Les tests génétiques peuvent-ils être utiles pour la prévention cardiovasculaire? [Are genetic tests useful for cardiovascular prevention?].

Recent progresses in genetics have opened new avenues to further our understanding of the pathophysiological mechanisms underlying cardiovascular disease, raising, new expectations in the field of personalized medicine. Genetic tests may have a high predictive value for rare monogenic diseases. The situation is very different for common polygenic diseases, such as myocardial infarction, type 2 diabetes or stroke. The results from recent genome-wide association studies have provided useful information for research, but have not yet been proven to be clinically useful. It is therefore currently not recommended to conducted genetic testing to guide cardiovascular prevention neither in clinical nor in public health settings.

A CRTC1 deficient mouse line study : relevance to mood disorders

Summary Mood disorders are among the most prevalent, psychosocial^ debilitating, chronic and relapsing forms of psychiatric illnesses. Despite considerable advances in their characterization, the heterogeneous nature of susceptibility factors and patient's symptoms could account for the lack of totally effective and remissive treatment. The neurobiological hypothesis of mood disorders etiology has evolved since the monoamine and neurotrophin theories and current evidence is pointing toward their integration in a broader polygenic epistatic model resulting in defective neuroplasticity of circuitries involved in emotion processing. Consequently, the unraveling of molecular underpinning pathways involved in neuronal plasticity, commonly altered among mood disorder syndromes and symptoms, should shed light on their etiology and provide new drug target. The transcription factor CREB has been critically involved in the long-lasting forms of neuronal plasticity and in the regulation of several mood disorders susceptibility genes. In addition, altered CREB activity has been associated with mood disorders pathophysiology and pharmacotherapy. Interestingly, the newly-identified protein CREB-regulated transcription coactivator 1 (CRTC1) was shown by previous studies in the laboratory to be a neuroactivity- dependent cAMP and calcium sensor, a potent activator of CREB-dependent transcription and involved in neuroplasticity mechanisms associated with long-term synaptic potentiation. Furthermore, the major mood disorder susceptibility gene Bdnf was suggested to be transcriptional regulated by CRTC1. Therefore, we aimed to investigate a role for CRTC1 in mood disorders by generating and characterizing a Crtcl deficient mouse model at the behavioral and molecular levels. Interestingly, their comprehensive characterization revealed a behavioral profile mirroring several major symptoms comorbid in mood disorders, including altered social interactions, aggressive behaviors, obesity, psychomotor retardation, increased emotional response to stress, decreased sexual drive and depression-like behaviors. To investigate the molecular mechanisms underlying these pathological behaviors and the implication of CRTC1 in the regulation of CREB-regulated genes in vivo, we also quantified transcript levels of several relevant CREB-regulated susceptibility genes in brain structures involved in the pathophysiology of mood disorders. Strikingly, we found the underexpression of primary components of the neurotrophin system: Bdnf and its cognate receptor TrkB, a marked decrease in the Nr4a family of transcription factors, implicated in neuroplasticity and associated with dopamine-related disorders, as well as in several other relevant CREB regulated genes. Moreover, neurochemical analysis revealed that Crtcl null mice presented alteration in prefrontal cortical monoamine turnover as well as in hippocampal and accumbal serotonin levels, similarly associated with mood disorders etiology and pharmacotherapy. Together, the present thesis supports the involvement of CRTC1 pathway hypofunction in the pathogenesis of mood disorders and specifically in pathological aggression, obesity and depression-related behavior comorbidities. Ultimately, CRTC1 may represent an interesting antidepressant, antiaggressive or mood stabilizer drug target candidate through the modulation of major CREB regulated susceptibility genes. Les troubles de l'humeur comptent parmi les maladies psychiatriques les plus prévalentes, psychosocialement débilitantes, chroniques et avec le plus grand risque de rechute. Malgré de considérable avancées dans leur caractérisation, la nature hétérogène des facteurs de susceptibilité et des symptômes présentés par les patients, semble justifier l'absence de traitement entraînant une rémission complète de la maladie. L'hypothèse de l'étiologie neurobiologique des troubles de l'humeur a évolué depuis la théorie des monoamines et des neurotrophines. Actuellement, elle tend à les englober dans un modèle polygénique épistatique induisant une déficience de la neuroplasticité des circuits impliqué dans la régulation des émotions. Par conséquent, il apparaît particulièrement relevant de caractériser des voies moléculaires impliquées dans la plasticité neuronale, communément altérées parmi les différents syndromes et symptômes des maladies de l'humeur, afin d'améliorer leur compréhension ainsi que de proposer de nouvelles cibles thérapeutiques potentielles. Le facteur de transcription CREB a été de façon répétée et cohérente impliqué dans les mécanismes à long terme de la plasticité neuronale, ainsi que dans la régulation de plusieurs gènes de susceptibilité aux maladies de l'humeur. De plus, une altération dans l'activité de CREB a été impliqué dans leur étiologie et pharmacothérapie. De façon intéressante, des résultats préliminaires sur la protéine récemment découverte CREB-regulated transcription coactivator 1 (CRTC1) ont indiqué que son activation était dépendante de l'activité neuronale, qu'il était un senseur du calcium et de l'AMPc, ainsi qu'un coactivateur de CREB requis et puissant impliqué dans les mécanismes de plasticité neuronale associés à la potentialisation à long terme. En outre, des résultats ont suggéré que le gène majeur de susceptibilité Bdnf est régulé par CRTC1. Ainsi, notre objectif a été d'investiguer un rôle éventuel de CRTC1 dans les maladies de l'humeur en générant et caractérisant une lignée de souris déficiente pour Crtcl, tant au niveau comportemental que moléculaire. De façon intéressante, leur caractérisation détaillée a révélé un profil comportemental reflétant de nombreux aspects des maladies de l'humeur incluant une altération des interactions sociales, une agression pathologique, l'obésité, un retard psychomoteur, une réponse émotionnelle au stress accrue, une diminution de la motivation sexuelle, et des comportements reliés à la dépression. Afin d'investiguer les mécanismes moléculaires sous- jacents cette altération du comportement, ainsi que l'implication de CRTC1 dans l'expression des gènes régulés par CREB in vivo, nous avons quantifié les niveaux de transcrits de plusieurs gènes de susceptibilité régulés par CREB et impliqués dans la physiopathologie des maladies de l'humeur. Remarquablement, nous avons trouvé la sous-expression de composants primordiaux du système neurotrophique: Bdnf et son récepteur TrkB, une diminution majeure de la famille des facteurs de transcription Nr4a, impliqués dans la neuroplasticité et associés à des désordres liés à la dopamine, ainsi que de nombreux autres gènes relevants régulés par CREB. De plus, une analyse neurochimique a révélé que les souris déficientes pour Crtcî présentent une altération du turn-over des monoamines du cortex préfrontal ainsi que des niveaux hippocampaux et accumbaux de sérotonine, associés de façon similaire dans l'étiologie et la pharmacothérapie des maladies de l'humeur. Vue dans son ensemble, la présente thèse supporte l'implication d'une sous-régulation de la voie de CRTCI dans la pathogenèse des maladies de l'humeur ainsi que dans la comorbidité de l'agression pathologique, l'obésité et la dépression. En conclusion, CRTCI pourrait représenter une cible médicamenteuse intéressante aux propriétés antidépressante, antiagressive ou stabilisatrice de l'humeur au travers de la modulation de gènes de susceptibilité majeurs régulés par CREB.

