of many cellular transmembrane signaling pathways. Psychiatry, like much of the rest of medicine, has entered a new and exciting age demarcated by the rapid advances and the promise of molecular and cellular biology and neuroimaging. Although we have yet to identify the specific abnormal genes or proteins in bipolar disorder, there have been major advances in our understanding of this illness, as well as in the mechanisms of action of the most effective treatments. The behavioral and physiological manifestations of bipolar disorder are complex and are likely mediated by a network of interconnected neuronal circuits. Since signal transduction pathways play a critical role in regulating the functional balance between neurotransmitter systems, they represent attractive putative mediators of the therapeutic effects of mood stabilizing agents. New genomics and proteomics technologies are also being utilized to facilitate the identification of genes that are regulated by mood stabilizers, and have led to novel and completely unexpected targets, most notably neurotrophic signaling cascades.  The identification of neurotrophic signaling cascades as targets for mood stabilizers is particularly noteworthy since – although bipolar disorder has traditionally been conceptualized as a neurochemical disorder -- there is now evidence from a variety of sources demonstrating regional reductions in CNS volume, as well as reductions in the numbers and/or sizes of glia and neurons in discrete brain areas. Although the precise cellular mechanisms underlying these morphometric changes remain to be fully elucidated, the data suggest that severe bipolar disorders are associated with impairments of structural plasticity and cellular resilience. It is thus noteworthy that recent preclinical studies have shown that critical molecules in neurotrophic signaling cascades (most notably CREB, BDNF, bcl-2 and MAP kinases) are long term targets for mood stabilizing agents.  Consistent with these biochemical effects, mood stabilizing agents (most notably lithium) have been demonstrated to exert robust neuroprotective and neurotrophic effects in a variety of preclinical paradigms. Complementary human studies have shown that chronic lithium significantly increases gray matter content in a regionally selective manner, suggesting a reversal of illness-related atrophy and an increase in the volume of the neuropil. These unique and unexpected properties of lithium and valproate suggest that they may have broader utility as adjunctive agents in the treatment of a variety of neuropsychiatric disorders associated with cell atrophy or loss. Furthermore, the growing body of preclinical and clinical data suggests that for many refractory patients, new drugs simply mimicking many ‘traditional’ drugs which directly or indirectly alter neurotransmitter levels and those which bind to cell surface receptors may be of limited benefit. For these patients, optimal treatment may only be attained by providing both trophic and neurochemical support; the trophic support would be envisioned as enhancing and maintaining normal synaptic connectivity, thereby allowing the chemical signal to reinstate the optimal functioning of critical circuits necessary for normal affective functioning. There are a number of pharmacologic “plasticity enhancing” strategies which may be of considerable utility in the treatment of mood disorders. Among the most immediate ones are NMDA antagonists, glutamate release reducing agents, AMPA potentiators, cAMP phosphodiesterase inhibitors, and glucocorticoid receptor antagonist. An increasing number of strategies are also being investigated to develop small molecule agents to regulate the activity of growth factors, MAP kinases cascades, and the bcl-2 family of proteins; this research hold much promise for the development of novel therapeutics for the treatment of severe, refractory mood disorders.


    Divers.


    LIVRES (en français).

    L'ADN et le secret de la vie -James Watson - Odile Jacob(2003)

    p403
    " Les deux maladies mentales qui ont le plus attirées l'attention des généticiens sont le maladie maniaco-dépressive et la schizoprhrénie. Ces deux troubles ont de fortes composantes génétiques - le degrè de concordance pour la maladie maniaco-dépressive chez des jumeaux monozygotes est de 80% et avoisine 50% pour la schizophrénie - , et sont extrêmement répandus dans le monde. La schizophrénie touche une personne sur 100 et l'incidence de la maladie maniaco-dépressive est quasiment aussi importante.
      Nous l'avons vu, localiser les gènes impliqués impliqués dans les troubles polygéniques est difficile, car chaque géne n'y produit qu'un effet limité et que ces troubles, comme c'est le cas ici, sont par ailleurs fortement soumis à l'influence de facteurs extérieurs. Aussi les chercheurs ont-ils pris la facheuse habitude de ne publier que des résultats positifs...
      La recherche des gènes en cause dans les maladies mentales se heurte également à d'autres obstacles. Bien que les manuels de psychiatrie aient tenté de fixer des normes pour le diagnostic, ce dernier relève souvent davantage de l'intuition que de la science. Il peut arriver que certains cas soient identifiés sur la base de symptômes  relativement ambigus. De telles erreurs de diagnostic, lorsqu'elles concernent des patients faisant partie d'un panel de recherche, faussent nécessairement les résultats d'une analyse de liaison génétique. Sachant par ailleurs que des causes génétiques différentes peuvent fort bien produire des effets similaires, le fait que ces troubles soient définis et diagnostiqués exclusivement sur la base de leurs symptômes constitue un facteur de complication supplèmentaire.. On peut très bien imaginer que les génes qui sont à l'origine des symptômes de la schizophrénie varient d'un patient à un autre. Même les différences qui semblent qui semblent distinguer  clairement plusieurs syndromes sont susceptibles de se brouiller lorsqu'on les examine du point de vue de la génétique.Depuis 1975 nous savons que la maladie manaico-dépressive et la dépression  sont des syndromes génétiquement distincts.  Pourtant on a fait la découverte troublante qu'il semblait y avoir une sorte de recoupement génétique entre les deux : la dépression est bien plus répandue parmi les proches de patients atteints de maladie maniaco-dépressive que dans le reste de la population .
      Partiellement en raison des difficultés que l'on vient d'évoquer, l'identification génétique des causes génétiques des maladies mentales demeure actuellement problèmatique Les cartes génétiques établies lirs d'une étude récente, montrent que pas moins de onze chromosomes - la moitié de tous ceux que nous possédons - semblent contenir des génes impliqués dans la schizophrénie. De même on a pu identifier dix chromosomes contenant des gènes susceptibles de jouer un rôle dans la maladie maniaco-dépressive. Element intéressant, certaines zones des régions génétiques identifiées dans les deux études semblent se chevaucher. Peut-être doit-on en conclure qu'il existe des génes responsables de l'organisation et de la structure d'ensemble de notre cerveau. Des dysfonctionnements affectant ces gènes pourraient être à l'origine des perceptions faussées et des hallucinations qui se manifestent dans les deux troubles. Malheureusement, les faux espoirs sont nombreux dans le domaine de la recherche. Il arrive souvent qu'une forte corrélation ait été identifiée chez un groupe de patients et qu'elle ne se vérifie pas chez un autre. Ce fut le cas d'une corrélation pour la psychose maniaco-dépressive découverte en 1987 au cours d'uen étude réalisée au sein de la communauté Amish. cette corrélation qui semblait prometteuse avait été localisée sur le chromosome 11, mais ne put être étendue à l'ensemble de la population. Les généticiens Neil Risch et David Botstein ont livré une des cription très juste des déceptions que ce domaine de la recherche réserve aux scientifiques.
      Dans aucun autre domaine, la difficulté [à localiser les génes d'une maladie] n'a été à l'origine de plus de déceptions que dans la génétqiue psychiatrique. Les recherches sur la maladie maniaco-dépressive livrent un exemple type de ce phénoméne. On pourrait même dire qu'il existe une étrange corrélation entre l'histoire récente de l'analyse de liaison génétique et les symptômes de la maladie elle-même. Le passage d'un état d'euphorie devant la découverte d'une liaison génétqiue à un état d'abattement  devant son absence [dans d'autres populations] est devenu un schéma de comportement universel , et rythme aujourd'hui l'existence de nombreux praticiens et de leurs observateurs intéressés "(cf N.Risch, D.Botstein "A manic depressive history", Nature genetics, n°12, 1996 p351-353

    Lenox RH, Gould TD, Manji HK.
    Endophenotypes in bipolar disorder [This article was prepared by a group consisting of both United States Government employees and non-United States Government employees, and as such is subject to 117 U.S.C. Sec. 105.]
    Am J Med Genet 2002 May 8;114(4):391-406
    "Findings in patients with bipolar disorder that may eventually be useful as endophenotypes include abnormal regulation of circadian rhythms (the sleep/wake cycle, hormonal rhythms, etc.), response to sleep deprivation, P300 event-related potentials, behavioral responses to psychostimulants and other medications, response to cholinergics, increase in white matter hyperintensities (WHIs), and biochemical observations in peripheral mononuclear cells."
    [Abstract]

    Dimitrova A, Milanova V, Krastev S, Nikolov I, Toncheva D, Owen MJ, Kirov G
    Association study of myo-inositol monophosphatase 2 (IMPA2) polymorphisms with bipolar affective disorder and response to lithium treatment.
    Pharmacogenomics J. 2005;5(1):35-41.
    Lithium is the most effective mood-stabilizing drug in the therapy of bipolar affective disorder (BP). It is thought to exert its effect via the phosphatidylinositol signalling system. Myo-inositol monophosphatase 2 (IMPA2) codes for an enzyme in this system that is inhibited by lithium. It is located on 18p11.2, a region implicated as a BP susceptibility locus. We examined eight single-nucleotide polymorphisms (SNPs) identified within this gene for association with BP, using 237 parents-offspring trios and in 174 cases and 170 controls. No SNP showed association with BP. When good responders to lithium treatment were compared with the poor responders, some statistically significant differences emerged for two SNPs; however, the sample became too small to draw definitive conclusions. We cannot find support for the involvement of variation in IMPA2 in susceptibility to bipolar disorder, but the role of this and other genes from the phosphoinositol signalling pathway in predicting response to lithium treatment merits further investigation.The Pharmacogenomics Journal (2005) 5, 35-41. doi:10.1038/sj.tpj.6500273 Published online 26 October 2004.