The gene MAPK8IP1, encoding islet-brain-1, is a candidate for type 2 diabetes.

Type 2 diabetes is a polygenic and genetically heterogeneous disease . The age of onset of the disease is usually late and environmental factors may be required to induce the complete diabetic phenotype. Susceptibility genes for diabetes have not yet been identified. Islet-brain-1 (IB1, encoded by MAPK8IP1), a novel DNA-binding transactivator of the glucose transporter GLUT2 (encoded by SLC2A2), is the homologue of the c-Jun amino-terminal kinase-interacting protein-1 (JIP-1; refs 2-5). We evaluated the role of IBi in beta-cells by expression of a MAPK8IP1 antisense RNA in a stable insulinoma beta-cell line. A 38% decrease in IB1 protein content resulted in a 49% and a 41% reduction in SLC2A2 and INS (encoding insulin) mRNA expression, respectively. In addition, we detected MAPK8IP1 transcripts and IBi protein in human pancreatic islets. These data establish MAPK8IP1 as a candidate gene for human diabetes. Sibpair analyses performed on i49 multiplex French families with type 2 diabetes excluded MAPK8IP1 as a major diabetogenic locus. We did, however, identify in one family a missense mutation located in the coding region of MAPK8IP1 (559N) that segregated with diabetes. In vitro, this mutation was associated with an inability of IB1 to prevent apoptosis induced by MAPK/ERK kinase kinase 1 (MEKK1) and a reduced ability to counteract the inhibitory action of the activated c-JUN amino-terminal kinase (JNK) pathway on INS transcriptional activity. Identification of this novel non-maturity onset diabetes of the young (MODY) form of diabetes demonstrates that IB1 is a key regulator of 3-cell function.