    John R. Kelsoe
    Arguments for the genetics basis of bipolar spectrum
    Journal of Affective Disorders january 2003 p183-197

    Family members of bipolar probands have been repeatedly shown to have an increased risk for mood disorders. However, a range of different syndromes in the bipolar spectrum are commonly observed in these relatives. This suggests the hypothesis that these different syndromes may be genetically related. It further suggests that bipolar disorder may be better conceptualized from a genetic standpoint as a quantitative trait. In such a model, the same genes may predispose to a variety of phenotypes ranging from schizoaffective disorder to cyclothymic temperament. Previous attempts to test such a multifactorial model have provided some limited support. However, other studies argue that some forms of bipolar disorder such as bipolar II may be genetically distinct. In this review, various quantitative and categorical models of illness are considered and the data supporting them reviewed. It is proposed that the existing data may best fit a model in which different sets of genes predispose to overlapping phenotypes that are in part both quantitative and distinct in nature.

    F M Benes1,2, D Matzilevich1,2, R E Burke1,2 and J Walsh1,2
    The expression of proapoptosis genes is increased in bipolar disorder, but not in schizophrenia
    Molecular Psychiatry (2006) 11, 241–251. doi:10.1038/sj.mp.4001758; published online 15 November 2005
    Keywords:   apoptosis, caspase, Bcl-x, BAX, APAF-1, c-myc, PARP-1

    1Program in Structural and Molecular Neuroscience, McLean Hospital, Belmont, MA, USA
    2    Program in Neuroscience and Department of Psychiatry, Harvard Medical School, Belmont, MA, USA
    Correspondence: Dr FM Benes, McLean Hospital, 115 Mill Street, Belmont, MA 02478, USA. E-mail: benesf@mclean.harvard.edu
    Received 19 July 2005; Revised 10 August 2005; Accepted 15 August 2005; Published online 15 November 2005.

    Post-mortem studies conducted over the past 15 years suggest that apoptosis could play a role in the pathophysiology of bipolar disorder (BD) and, to a lesser degree, schizophrenia (SZ). To test this hypothesis, we have performed a post hoc analysis of an extant gene expression profiling database obtained from the hippocampus using a novel methodology with improved sensitivity. Consistent with the working hypothesis, BDs showed a marked upregulation of 19 out of 44 apoptosis genes; however, contrary to the hypothesis, the SZ group showed a downregulation of genes associated with apoptotic injury and death. These changes in the regulation of apoptosis genes were validated using quantitative RT–PCR. Additionally, antioxidant genes showed a marked downregulation in BDs, suggesting that accumulation of free radicals might occur in the setting of a previously reported decrease of the electron transport chain in this disorder. Overall, the changes seen in BDs and SZs do not appear to be related to exposure to either neuroleptics or mood stabilizers. We conclude that fundamental differences in the genetic regulation of apoptosis and antioxidant genes may help discriminate between the pathophysiology of BD and SZ and potentially point to new treatment strategies that are specific for each disorder.


    A Montero-Pedrazuela1, C Venero2, R Lavado-Autric1, I Fernández-Lamo1, J M García-Verdugo3, J Bernal1 and A Guadaño-Ferraz
    Modulation of adult hippocampal neurogenesis by thyroid hormones: implications in depressive-like behavior
    Molecular Psychiatry (2006) 11, 361–371. doi:10.1038/sj.mp.4001802; published online 31 January 2006
    Keywords:  thyroid hormones, adult neurogenesis, dentate gyrus, proliferation, doublecortin, depressive disorder

    1Department of Molecular Endocrinology, Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain
    2    Department of Psychobiology, Universidad Nacional de Educación a Distancia, Madrid, Spain
    3    Laboratorio de Morfologia Celular, Unidad Mixta CIPF-UVEG, Valencia, Spain
    Correspondence: Dr A Guadaño-Ferraz, Instituto de Investigaciones Biomédicas, CSIC-UAM, Arturo Duperier 4, E-28029 Madrid, Spain. E-mail: aguadano@iib.uam.es
    Received 25 October 2005; Revised 19 December 2005; Accepted 3 January 2006; Published online 31 January 2006.

    Hormonal imbalances are involved in many of the age-related pathologies, as neurodegenerative and psychiatric diseases. Specifically, thyroid state alterations in the adult are related to psychological changes and mood disorders as depression. The dentate gyrus of the hippocampal formation undergoes neurogenesis in adult mammals including humans. Recent evidence suggests that depressive disorders and their treatment are tightly related to the number of newly born neurons in the dentate gyrus. We have studied the effect of thyroid hormones (TH) on hippocampal neurogenesis in adult rats in vivo. A short period of adult-onset hypothyroidism impaired normal neurogenesis in the subgranular zone of the dentate gyrus with a 30% reduction in the number of proliferating cells. Hypothyroidism also reduced the number of newborn neuroblasts and immature neurons (doublecortin (DCX) immunopositive cells) which had a severely hypoplastic dendritic arborization. To correlate these changes with hippocampal function, we subjected the rats to the forced swimming and novel object recognition tests. Hypothyroid rats showed normal memory in object recognition, but displayed abnormal behavior in the forced swimming test, indicating a depressive-like disorder. Chronic treatment of hypothyroid rats with TH not only normalized the abnormal behavior but also restored the number of proliferative and DCX-positive cells, and induced growth of their dendritic trees. Therefore, hypothyroidism induced a reversible depressive-like disorder, which correlated to changes in neurogenesis. Our results indicate that TH are essential for adult hippocampal neurogenesis and suggest that mood disorders related to adult-onset hypothyroidism in humans could be due, in part, to impaired neurogenesis.

     B Etain1,2,21, F Mathieu1,21, M Rietschel3, W Maier4, M Albus5, P McKeon6, S Roche7, C Kealey8, D Blackwood9, W Muir9, F Bellivier1,2, C Henry10, C Dina11, S Gallina11, H Gurling12, A Malafosse13, M Preisig14, F Ferrero15, S Cichon16, J Schumacher17, S Ohlraun3, M Borrmann-Hassenbach5, P Propping17, R Abou Jamra17, T G Schulze3, A Marusic18, Z M Dernovsek18, B Giros1, T Bourgeron19, A Lemainque20, D Bacq20, C Betard20, C Charon20, M M Nöthen16, M Lathrop20 and M Leboyer1,2
    Genome-wide scan for genes involved in bipolar affective disorder in 70 European families ascertained through a bipolar type I early-onset proband: supportive evidence for linkage at 3p14
    Molecular Psychiatry advance online publication 14 March 2006; doi: 10.1038/sj.mp.4001815
    Keywords:  bipolar disorder, age at onset, genome-wide search, linkage
    Correspondence: Dr B Etain, Unité de Recherche Clinique, Département Hospitalo-Universitaire de psychiatrie, Hôpital Albert Chenevier, 40 rue de Mesly, Créteil 94000, France. E-mail: etain@im3.inserm.fr
    21These authors contributed equally to this work.
    Received 24 May 2005; Revised 3 January 2006; Accepted 19 January 2006; Published online 14 March 2006.

    Preliminary studies suggested that age at onset (AAO) may help to define homogeneous bipolar affective disorder (BPAD) subtypes. This candidate symptom approach might be useful to identify vulnerability genes. Thus, the probability of detecting major disease-causing genes might be increased by focusing on families with early-onset BPAD type I probands. This study was conducted as part of the European Collaborative Study of Early Onset BPAD (France, Germany, Ireland, Scotland, Switzerland, England, Slovenia). We performed a genome-wide search with 384 microsatellite markers using non-parametric linkage analysis in 87 sib-pairs ascertained through an early-onset BPAD type I proband (AAO of 21 years or below). Non-parametric multipoint analysis suggested eight regions of linkage with P-values<0.01 (2p21, 2q14.3, 3p14, 5q33, 7q36, 10q23, 16q23 and 20p12). The 3p14 region showed the most significant linkage (genome-wide P-value estimated over 10 000 simulated replicates of 0.015 [0.01–0.02]). After genome-wide search analysis, we performed additional linkage analyses with increased marker density using markers in four regions suggestive for linkage and having an information contents lower than 75% (3p14, 10q23, 16q23 and 20p12). For these regions, the information content improved by about 10%. In chromosome 3, the non-parametric linkage score increased from 3.51 to 3.83. This study is the first to use early-onset bipolar type I probands in an attempt to increase sample homogeneity. These preliminary findings require confirmation in independent panels of families.

    Nievergelt CM, Kripke DF, Barrett TB, Burg E, Remick RA, Sadovnick AD, McElroy SL, Keck PE, Schork NJ, Kelsoe JR
    Suggestive evidence for association of the circadian genes PERIOD3 and ARNTL with bipolar disorder.
    Am J Med Genet B Neuropsychiatr Genet. 2006 Mar 9;141B(3):234-241.

    Bipolar affective disorder (BPAD) is suspected to arise in part from malfunctions of the circadian system, a system that enables adaptation to a daily and seasonally cycling environment. Genetic variations altering functions of genes involved with the input to the circadian clock, in the molecular feedback loops constituting the circadian oscillatory mechanism itself, or in the regulatory output systems could influence BPAD as a result. Several human circadian system genes have been identified and localized recently, and a comparison with linkage hotspots for BPAD has revealed some correspondences. We have assessed evidence for linkage and association involving polymorphisms in 10 circadian clock genes (ARNTL, CLOCK, CRY2, CSNK1epsilon, DBP, GSK3beta, NPAS2, PER1, PER2, and PER3) to BPAD. Linkage analysis in 52 affected families showed suggestive evidence for linkage to CSNK1epsilon. This finding was not substantiated in the association study. Fifty-two SNPs in 10 clock genes were genotyped in 185 parent proband triads. Single SNP TDT analyses showed no evidence for association to BPAD. However, more powerful haplotype analyses suggest two candidates deserving further studies. Haplotypes in ARNTL and PER3 were found to be significantly associated with BPAD via single-gene permutation tests (P(G) = 0.025 and 0.008, respectively). The most suggestive haplotypes in PER3 showed a Bonferroni-corrected P-value of P(GC) = 0.07. These two genes have previously been implicated in circadian rhythm sleep disorders and affective disorders. With correction for the number of genes considered and tests conducted, these data do not provide statistically significant evidence for association. However, the trends for ARNTL and PER3 are suggestive of their involvement in bipolar disorder and warrant further study in a larger sample. (c) 2006 Wiley-Liss, Inc.
    Mansour HA, Wood J, Logue T, Chowdari KV, Dayal M, Kupfer DJ, Monk TH, Devlin B, Nimgaonkar VL
    Association study of eight circadian genes with bipolar I disorder, schizoaffective disorder and schizophrenia.
    Genes Brain Behav. 2006 Mar;5(2):150-7.
    We hypothesize that circadian dysfunction could underlie, at least partially, the liability for bipolar 1 disorder (BD1). Our hypothesis motivated tests for the association between the polymorphisms of genes that mediate circadian function and liability for BD1. The US Caucasian patients with BD1 (DSM-IV criteria) and available parents were recruited from Pittsburgh and surrounding areas (n = 138 cases, 196 parents) and also selected from the NIMH Genetics Collaborative Initiative (n = 96 cases, 192 parents). We assayed 44 informative single-nucleotide polymorphisms (SNPs) from eight circadian genes in the BD1 samples. A population-based sample, specifically cord blood samples from local live births, served as community-based controls (n = 180). It was used as a contrast for genotype and haplotype distributions with those of patients. US patients with schizophrenia/schizoaffective disorder (SZ/SZA, n = 331) and available parents from Pittsburgh (n = 344) were assayed for a smaller set of SNPs based on the results from the BD1 samples. Modest associations with SNPs at ARNTL (BmaL1) and TIMELESS genes were observed in the BD1 samples. The associations were detected using family-based and case-control analyses, albeit with different SNPs. Associations with TIMELESS and PERIOD3 were also detected in the Pittsburgh SZ/SZA group. Thus far, evidence for association between specific SNPs at the circadian gene loci and BD1 is tentative. Additional studies using larger samples are required to evaluate the associations reported here.

    Shaltiel G, Shamir A, Levi I, Bersudsky Y, Agam G
    Lymphocyte G-protein receptor kinase (GRK)3 mRNA levels in bipolar disorder.
    Int J Neuropsychopharmacol. 2005 Dec 19;1-6.
    Linkage studies in bipolar disorder were positive for markers in the region of chromosome 22q12.1 including the gene coding for G-protein receptor kinase (GRK)3. Two of six variants of the GRK3 5'-UTR/promoter were reported to be associated with bipolar disorder. GRK3 protein levels in lymphoblastoid cell lines derived from bipolar patients originating from families with linkage to chromosome 22q11 were reported to be decreased compared to those of control subjects and correlated with disease severity. We compared GRK3 mRNA levels in fresh lymphocytes from 31 bipolar patients vs. 26 control subjects, using real-time RT-PCR. No overall difference was found between patients and controls. However, GRK3 mRNA levels were markedly and significantly reduced in the subgroup of patients with no family history of a major psychiatric disorder compared with patients with family history.     Rao AS, Kremenevskaja N, Resch J, Brabant G
    Lithium stimulates proliferation in cultured thyrocytes by activating Wnt/beta-catenin signalling.
    Eur J Endocrinol. 2005 Dec;153(6):929-38.
    BACKGROUND: Lithium, clinically used in the treatment of bipolar disorders, is well known to induce thyroid growth. However, the mechanism involved is only incompletely characterized. Although it is conventionally believed that thyroid proliferation depends on the thyroid-stimulating hormone (TSH)/cAMP/cAMP response element binding protein (CREB) pathway, recent data indicate that Wnt/beta-catenin signalling may be of critical importance. In other cell types lithium activates canonical Wnt signalling by GSK-3beta inhibition, which in turn stabilizes cytosolic free beta-catenin. Here we investigated the potential modulation of Wnt/beta-catenin signalling under lithium treatment in primary and neoplastic human thyrocytes. METHODS: Primary (S18) and neoplastic (NPA, FTC133) thyrocytes treated with and without LiCl were analysed using Western blotting, immunoprecipitation, reporter-gene assay, MTT proliferation assay and transfection studies. RESULTS: LiCl dose-dependently inhibited GSK-3beta, stabilized free beta-catenin and inhibited beta-catenin degradation. Furthermore, LiCl altered the assembly of adherens junction by upregulating the E-cad-herin repressor, Snail, and downregulated E-cadherin expression. At a dose of 5 mM, LiCl significantly increased the proliferative potency of thyrocytes, which appeared to be mediated by beta-catenin, since nuclear beta-catenin stimulated T-cell factor/lymphoid enhancer factor (TCF/LEF)-mediated transcription and upregulated downstream targets like cyclin D1. To characterize the specificity of Wnt/beta-catenin-driven thyrocyte proliferation, we transfected primary thyrocytes and FTC133 cells with dominant negative TCF4 to block Wnt-dependent pathways or with dominant negative CREB to inhibit the TSH/cAMP cascade. In cells transfected with dominant negative CREB lithium-stimulated proliferation was unchanged whereas blocking Wnt/beta-catenin by dominant negative TCF4 reduced proliferation by approx. 50%. CONCLUSION: Our data indicate that Wnt/beta-catenin signalling is of major importance in the control of lithium-dependent thyrocyte proliferation.    Rao AS, Kremenevskaja N, Resch J, Brabant G
    Lithium stimulates proliferation in cultured thyrocytes by activating Wnt/beta-catenin signalling.
    Eur J Endocrinol. 2005 Dec;153(6):929-38.
    BACKGROUND: Lithium, clinically used in the treatment of bipolar disorders, is well known to induce thyroid growth. However, the mechanism involved is only incompletely characterized. Although it is conventionally believed that thyroid proliferation depends on the thyroid-stimulating hormone (TSH)/cAMP/cAMP response element binding protein (CREB) pathway, recent data indicate that Wnt/beta-catenin signalling may be of critical importance. In other cell types lithium activates canonical Wnt signalling by GSK-3beta inhibition, which in turn stabilizes cytosolic free beta-catenin. Here we investigated the potential modulation of Wnt/beta-catenin signalling under lithium treatment in primary and neoplastic human thyrocytes. METHODS: Primary (S18) and neoplastic (NPA, FTC133) thyrocytes treated with and without LiCl were analysed using Western blotting, immunoprecipitation, reporter-gene assay, MTT proliferation assay and transfection studies. RESULTS: LiCl dose-dependently inhibited GSK-3beta, stabilized free beta-catenin and inhibited beta-catenin degradation. Furthermore, LiCl altered the assembly of adherens junction by upregulating the E-cad-herin repressor, Snail, and downregulated E-cadherin expression. At a dose of 5 mM, LiCl significantly increased the proliferative potency of thyrocytes, which appeared to be mediated by beta-catenin, since nuclear beta-catenin stimulated T-cell factor/lymphoid enhancer factor (TCF/LEF)-mediated transcription and upregulated downstream targets like cyclin D1. To characterize the specificity of Wnt/beta-catenin-driven thyrocyte proliferation, we transfected primary thyrocytes and FTC133 cells with dominant negative TCF4 to block Wnt-dependent pathways or with dominant negative CREB to inhibit the TSH/cAMP cascade. In cells transfected with dominant negative CREB lithium-stimulated proliferation was unchanged whereas blocking Wnt/beta-catenin by dominant negative TCF4 reduced proliferation by approx. 50%. CONCLUSION: Our data indicate that Wnt/beta-catenin signalling is of major importance in the control of lithium-dependent thyrocyte proliferation.    Rao AS, Kremenevskaja N, Resch J, Brabant G
    Lithium stimulates proliferation in cultured thyrocytes by activating Wnt/beta-catenin signalling.
    Eur J Endocrinol. 2005 Dec;153(6):929-38.
    BACKGROUND: Lithium, clinically used in the treatment of bipolar disorders, is well known to induce thyroid growth. However, the mechanism involved is only incompletely characterized. Although it is conventionally believed that thyroid proliferation depends on the thyroid-stimulating hormone (TSH)/cAMP/cAMP response element binding protein (CREB) pathway, recent data indicate that Wnt/beta-catenin signalling may be of critical importance. In other cell types lithium activates canonical Wnt signalling by GSK-3beta inhibition, which in turn stabilizes cytosolic free beta-catenin. Here we investigated the potential modulation of Wnt/beta-catenin signalling under lithium treatment in primary and neoplastic human thyrocytes. METHODS: Primary (S18) and neoplastic (NPA, FTC133) thyrocytes treated with and without LiCl were analysed using Western blotting, immunoprecipitation, reporter-gene assay, MTT proliferation assay and transfection studies. RESULTS: LiCl dose-dependently inhibited GSK-3beta, stabilized free beta-catenin and inhibited beta-catenin degradation. Furthermore, LiCl altered the assembly of adherens junction by upregulating the E-cad-herin repressor, Snail, and downregulated E-cadherin expression. At a dose of 5 mM, LiCl significantly increased the proliferative potency of thyrocytes, which appeared to be mediated by beta-catenin, since nuclear beta-catenin stimulated T-cell factor/lymphoid enhancer factor (TCF/LEF)-mediated transcription and upregulated downstream targets like cyclin D1. To characterize the specificity of Wnt/beta-catenin-driven thyrocyte proliferation, we transfected primary thyrocytes and FTC133 cells with dominant negative TCF4 to block Wnt-dependent pathways or with dominant negative CREB to inhibit the TSH/cAMP cascade. In cells transfected with dominant negative CREB lithium-stimulated proliferation was unchanged whereas blocking Wnt/beta-catenin by dominant negative TCF4 reduced proliferation by approx. 50%. CONCLUSION: Our data indicate that Wnt/beta-catenin signalling is of major importance in the control of lithium-dependent thyrocyte proliferation.    Rao AS, Kremenevskaja N, Resch J, Brabant G
    Lithium stimulates proliferation in cultured thyrocytes by activating Wnt/beta-catenin signalling.
    Eur J Endocrinol. 2005 Dec;153(6):929-38.
    BACKGROUND: Lithium, clinically used in the treatment of bipolar disorders, is well known to induce thyroid growth. However, the mechanism involved is only incompletely characterized. Although it is conventionally believed that thyroid proliferation depends on the thyroid-stimulating hormone (TSH)/cAMP/cAMP response element binding protein (CREB) pathway, recent data indicate that Wnt/beta-catenin signalling may be of critical importance. In other cell types lithium activates canonical Wnt signalling by GSK-3beta inhibition, which in turn stabilizes cytosolic free beta-catenin. Here we investigated the potential modulation of Wnt/beta-catenin signalling under lithium treatment in primary and neoplastic human thyrocytes. METHODS: Primary (S18) and neoplastic (NPA, FTC133) thyrocytes treated with and without LiCl were analysed using Western blotting, immunoprecipitation, reporter-gene assay, MTT proliferation assay and transfection studies. RESULTS: LiCl dose-dependently inhibited GSK-3beta, stabilized free beta-catenin and inhibited beta-catenin degradation. Furthermore, LiCl altered the assembly of adherens junction by upregulating the E-cad-herin repressor, Snail, and downregulated E-cadherin expression. At a dose of 5 mM, LiCl significantly increased the proliferative potency of thyrocytes, which appeared to be mediated by beta-catenin, since nuclear beta-catenin stimulated T-cell factor/lymphoid enhancer factor (TCF/LEF)-mediated transcription and upregulated downstream targets like cyclin D1. To characterize the specificity of Wnt/beta-catenin-driven thyrocyte proliferation, we transfected primary thyrocytes and FTC133 cells with dominant negative TCF4 to block Wnt-dependent pathways or with dominant negative CREB to inhibit the TSH/cAMP cascade. In cells transfected with dominant negative CREB lithium-stimulated proliferation was unchanged whereas blocking Wnt/beta-catenin by dominant negative TCF4 reduced proliferation by approx. 50%. CONCLUSION: Our data indicate that Wnt/beta-catenin signalling is of major importance in the control of lithium-dependent thyrocyte proliferation.    Rao AS, Kremenevskaja N, Resch J, Brabant G
    Lithium stimulates proliferation in cultured thyrocytes by activating Wnt/beta-catenin signalling.
    Eur J Endocrinol. 2005 Dec;153(6):929-38.
    BACKGROUND: Lithium, clinically used in the treatment of bipolar disorders, is well known to induce thyroid growth. However, the mechanism involved is only incompletely characterized. Although it is conventionally believed that thyroid proliferation depends on the thyroid-stimulating hormone (TSH)/cAMP/cAMP response element binding protein (CREB) pathway, recent data indicate that Wnt/beta-catenin signalling may be of critical importance. In other cell types lithium activates canonical Wnt signalling by GSK-3beta inhibition, which in turn stabilizes cytosolic free beta-catenin. Here we investigated the potential modulation of Wnt/beta-catenin signalling under lithium treatment in primary and neoplastic human thyrocytes. METHODS: Primary (S18) and neoplastic (NPA, FTC133) thyrocytes treated with and without LiCl were analysed using Western blotting, immunoprecipitation, reporter-gene assay, MTT proliferation assay and transfection studies. RESULTS: LiCl dose-dependently inhibited GSK-3beta, stabilized free beta-catenin and inhibited beta-catenin degradation. Furthermore, LiCl altered the assembly of adherens junction by upregulating the E-cad-herin repressor, Snail, and downregulated E-cadherin expression. At a dose of 5 mM, LiCl significantly increased the proliferative potency of thyrocytes, which appeared to be mediated by beta-catenin, since nuclear beta-catenin stimulated T-cell factor/lymphoid enhancer factor (TCF/LEF)-mediated transcription and upregulated downstream targets like cyclin D1. To characterize the specificity of Wnt/beta-catenin-driven thyrocyte proliferation, we transfected primary thyrocytes and FTC133 cells with dominant negative TCF4 to block Wnt-dependent pathways or with dominant negative CREB to inhibit the TSH/cAMP cascade. In cells transfected with dominant negative CREB lithium-stimulated proliferation was unchanged whereas blocking Wnt/beta-catenin by dominant negative TCF4 reduced proliferation by approx. 50%. CONCLUSION: Our data indicate that Wnt/beta-catenin signalling is of major importance in the control of lithium-dependent thyrocyte proliferation.    Csutora P, Karsai A, Nagy T, Vas B, L Kovács G, Rideg O, Bogner P, Miseta A
    Lithium induces phosphoglucomutase activity in various tissues of rats and in bipolar patients.
    Int J Neuropsychopharmacol. 2005 Nov 1;1-7.
    Phosphoglucomutase catalyses the reversible conversion of glucose-6-P and glucose-1-P. Lithium is a potent inhibitor of phosphoglucomutase in vitro, however, it is not known if phosphoglucomutase was significantly inhibited by Li+ in Li+-treated bipolar patients. Here, we demonstrate that phosphoglucomutase inhibition by chronic Li+ treatment causes alterations of glucose-phosphate levels in various tissues of rats. Also, phosphoglucomutase inhibition results in compensatory elevation of phosphoglucomutase activity in rat tissues and in leukocytes isolated from Li+-treated bipolar patients. The increase of uninhibited phosphoglucomutase activity in leukocytes of Li+-treated bipolar patients is due to the increased expression of the PGM1 gene.