Hundreds of variants clustered in genomic loci and biological pathways affect human height.

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Deletion of CREB-Regulated Transcription Coactivator 1 Induces Pathological Aggression, Depression-Related Behaviors, and Neuroplasticity Genes Dysregulation in Mice.

BACKGROUND: Mood disorders are polygenic disorders in which the alteration of several susceptibility genes results in dysfunctional mood regulation. However, the molecular mechanisms underlying their transcriptional dysregulation are still unclear. The transcription factor cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) and the neurotrophin brain-derived neurotrophic factor (BDNF) have been implicated in rodent models of depression. We previously provided evidence that Bdnf expression critically rely on a potent CREB coactivator called CREB-regulated transcription coactivator 1 (CRTC1). METHODS: To further evaluate the role of CRTC1 in the brain, we generated a knockout mouse line and analyzed its behavioral and molecular phenotype. RESULTS: We found that mice lacking CRTC1 associate neurobehavioral endophenotypes related to mood disorders. Crtc1(-/-) mice exhibit impulsive aggressiveness, social withdrawal, and decreased sexual motivation, together with increased behavioral despair, anhedonia, and anxiety-related behavior in the novelty-induced hypophagia test. They also present psychomotor retardation as well as increased emotional response to stressful events. Crtc1(-/-) mice have a blunted response to the antidepressant fluoxetine in behavioral despair paradigms, whereas fluoxetine normalizes their aggressiveness and their behavioral response in the novelty-induced hypophagia test. Crtc1(-/-) mice strikingly show, in addition to a reduced dopamine and serotonin turnover in the prefrontal cortex, a concomitant decreased expression of several susceptibility genes involved in neuroplasticity, including Bdnf, its receptor TrkB, the nuclear receptors Nr4a1-3, and several other CREB-regulated genes. CONCLUSIONS: Collectively, these findings support a role for the CRTC1-CREB pathway in mood disorders etiology and behavioral response to antidepressants and identify CRTC1 as an essential coactivator of genes involved in mood regulation.

Genome-wide profiling of blood pressure in adults and children.

Hypertension is an important determinant of cardiovascular morbidity and mortality and has a substantial heritability, which is likely of polygenic origin. The aim of this study was to assess to what extent multiple common genetic variants contribute to blood pressure regulation in both adults and children and to assess overlap in variants between different age groups, using genome-wide profiling. Single nucleotide polymorphism sets were defined based on a meta-analysis of genome-wide association studies on systolic blood pressure and diastolic blood pressure performed by the Cohort for Heart and Aging Research in Genome Epidemiology (n=29 136), using different P value thresholds for selecting single nucleotide polymorphisms. Subsequently, genetic risk scores for systolic blood pressure and diastolic blood pressure were calculated in an independent adult population (n=2072) and a child population (n=1034). The explained variance of the genetic risk scores was evaluated using linear regression models, including sex, age, and body mass index. Genetic risk scores, including also many nongenome-wide significant single nucleotide polymorphisms, explained more of the variance than scores based only on very significant single nucleotide polymorphisms in adults and children. Genetic risk scores significantly explained ≤1.2% (P=9.6*10(-8)) of the variance in adult systolic blood pressure and 0.8% (P=0.004) in children. For diastolic blood pressure, the variance explained was similar in adults and children (1.7% [P=8.9*10(-10)] and 1.4% [P=3.3*10(-5)], respectively). These findings suggest the presence of many genetic loci with small effects on blood pressure regulation both in adults and children, indicating also a (partly) common polygenic regulation of blood pressure throughout different periods of life.

Treatment of adult-onset Still's disease: a review

Adult-onset Still's disease (AOSD) is a rare inflammatory disorder that has been recently classified as a polygenic autoinflammatory disorder. The former classification, based on the disease course, seems to be quite dated. Indeed, there is accumulating evidence that AOSD can be divided into two distinct phenotypes based on cytokine profile, clinical presentation, and outcome, ie, a "systemic" pattern and an "articular" pattern. The first part of this review deals with the treatments that are currently available for AOSD. We then present the different strategies based on the characteristics of the disease according to clinical presentation. To do so, we focus on the two subsets of the disease. Finally, we discuss the management of life-threatening complications of AOSD, along with the therapeutic options during pregnancy.