    Lin PI, McInnis MG, Potash JB, Willour VL, Mackinnon DF, Miao K, Depaulo JR, Zandi PP
    Assessment of the effect of age at onset on linkage to bipolar disorder: evidence on chromosomes 18p and 21q.
    Am J Hum Genet. 2005 Oct;77(4):545-55.
    Previous evidence suggests that the inheritance of bipolar disorder (BP) may vary depending on the age at onset (AAO). Therefore, we sought to incorporate AAO as a covariate in linkage analyses of BP using two different methods, LODPAL and ordered-subset analysis (OSA), in genomewide scans of 150 multiplex pedigrees with 874 individuals. The LODPAL analysis identified two loci, on chromosomes 21q22.13 (LOD = 3.29; empirical chromosomewide P value = .009) and 18p11.2 (LOD = 2.83; empirical chromosomewide P = .05), with increased linkage among subjects who had early onset (AAO < or = 21 years) and later onset (AAO >21 years), respectively. The finding on 21q22.13 was significant at the chromosomewide level, even after correction for multiple testing. Moreover, a similar finding was observed in an independent sample of 65 pedigrees (LOD = 2.88; empirical chromosomewide P = .025). The finding on 18p11.2 was only nominally significant and was not observed in the independent sample. However, 18p11.2 emerged as one of the strongest regions in the OSA (LOD = 2.92; empirical P = .001), in which it was the only finding to meet chromosomewide levels of significance after correction for multiple testing. These results suggest that 21q22.13 and 18p11.2 may harbor genes that increase the risks for early-onset and later-onset forms of BP, respectively. There have been previous reports of linkage on 21q22.13 and 18p11.2, but the findings have not been consistent. This inconsistency may be due to differences in the AAO characteristics of the samples examined. Future studies to fine map susceptibility genes for BP on chromosomes 21q22.13 and 18p11.2 should take AAO into account.


     Reflections on the Relationship Between Psychiatric Genetics and Psychiatric Nosology
    Kenneth S. Kendler, M.D, American Journal of Psychiatry 163:1138-1146, July 2006
    doi: 10.1176/appi.ajp.163.7.1138

    Research advances in psychiatric genetics have raised expectations that genetic findings might lead to major breakthroughs in psychiatric nosology. The author reviews the plausibility of these claims. Four areas are addressed. First, it is argued that familial aggregation of a single putative psychiatric syndrome provides at best limited evidence for the validity of that syndrome. Second, both traditional and molecular genetic strategies can supply important insights into major diagnostic conundrums. However, evidence that one or a few individual genes impact on risk for two disorders is not likely to resolve definitively the nosologic relationship between the two syndromes. Third, while gene-based essentialist models for psychiatric disorders are conceptually appealing, they are not well supported empirically. Gene discovery in psychiatry is, on its own, unlikely to allow us to "carve nature at its joints," thereby validating categorical psychiatric diagnoses. Fourth, the project to ground "messy" psychiatric categories on the firm foundation of genes—as an archetypal natural kind—may be fundamentally flawed because the very concept of "the gene" as a discrete entity is itself increasingly in doubt. Whereas psychiatric genetics has and will continue to provide important insights into the etiology of psychiatric and substance use disorders, it is not likely alone to provide deep answers to the complex and multifaceted problems facing psychiatric nosology.

    Genetics of bipolar disorder may be more complex than common allele model

    MedWire – CINP (Chicago, Illinois, USA)   July 11, 2006: As genetic research technology advances, it is developing new ways to understand the complex genetics that may influence individuals’ susceptibility to bipolar disorder. Here on the second day of the conference, researchers presented new evidence that a particular well established model based on a single common allele causing a relatively common disease, may not be adequate for understanding the genetic influences underlying bipolar disorder.

    “We are still at the front edge of studying genetic influences in bipolar disorder,” stated investigator Dr. Chunyu Liu after his presentation on the potential role of trace amines when using allele models.

    “We are trying to find the real genes responsible for psychiatric disease, but we still have some problems in advancing the knowledge,” he said. “Even though we have some candidate genes, we don’t know what the problem is in those genes that cause the disorder. But the technology regarding genomic information is so developed, we are pretty confident that we should get the answer pretty soon, within the next five to ten years.”

    Multiple rare alleles may influence susceptibility to bipolar disorder
    Dr. Chunyu Liu, assistant professor of psychiatry, J. F. Knapp Research Center, University of Chicago, Chicago, IL, USA
    Dr. Frank Middleton, Center for Neuropsychiatric Genetics, Upstate Medical University, Syracuse, New York, NY, USA
     
     Trace amines may play a role in the genetic pathogenesis of bipolar disorder, but the linkage is not obvious when conventional common allele, common disease models are used. Alternatively, a multiple rare allele model may elucidate the association.

    “We did not find strong linkage for any of the trace amines that we studied,” said Dr. Liu during his presentation. “When we tried to code the variance with the disease, we found them to occur more frequently in cases than controls, but the differences were not statistically significant.”

    Trace amines, which act as neurotransmitters in invertebrate species, also exist in the human genome at 6q23.2. Although trace amines are known to be biogenic in invertebrates, their role in mammals is not fully understood. However, the locus on which they are found is interesting, because 6q24 has been implicated as a locus for both schizophrenia and bipolar disorder. Furthermore, one trace amine, TRAR4, which has recently been renamed TAAR6, is associated with schizophrenia.

    Because some research has shown that schizophrenia and bipolar disorder may share genes, the investigators wanted to know if trace amine receptors are implicated in bipolar disorder. Therefore, Dr. Liu and co-investigators’ took 25 single nucleotide polymorphisms (SNPs) from regions of the genome where all nine known human trace amine receptors are located, and used them in an association test for bipolar disorder. The investigators studied the genetic information for 557 Caucasian individuals from 177 families with bipolar disorder.

    Of the SNPs implicated in schizophrenia   rs8192625, rs4305745, rs6903874, and rs6937506   none were shown to be associated with bipolar disorder. However, two distal markers, rs9389008 and rs9321360, were shown to be significantly associated. Interestingly, rs938908 is close in location to TAAR4, and rs9321360 is slightly upstream to TAAR1.

    Disappointingly though, when Dr. Liu and team corrected for multiple testing with permutations, none of these results were significant. Furthermore, the haplotype block and mapping data showed that the markers covered the genomic region adequately.

    These findings do not rule out a role for the trace amine system in the genetic pathogenesis for bipolar disorder, Dr. Liu said. Instead, the findings may expose the flaws in the model, which assumes a commonly found allele and a common disease. Therefore, he and his team are currently re-analyzing the data using a model that assumes multiple rare alleles, and this investigation is ongoing.

    There is a need for new approaches throughout psychiatric genetics research, and this need is consistent and feasible with the new technology, according to Dr. Middleton. “Very few whole genome linkage or candidate gene studies have yielded results about major mental disorders that generalize to different populations,” he said, noting that the limitations of previously used technologies may have played a role in these frustrating results.

    “Recent advances make it possible to rapidly perform highly informative, whole genome linkage, family-based association, and case-control association analyses,” he said. In recent research, he and his co-investigators used an integrated approach with DNA samples from 400 subjects who were from 55 pedigrees with schizophrenia, other psychotic disorders, and bipolar disorders, as well as a case-control analysis for bipolar disorder involving 100 familial cases, 100 controls and 500,000 SNPs.

    Although each method yielded promising results, “when the results were combined, only a small number of specific haplotypes and genes were implicated by more than one approach,” he said, adding that these findings underscore the need to use approaches that utilize high-quantity data, such as high-throughput genetic data from multiple approaches. In this way, he said, investigators may then obtain new insights regarding the biological underpinnings for major mental disorders. He concluded by emphasising that “the combined approach is greater than that of any single mode” when investigating complex genetic diseases.


    Animal models and brain autopsies show the potential role for novel genes in schizophrenia and bipolar disorder

    MedWire – CINP (Chicago, Illinois, USA) – July 13, 2006:     There is a widespread acceptance of psychiatric disease stemming from molecular changes in the brain due to an interaction between susceptibility genes and environmental stresses. Therefore, investigators are now using both animal models and brain autopsies to explore the role of novel genes that may be involved in severe mental illness such as bipolar disorder and schizophrenia.

    Here on the fourth day of the conference, investigators presented research on animal models showing roles for apolipoprotein E and mitochondrial dysfunction, respectively. Apolipoprotein E may be involved in both schizophrenia and bipolar disorder I more frequently referred to as bipolar I disorder, stated Dr. Brian Dean, of the University of Melbourne, Australia. Noting that administration of haloperidol decreases frontal cortical levels of this protein, he suggested that other neurotransmitters may affect apolipoprotein E expression.

    The use of phosphorus-31 magnetic resonance spectroscopic (MRS) studies in bipolar disorder has established the role of mitochondrial dysfunction in bipolar disorder, according to Dr. Kato, of the RIKEN Brain Science Institute, Japan. Therefore, he and co-investigators want to know whether mutations or polymorphisms of mitochondrial DNA promote bipolar disorder by causing altered calcium signalling.

    By conducting gene expression analysis of autopsied brains of patients with bipolar disorder, they have found upregulation of several nuclear-encoded mitochondria-related genes. These findings, combined with studies involving transgenic mice, have shown that mitochondrial dysfunction may promote bipolar disorder by causing neuronal cells to be vulnerable to abnormal plasticity.

    Apolipoprotein E may be implicated in schizophrenia and bipolar disorder
    Dr. Brian Dean, associate professor of psychiatry, The Mental Health Research Institute of Victoria, University of Melbourne, Melbourne, Australia

     Changes in the apolipoprotein E expression in the matrix involving pre- and post-synaptic neurons and associated glia may play a role in the biological pathogenesis of both schizophrenia and bipolar disorder, according to Dr. Dean.

    “We now accept that changes in the molecular milieu of the central nervous system can precipitate psychiatric illness, due to the combined impact of susceptibility genes and environmental stressors,” he said. He and co-investigators have found evidence of altered levels of apolipoprotein E in the cerebrospinal fluid of patients with schizophrenia and in those with bipolar disorder. They have also found that treating rats with haloperidol decreases level of frontal cortical apolipoprotein E.

    These findings suggest that the regulation of apolipoprotein E might be a way that antipsychotic drugs are effective, Dr. Dean said. Haloperidol is thought to affect apolipoprotein levels by inhibiting dopaminergic activity. Other research has shown that serotonin, acetylcholine, and glutamate also influence apolipoprotein E expression. Furthermore, other studies show changes in neuronally derived proteins in the brains of patients with schizophrenia and bipolar disorder.

    When the findings of all of these studies are examined together, they show that changes in tripartite synaptic function are altered in the CNS of some subjects with these conditions, Dr. Dean concluded. The tripartite synaptic function is the matrix involving pre- and post-synaptic neurons and associated glia.


    Molecular genetics technology shows mitochondrial dysfunction may promote bipolar disorder
    Dr. Tadafumi Kato, laboratory head, Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Saitama, Japan

     Polymorphisms of mitochondrial DNA can cause altered calcium signalling, neuronal plasticity and eventually promote bipolar disorder, according to Dr. Kato. Studies of the autopsied brains of bipolar patients and of transgenic mice combine to support the potential role for mitochondrial dysfunction, he stated.

    The alterations in mitochondrial DNA can either be inherited maternally, or caused by mutations of nuclear encoded mitochondria. He and co-investigators built on findings by phosphorous 31-MRS and analyzed mitochondrial DNA mitochondria-related nuclear genes in patients’ autopsied brains by gene expression analysis and molecular genetic analysis. These findings showed that patients with bipolar disorder had elevated levels of several nuclear-encoded mitochondria-related genes, including mitochondrial leucyl-tRNA synthetase 2 (LARS-2). “This finding reflected an accumulation of mitochondrial 3243A>G mutation in the brain,” Dr. Kato said.

    In studies utilizing whole mitochondrial DNA sequence analysis of bipolar patients with somatic symptoms, Dr. Kato and team have found that mitochondrial DNA 3644 mutation is linked to bipolar disorder. The somatic symptoms ranged from cardiomyopathy to neurologic symptoms such as ptosis. In animal studies involving transgenic mice with neuron-specific accumulation of mitochondrial DNA deletions, the animals are seen to have phenotypes that mimic bipolar disorder. These include circadian disruption, so that the mice are active in both daytime and night; further, administration of the tricyclic antidepressant amitriptyline triggered increased activity in the mice, while lithium restored circadian function to nearer normal.

    These findings support the hypothesis of Dr. Kato and co-investigators that mutations of the mitochondrial DNA may cause brain cells to be vulnerable to abnormal neuronal plasticity. Combined with other research showing a role for endoplasmic reticulum stress signalling in bipolar disorder, these findings show that alterations in mitochondrial DNA may be a risk factor for the development of bipolar disorder, he concluded.

     

    Editorial :     Genetics and the Future of Clinical Psychiatry
    Ahmad R. Hariri, Ph.D. and David A. Lewis, M.D.
    American Journal of Psychiatry 163:1676-1678, October 2006

    The field of human genetics has advanced rapidly in the past 50 years, from the determination of the correct number of human chromosomes to the development of a reference map of the approximately 25,000 genes in the human genome. Moreover, we are now systematically identifying common variations in the DNA sequence of the human family (1) that likely affect the biological processes that contribute to individual differences in behavior. Although uncertainties abound (e.g., the definition of a gene is still under revision [2, 3]), the integration of human genetics and neuroscience is leading to major advances in our understanding of the biology of human mental health and disease.

    Although individual differences in brain information processing and function cannot be explained by genes alone, variations in genetic sequence that affect gene function very likely contribute substantially to the variance in the resulting complex behavioral phenomena. For example, studies of twins have revealed that 40%–70% of various aspects of cognition, temperament, and personality are attributable to genetic factors (4). For some psychiatric disorders, specific genes have been identified as putative risk factors across populations. Indeed, the majority of the susceptibility for certain psychiatric disorders, such as bipolar disorder and schizophrenia, is due to inheritance (5). Thus, the study of human genetics offers the potential to identify at-risk individuals and determine novel molecular targets for therapeutic interventions.

    Understanding the pursuit of this promise requires knowledge of two approaches—genetic linkage and genetic association—that are used to identify the contributions of alternative forms of a gene or DNA sequence (i.e., alleles) to phenotypic outcomes. The combination of two alleles, one inherited from each parent, at a specific chromosomal location or locus is referred to as a genotype. Genetic linkage and genetic association capture somewhat different pictures of the relationship between genes and behavior. Linkage studies are designed to determine whether a behavioral phenotype, such as a dimensional trait (e.g., personality or temperament) or a clinical disorder, is physically linked to a genetic marker—a segment of DNA with a known physical location on a chromosome. The identification of significant linkage then permits the detailed sequencing of genes in that general region of the chromosome in search of specific variants or alleles that may alter gene function in a manner that influences the expression of the trait or increases the risk for the disorder. Often such variants are in the form of a polymorphism, which is defined as a difference in the DNA sequence that occurs in >1% of the population. Most of the variants studied to date, such as single-nucleotide polymorphisms, have minor allele frequencies exceeding 10%, which suggests that they have the potential to broadly affect the risk for psychiatric illness. Mutations, by contrast, are variants that occur in <1% of the population and are unlikely to contribute to the general risk for illness. However, because mutations often have substantial effects on the function of the protein encoded by the gene, they can contribute to rare familial forms of psychiatric illness.

    The study by Kassem et al. in this issue of the Journal effectively illustrates how genetic linkage studies designed to identify novel genetic mechanisms contributing to psychiatric illness can be buttressed by astute clinical observations and the dissection of current diagnostic categories. By stratifying patients with bipolar disorder along the polarity of their first episode (depression, mania, or mixed), Kassem et al. found that polarity at onset is significantly familial—it occurs more commonly in siblings than would be expected by chance. Moreover, restricting their analyses to patients whose onset episode was manic substantially increased the genetic linkage with a locus on chromosome 16p, a region that was only weakly linked with bipolar disorder broadly in the same sample population (6). These results suggest that polarity at onset defines subtypes of bipolar disorder that reflect distinct underlying genetic mechanisms. These findings also provide a new impetus for studies to systematically query this region of chromosome 16p for variants in specific genes that could contribute to the pathophysiology of the mania-at-onset subtype of bipolar disorder by affecting the amount or function of the encoded protein.

    In contrast to using genome scans with hundreds of gene markers to implicate genetic loci through linkage approaches, genetic association studies search for a relationship between specific alleles in a given gene and a target behavior. This approach typically involves 1) the selection of a certain feature of an illness (such as heightened threat sensitivity in anxiety disorders or impaired working memory in schizophrenia), 2) the identification of variants in genes (such as serotonin transporter or catechol O-methyltransferase, respectively) that are thought to affect the candidate biological process (serotonin or dopamine neurotransmission, respectively), and 3) the determination of whether a particular allele of the candidate gene is found at a greater frequency among individuals who exhibit the target behavior. The association of a specific allele with a target behavior suggests that the genetic variant is potentially a causative factor for that phenotype. Causality is bolstered if the candidate polymorphism has a clear functional effect on the relevant neurobiological processes at the molecular, cellular, or circuit level.

    This type of functional candidate gene analysis is at the core of the report by Reynolds et al. in this issue. These investigators examined the moderating effects of a functional single-nucleotide polymorphism in the human gene for the serotonin receptor 1A subtype (5-HT1A) on antipsychotic treatment response in a group of treatment-naive patients with first-episode psychosis. At this polymorphism in the promoter region of the gene, a guanine nucleotide is exchanged for a cytosine [G(–1019)C]. Promoter regions are located upstream or before the exons (i.e., coding regions) of a gene that contain the information needed to direct the amino acid sequence of the functional protein product. Thus, variations in promoter regions do not directly affect protein function but regulate the level of gene expression via the binding of various transcription factors. In vitro studies have suggested that the G(–1019) allele reduces the ability of transcription factors to repress or shut down promoter activity, leading to increased expression of the 5-HT1A autoreceptor. The 5-HT1A autoreceptor mediates negative feedback regulation of serotonin neuron activity in the brainstem and, in turn, serotonin release in target regions such as the amygdala and prefrontal cortex. Thus, the G(–1019) allele, through increased autoreceptor expression and negative feedback mediation, may function to reduce serotonin release.

    Reynolds et al. show that after 3 months of antipsychotic treatment, the presence of a 5-HT1A G(–1019) allele was associated with no improvement in negative symptoms and less improvement in patients’ general psychopathology compared with patients who were homozygous for the C allele. Patients who were homozygous for the G allele actually showed a worsening of depressive symptoms relative to those who were homozygous for the C allele. Improvement in psychotic symptoms, however, did not differ as a function of genotype. Thus, these data suggest that the impact of the G allele on 5-HT1A expression, and presumably on 5-HT neurotransmission, predicts aspects of the response of first-episode psychotic patients to antipsychotic treatment. Of course, this naturalistic treatment study does not reveal how this polymorphism influences treatment response, especially given the lack of specificity of antipsychotic drugs for the 5-HT1A receptor. However, the functional nature of the 5-HT1A G(–1019)C polymorphism represents an important foothold for launching basic studies to identify these mechanisms.

    The type of genome-wide linkage studies conducted by Kassem et al. may lead to the identification of genes that contribute to the pathogenesis of psychiatric illnesses with specific phenotypes, whereas genetic association studies like those employed by Reynolds et al. will be instrumental in establishing direct associations between specific genetic polymorphisms and target behavioral or biological processes. Although linkage findings implicate genetic loci in a behavior or illness that can differ across families, association studies imply that the same allelic polymorphism is predictive of the trait in the same way for all individuals in a population. However, both effects need to be replicated in independent samples of populations from different genetic backgrounds, because the true relevance of any genetic difference must be established against the remarkable variability of the entire human genome.

    Although the findings of these studies are not readily translated to the clinical practice of psychiatry today, they do provide examples of how the integration of advances in molecular and functional genetics with clinical phenomenology will lead to the eventual application of genotyping in the diagnosis and treatment of psychiatric illness. Such integrated studies of another common functional polymorphism in the serotonin family, the serotonin transporter promoter length variant (5-HTTLPR), have illustrated how candidate genotyping can rapidly expand our understanding of the mechanisms through which genes can influence the risk for psychiatric illness by biasing the response of brain systems to environmental challenges (7).

    To date, we have identified only a handful of informative genetic polymorphisms, and these account for only a modest proportion of the variance in certain behaviors or risk for psychiatric disorders. We can improve this yield by identifying additional polymorphisms in candidate genes, which will increase the power of association studies. At the same time, the identification of novel genes within chromosomal regions identified through linkage studies is critical for the development of a comprehensive catalog of genetic variation that contributes to specific behaviors and illness risk. The parallel dissection of environmental factors will permit the construction of gene-by-environment interaction backgrounds that will likely account for a greater degree of the liability for a given illness. A growing synergy across such studies and with basic neuroscience investigations (8) is needed before we can genotype patients for candidate polymorphisms with enough confidence to allow us to determine the nature of their illness and predict the most effective course of treatment.


           Footnotes
     
    Address correspondence and reprint requests to Dr. Hariri, Director, Developmental Imaging Genetics Program, Department of Psychiatry, University of Pittsburgh, 3811 O’Hara St., E-729, Pittsburgh, PA 15213; haririar{at}upmc.edu (e-mail). Dr. Hariri reports no competing interests. Dr. Lewis received investigator-initiated research support from Eli Lilly, Merck, and Pfizer and served as a consultant to Eli Lilly, Merck, Pfizer, and Sepracor. Dr. Freedman has reviewed this editorial and found no evidence of influence from these relationships.


           References

           1. Hinds DA, Stuve LL, Nilsen GB, Halperin E, Eskin E, Ballinger DG, Frazer KA, Cox DR: Whole-genome patterns of common DNA variation in three human populations. Science 2005; 307:1072–1079[Abstract/Free Full Text]
       2. Richards EJ: Inherited epigenetic variation: revisiting soft inheritance. Nat Rev Genet 2006; 7:395–401[CrossRef][Medline]
       3. Mattick JS: RNA regulation: a new genetics? Nat Rev Genet 2004; 5:316–323[CrossRef][Medline]
       4. Plomin R, Owen MJ, McGuffin P: The genetic basis of complex human behaviors. Science 1994; 264:1733–1739[Abstract/Free Full Text]
       5. Gershon ES: Bipolar illness and schizophrenia as oligogenic diseases: implications for the future. Biol Psychiatry 2000; 47:240–244[CrossRef][Medline]
       6. Dick DM, Foroud T, Edenberg HJ, Miller M, Bowman E, Rau NL, DePaulo JR, McInnis M, Gershon E, McMahon F, Rice JP, Bierut LJ, Reich T, Nurnberger J Jr: Apparent replication of suggestive linkage on chromosome 16 in the NIMH genetics initiative bipolar pedigrees. Am J Med Genet 2002; 114:407–412[CrossRef][Medline]
       7. Hariri AR, Holmes A: Genetics of emotional regulation: the role of the serotonin transporter in neural function. Trends Cogn Sci 2006; 10:182–191[CrossRef][Medline]
       8. Caspi A, Moffitt TE: Gene-environment interactions in psychiatry: joining forces with neuroscience. Nat Rev Neurosci 2006; 7:583–590[Medline]

     
    Familiality of Polarity at Illness Onset in Bipolar Affective Disorder
    Layla Kassem, Psy.D., Victor Lopez, M.D., Don Hedeker, Ph.D., Jo Steele, B.Eng., Peter Zandi, Ph.D. and NIMH Genetics Initiative Bipolar Disorder Consortium Francis J. McMahon, M.D.
    American Journal of Psychiatry 163:1754-1759, October 2006

    OBJECTIVE:     Bipolar affective disorder is clinically heterogeneous, and clinical features that run in families may help define more homogeneous phenotypes. The authors sought to establish whether polarity at illness onset, which is related to severity and course, is a familial feature of bipolar affective disorder.

    METHOD:     The authors studied 971 subjects from 507 families ascertained through sibling pairs with bipolar I or schizoaffective bipolar disorder. Self-reported ages at onset of mania and major depression were used to code polarity at onset as manic, major depressive, or both (mania and major depression in the same onset year). Familial clustering was estimated by using mixed-effects regression analysis, and the relationship between polarity at onset and several other clinical features was assessed. As a preliminary test of genetic validity, the authors assessed the impact of polarity at onset on genetic linkage findings previously detected in this sample.

    RESULTS:     Polarity at onset was significantly familial in this sample. This largely reflected relative pairs concordant for mania at onset, which occurred significantly more frequently than would be expected by chance. Mania at onset substantially increased the genetic linkage signal on chromosome 16p (maximum lod score=4.5) but had no effect on linkage to chromosome 6q. Mania at onset occurred at a later age on average than major depression at onset and was less likely to be complicated by panic attacks or alcoholism.

     CONCLUSIONS:     Polarity at illness onset is a familial feature of bipolar affective disorder and is associated with important clinical indicators, which may help define more homogeneous subtypes of bipolar affective disorder.


    Gene variations influence antidepressant response
     J Am Med Assoc 2006; 296: 1609–1618
    Hyeran Kim (Sungkyunkwan University School of Medicine, Seoul, Korea) et col.

    Study findings suggest that gene polymorphisms play a role in how well people with depression will respond to antidepressant treatment.

    Hyeran Kim (Sungkyunkwan University School of Medicine, Seoul, Korea) and colleagues found that variations in a serotonin transporter (5-HTT) gene predicted which patients would respond to selective serotonin reuptake inhibitors (SSRIs), while variations in the norepinephrine transporter (NET) gene were linked to norepinephrine reuptake inhibitor (NRI) response.

    The researchers believe that their findings, if confirmed, could help to tailor antidepressant treatments to individual patients.

    "Initial drug treatments fail in 30% to 40% of patients with major depression," they explain. "Pharmacogenetic prediction of response is one possibility for improving the efficiency of antidepressant treatment."

    They team studied the genotypes of 241 Korean patients with major depression in line with their response to treatment with an SSRI (fluoxetine or sertraline) or the NRI nortriptyline.

    Defining response as a 50% or greater decrease in scores on the Hamilton Rating Scale for Depression at 6 weeks, the findings showed that a response to NRI treatment was associated with the NET G1287A polymorphism, at an odds ratio of 7.54, compared with other polymorphisms.

    A response to SSRIs was 20.11 times more likely if people had the 5-HTT intron 2 short/long variation, and 3.34 times more likely if they had short/long polymorphisms in the 5-HTT promotor region (5-HTTLPR), compared with other polymorphisms.

    The researchers note that the 5-HTTLPR short/long variant also predicted NRI response, at an odds ratio of 3.73.

    "'Cross-talk' between the noradrenergic and serotonergic systems may explain why drugs acting selectively on either one or other of these systems are both active at relieving symptoms of depression," they comment in the Journal of the American Medical Association.

    Comparing the response rates to NRI and SSRI by genotype, Kim et al found one strong association, with patients carrying the GG polymorphism of NET G1287A having a higher response to NRI treatment than to SSRI treatment, at 83.3% versus 58.7%, respectively.

    "This study demonstrates that responses to antidepressants with different targets have significant associations with homologous monoamine transporter gene polymorphisms," the team concludes.

    "Confirmation of these preliminary findings would permit refined pharmacogenetic selection of antidepressant treatment."

     Am J Psychiatry 164:236-247, February 2007
    doi: 10.1176/appi.ajp.164.2.236

    Mood-Incongruent Psychotic Features in Bipolar Disorder: Familial Aggregation and Suggestive Linkage to 2p11-q14 and 13q21-33
    Fernando S. Goes, M.D., Peter P. Zandi, Ph.D., Kuangyi Miao, M.S., Francis J. McMahon, M.D., Jo Steele, B.Eng., Virginia L. Willour, Ph.D., Dean F. MacKinnon, M.D., Francis M. Mondimore, M.D., Barbara Schweizer, R.N., B.S., John I. Nurnberger Jr., , M.D., John P. Rice, Ph.D., William Scheftner, M.D., William Coryell, M.D., Wade H. Berrettini, M.D., Ph.D., John R. Kelsoe, M.D., William Byerley, M.D., Dennis L. Murphy, M.D., Elliot S. Gershon, M.D., Bipolar Disorder Phenome Group, J. Raymond DePaulo Jr., M.D., Melvin G. McInnis, M.D. and James B. Potash, M.D., M.P.H.

    OBJECTIVE: Mood-incongruent psychotic features in bipolar disorder may signify a more severe form of the illness and might represent phenotypic manifestations of susceptibility genes shared with schizophrenia. This study attempts to characterize clinical correlates, familial aggregation, and genetic linkage in subjects with these features.

    METHOD: Subjects were drawn from The National Institute of Mental Health (NIMH) Genetics Initiative Bipolar Disorder Collaborative cohort, consisting of 708 families recruited at 10 academic medical centers. Subjects with mood-incongruent and mood-congruent psychotic features were compared on clinical variables. Familial aggregation was tested using a proband-predictive model and generalized estimating equations. A genome-wide linkage scan incorporating a mood-incongruence covariate was performed.

    RESULTS: Mood-incongruent psychotic features were associated with an increased rate of hospitalization and attempted suicide. A proband with mood-incongruence predicted mood-incongruence in relatives with bipolar I disorder when compared with all other subjects and when compared with subjects with mood-congruent psychosis. The presence of mood-incongruent psychotic features increased evidence for linkage on chromosomes 13q21-33 and 2p11-q14. These logarithm of the odds ratio (LOD) scores and their increase from baseline met empirical genome-wide suggestive criteria for significance.
     
    CONCLUSIONS: Mood-incongruent psychotic features showed evidence of a more severe course, familial aggregation, and suggestive linkage to two chromosomal regions previously implicated in major mental illness susceptibility. The 13q21-33 finding supports prior evidence of bipolar disorder/schizophrenia overlap in this region, while the 2p11-q14 finding is, to the authors’ knowledge, the first to suggest that this schizophrenia linkage region might also harbor a bipolar disorder susceptibility gene.


    9 February 2007 (résumé de l'aticle précédent sur psychiatry source)

    Research findings suggest that mood-incongruent psychotic symptoms may arise in patients with bipolar disorder due to genetic variation within chromosomes previously linked to schizophrenia.

    In their study of 708 families and 1561 bipolar disorder patients, James Potash, from Johns Hopkins Hospital in Baltimore, Maryland, USA, and colleagues found that mood-incongruent psychotic features were associated with a more severe course of illness, familial aggregation, and suggestive linkage to two chromosomal regions.

    Bipolar I disorder patients with mood-incongruent psychotic features were more likely to have been hospitalized, attempted suicide, and to have a history of substance abuse or dependence than those with mood-congruent or no psychosis. They also had lower Global Assessment Scale scores, at 63.5 versus 69.3 and 68.5, respectively.

    Familial aggregation analysis carried out on 708 bipolar I disorder patients and 1224 of their first-degree relatives showed that patients with mood-incongruent psychotic features were significantly more likely to have relatives with these features than the other bipolar patients, at 21.5% and 12.0%, respectively.

    Restricting the analysis to bipolar I disorder first degree relatives increased the aggregation, at 29.8% versus 14.4%.

    The researchers then genotyped 2899 individuals. Of these, 2034 had a major mood disorder, with 322 experiencing mood-incongruent symptoms.

    The presence of mood-incongruent psychotic features was linked to chromosomes 13q21-33 and 2p11-q14. The logarithm of the odds ratios and their increase from baseline met "empirical genome-wide suggestive criteria for significance," the team notes in the American Journal of Psychiatry.

    "The 13q21-33 finding supports prior evidence of bipolar disorder/schizophrenia overlap in this region, while the 2p11-q14 finding is, to the author's knowledge, the first to suggest that this schizophrenia linkage region might also harbor a bipolar disorder susceptibility gene," say Potash et al.

    "Our results support the validity of mood-incongruent psychosis as a subset of bipolar disorder with increased clinical severity and closer ties to putative psychosis vulnerability genes shared with schizophrenia."

    Source: Am J Psych 2007; 164: 236–247

    Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls
    Wellcome Trust, Nature 447, 661-678 (7 June 2007) | doi:10.1038/nature05911; Received 26 March 2007; Accepted 11 May 2007

    http://www.nature.com/nature/journal/v447/n7145/full/nature05911.html

      L'avancée fulgurante des techniques de génotypage et de bioinformatique permet de ne pas concentrer les analyses génétiques sur un "gène candidat", mais de tester systèmatiquement tous les génes qui différent entre une population témoin et une population de patient. Cette analyse est permise par l'usage des "puces à ADN" contenant une collection de SNP couvrant l'ensemble du génome. L'avantage de cette méthode est de n'avoir aucun a priori sur les génes à étudier et d'être exhaustive. (cf http://aitb-bipolaire.org/pharmacogénétique.html)

      Une étude "génome entier" a déjà été réalisée pour le trouble bipolaire.

      L'analyse publiée dans Nature du 7 juin 2007, et financée par le Wellcome Trust (une fondation de recherche anglaise à but non lucratif) concerne 7 pathologies majeures, dont la liaison génotype-phénotype est analysée avec 2000 malades (par pathologie) et une population témoin de 3000 personnes et condute avec un grand luxe de moyens bio-informatique.

    Ci-dessous les extraits concernant spécifiquement le trouble bipolaire

      Bipolar disorder (BD)

    Bipolar disorder (BD; manic depressive illness26) refers to an episodic recurrent pathological disturbance in mood (affect) ranging from extreme elation or mania to severe depression and usually accompanied by disturbances in thinking and behaviour: psychotic features (delusions and hallucinations) often occur. Pathogenesis is poorly understood but there is robust evidence for a substantial genetic contribution to risk27, 28. The estimated sibling recurrence risk (lambdas) is 7–10 and heritability 80–90%27, 28. The definition of BD phenotype is based solely on clinical features because, as yet, psychiatry lacks validating diagnostic tests such as those available for many physical illnesses. Indeed, a major goal of molecular genetics approaches to psychiatric illness is an improvement in diagnostic classification that will follow identification of the biological systems that underpin the clinical syndromes. The phenotype definition that we have used includes individuals that have suffered one or more episodes of pathologically elevated mood (see Methods), a criterion that captures the clinical spectrum of bipolar mood variation that shows familial aggregation29.

    Several genomic regions have been implicated in linkage studies30 and, recently, replicated evidence implicating specific genes has been reported. Increasing evidence suggests an overlap in genetic susceptibility with schizophrenia, a psychotic disorder with many similarities to BD. In particular association findings have been reported with both disorders at DAOA (D-amino acid oxidase activator), DISC1 (disrupted in schizophrenia 1), NRG1 (neuregulin1) and DTNBP1 (dystrobrevin binding protein 1)31.

    The strongest signal in BD was with rs420259 at chromosome 16p12 (genotypic test P = 6.3 times 10-8; Table 3) and the best-fitting genetic model was recessive (Supplementary Table 8). Although recognizing that this signal was not additionally supported by the expanded reference group analysis (see below and Supplementary Table 9) and that independent replication is essential, we note that several genes at this locus could have pathological relevance to BD, (Fig. 5). These include PALB2 (partner and localizer of BRCA2), which is involved in stability of key nuclear structures including chromatin and the nuclear matrix; NDUFAB1 (NADH dehydrogenase (ubiquinone) 1, alpha/beta subcomplex, 1), which encodes a subunit of complex I of the mitochondrial respiratory chain; and DCTN5 (dynactin 5), which encodes a protein involved in intracellular transport that is known to interact with the gene 'disrupted in schizophrenia 1' (DISC1)32, the latter having been implicated in susceptibility to bipolar disorder as well as schizophrenia33.

    Of the four regions showing association at P < 5 times 10-7 in the expanded reference group analysis (Supplementary Table 9), it is of interest that the closest gene to the signal at rs1526805 (P = 2.2 times 10-7) is KCNC2 which encodes the Shaw-related voltage-gated potassium channel. Ion channelopathies are well-recognized as causes of episodic central nervous system disease, including seizures, ataxias and paralyses34. It is possible that this may extend to episodic disturbances of mood and behaviour.

    Amongst the other higher ranked signals in the BD data set (Supplementary Table 7), there is support for the previously suggested importance of GABA neurotransmission (rs7680321 (P = 6.2 times 10-5) in GABRB1 encoding a ligand-gated ion channel (GABA A receptor, beta 1))35, glutamate neurotransmission (rs1485171 (P = 9.7 times 10-5) in GRM7 (glutamate receptor, metabotropic 7))35 and synaptic function (rs11089599 (P = 7.2 times 10-5) in SYN3 (synapsin III)36).

    We note that a broad range of genetic and non-genetic data point to the importance of analyses that use alternative approaches to phenotype definition, including symptom dimensions31. Although beyond the scope of the current paper, such analyses will be required to maximize the potential of the current BD data set.

    BD phenotype description

    BD cases were all over the age of 16 yr, living in mainland UK and of European descent. Recruitment was undertaken throughout the UK by teams based in Aberdeen (8% of cases), Birmingham (35% cases), Cardiff (33% cases), London (15% cases) and Newcastle (9% cases). Individuals who had been in contact with mental health services were recruited if they suffered with a major mood disorder in which clinically significant episodes of elevated mood had occurred. This was defined as a lifetime diagnosis of a bipolar mood disorder according to Research Diagnostic Criteria119 and included the bipolar subtypes that have been shown in family studies to co-aggregate for example29: bipolar I disorder (71% cases), schizoaffective disorder bipolar type (15% cases), bipolar II disorder (9% cases) and manic disorder (5% cases). After providing written informed consent, all subjects were interviewed by a trained psychologist or psychiatrist using a semi-structured lifetime diagnostic psychiatric interview (in most cases the Schedules for Clinical Assessment in Neuropsychiatry120 and available psychiatric medical records were reviewed). Using all available data, best-estimate ratings were made for a set of key phenotypic measures on the basis of the OPCRIT checklist (which covers both psychopathology and course of illness)121, 122 and lifetime psychiatric diagnoses were assigned according to the Research Diagnostic Criteria119. The reliability of these methods has been shown to be high119, 123, 124. Further details of clinical methodology can be found in Green, 2005 (ref. 123) and Green, 2006 (ref. 124).

    Une piste de traitement inspirée par la recherche à l’échelle de tout le génome

    dimanche 13 mai 2007. Nouvelles brèves  http://www.aitb-bipolaire.org/spip/spip.php?breve93

    La première étude génétique portant sur l’ensemble du génome et visant à déterminer le génes impliqués dans la prédisition du trouble bipolaire vient de révéler ses premiers résultats dans la revue Molecular Psychiatry le 8 mai 2007. Un enzyme, le DGKH issu d’un gène du chromosome 13q, impliqué dans le cycle de l’insotil phosphatase, représente une nouvelle cible prometteuse pour un futur médicament.

    L’intérêt principal de cette étude n’est pas dans la découverte d’une nouvelle liaison génétique. Il en parait une par trimestre et bien peu sont confirmées sur des échantillons différents. L’intérêt réside dans la méthode employé. Pour la première fois, les méthodes "bulldozer" d’analyse de la génétique moléculaire sur l’ensemble du génome (wide scan genome) ont été mises en oeuvre pour déterminer les gènes les plus "liés" au trouble bipolaire type 1. Les changement du génome portant sur un seul nucleotide sont appelés des SNP (prononcer SNIP) et servent souvent de marqueurs génétiques. 550 000 SNP ont été examinés, 2000 SNP "candidats" ont fait l’objet d’une étude approfondie, 88 retenus et 37 ont fait l’objet d’un génotypage individuel. Le géne le plus lié au TB-1 est le DGKH avec 3 SNP montrant un fort facteur d’association. Mais chaque SNP retenu n’a qu’un faible coefficient de corrélation (le DGKH a un odds ratio de 1,59 alors qu’un OD de 3,0 minimum est la norme habituelle pour les publications).

    Baum et col concluent : Le trouble bipolaire ne peut être qu’une affection polygénique pour laquelle la modification d’un seul géne n’est ni nécessaire, ni suffisante pour son développement.

    Qu’en conclure, pratiquement pour l’avenir du traitement des personnes atteintes de trouble bipolaire ?

    1). Constatons d’abord que la génétique moléculaire n’est à l’origine, pour l’instant, d’aucun médicament thymorégulateur. Ceux-ci ont été découvert, soit par le hasard d’observations cliniques (lithium), soit en testant pour cet usage des médicaments d’abord utilisés dans d’autres troubles psychiatriques (anti-épileptiques et neuroleptiques).

    2). Les techniques de génétique moléculaire sont en croissance exponentielle, et les progrès viendront certainement par cette voie.

    3). La première étape sera la découverte du mécanisme (de l’étiologie) du trouble. C’est infiniment plus complexe pour les mécanismes cérébraux, où les voies de régulation sont nombreuses et corrélées, que pour les maladies vasculaires ou musculaires.

    4). Une fois les mécanismes moléculaires déterminés, comme pour la chorée de Huntington (1993, huntingtine) ou la myopathie de Duchenne (1986, dystrophine), ce n’est pas pour autant qu’un traitement sera disponible à court terme. Dans les deux maladies citées, il n’y a toujours pas de traitement efficace en 2007.

    Les avancées scientifiques sont porteuses d’espoir pour le futur, mais sans qu’il soit possible de fixer une date pour la disposition d’un traitement efficace.

    REFERENCES

    Ref 1. Molecular Psychiatry advance online publication 8 May 2007 ; doi : 10.1038/sj.mp.4002012 A genome-wide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder A E Baum1, N Akula1, M Cabanero1, I Cardona1, W Corona1, B Klemens1,2, T G Schulze3, S Cichon4,5, M Rietschel3, M M Nöthen4,5, A Georgi3, J Schumacher4, M Schwarz6, R Abou Jamra4, S Höfels7, P Propping4, J Satagopan8, S D Detera-Wadleigh1, J Hardy19 and F J McMahon1 NIMH Genetics Initiative Bipolar Disorder Consortium

    Résumé de l’article (abstract) :

    The genetic basis of bipolar disorder has long been thought to be complex, with the potential involvement of multiple genes, but methods to analyze populations with respect to this complexity have only recently become available. We have carried out a genome-wide association study of bipolar disorder by genotyping over 550 000 single-nucleotide polymorphisms (SNPs) in two independent case-control samples of European origin. The initial association screen was performed using pooled DNA, and selected SNPs were confirmed by individual genotyping. While DNA pooling reduces power to detect genetic associations, there is a substantial cost saving and gain in efficiency. A total of 88 SNPs, representing 80 different genes, met the prior criteria for replication in both samples. Effect sizes were modest : no single SNP of large effect was detected. Of 37 SNPs selected for individual genotyping, the strongest association signal was detected at a marker within the first intron of diacylglycerol kinase eta (DGKH ; P=1.5 times 10-8, experiment-wide P<0.01, OR=1.59). This gene encodes DGKH, a key protein in the lithium-sensitive phosphatidyl inositol pathway. This first genome-wide association study of bipolar disorder shows that several genes, each of modest effect, reproducibly influence disease risk. Bipolar disorder may be a polygenic disease.