The protective effect of the obesity-associated rs9939609 A variant in fat mass- and obesity-associated gene on depression.

Candidate gene and genome-wide association studies have not identified common variants, which are reliably associated with depression. The recent identification of obesity predisposing genes that are highly expressed in the brain raises the possibility of their genetic contribution to depression. As variation in the intron 1 of the fat mass- and obesity-associated (FTO) gene contributes to polygenic obesity, we assessed the possibility that FTO gene may contribute to depression in a cross-sectional multi-ethnic sample of 6561 depression cases and 21 932 controls selected from the EpiDREAM, INTERHEART, DeCC (depression case-control study) and Cohorte Lausannoise (CoLaus) studies. Major depression was defined according to DSM IV diagnostic criteria. Association analyses were performed under the additive genetic model. A meta-analysis of the four studies showed a significant inverse association between the obesity risk FTO rs9939609 A variant and depression (odds ratio=0.92 (0.89, 0.97), P=3 × 10(-4)) adjusted for age, sex, ethnicity/population structure and body-mass index (BMI) with no significant between-study heterogeneity (I(2)=0%, P=0.63). The FTO rs9939609 A variant was also associated with increased BMI in the four studies (β 0.30 (0.08, 0.51), P=0.0064) adjusted for age, sex and ethnicity/population structure. In conclusion, we provide the first evidence that the FTO rs9939609 A variant may be associated with a lower risk of depression independently of its effect on BMI. This study highlights the potential importance of obesity predisposing genes on depression.

GWAS of 126,559 individuals identifies genetic variants associated with educational attainment.

A genome-wide association study (GWAS) of educational attainment was conducted in a discovery sample of 101,069 individuals and a replication sample of 25,490. Three independent single-nucleotide polymorphisms (SNPs) are genome-wide significant (rs9320913, rs11584700, rs4851266), and all three replicate. Estimated effects sizes are small (coefficient of determination R(2) ≈ 0.02%), approximately 1 month of schooling per allele. A linear polygenic score from all measured SNPs accounts for ≈2% of the variance in both educational attainment and cognitive function. Genes in the region of the loci have previously been associated with health, cognitive, and central nervous system phenotypes, and bioinformatics analyses suggest the involvement of the anterior caudate nucleus. These findings provide promising candidate SNPs for follow-up work, and our effect size estimates can anchor power analyses in social-science genetics.

Developmental regulation of expression of schizophrenia susceptibility genes in the primate hippocampal formation

The hippocampal formation is essential for normal memory function and is implicated in many neurodevelopmental, neurodegenerative and neuropsychiatric disorders. In particular, abnormalities in hippocampal structure and function have been identified in schizophrenic subjects. Schizophrenia has a strong polygenic component, but the role of numerous susceptibility genes in normal brain development and function has yet to be investigated. Here we described the expression of schizophrenia susceptibility genes in distinct regions of the monkey hippocampal formation during early postnatal development. We found that, as compared with other genes, schizophrenia susceptibility genes exhibit a differential regulation of expression in the dentate gyrus, CA3 and CA1, over the course of postnatal development. A number of these genes involved in synaptic transmission and dendritic morphology exhibit a developmental decrease of expression in CA3. Abnormal CA3 synaptic organization observed in schizophrenics might be related to some specific symptoms, such as loosening of association. Interestingly, changes in gene expression in CA3 might occur at a time possibly corresponding to the late appearance of the first clinical symptoms. We also found earlier changes in expression of schizophrenia susceptibility genes in CA1, which might be linked to prodromal psychotic symptoms. A number of schizophrenia susceptibility genes including APOE, BDNF, MTHFR and SLC6A4 are involved in other disorders, and thus likely contribute to nonspecific changes in hippocampal structure and function that must be combined with the dysregulation of other genes in order to lead to schizophrenia pathogenesis.

Earliness per se and its dependence upon temperature in diploid wheat lines differing in the major gene Eps-Am1 alleles

Differences in development among wheat cultivars are not only restricted to photoperiod and vernalization responses. When both requirements are fully satisfied differences may still arise due to earliness per se. It is not clear at present to what extent this trait is ‘ intrinsically ’ expressed (a constitutive trait) independently of the environmental conditions so that it might be selected under any thermal condition or if it may be altered to the extent of showing a crossover interaction with temperature in which the ranking of wheat genotypes may be altered. The present study assessed the influence of temperature on the intrinsic earliness for lines of diploid wheat characterized for their differences in a major gene for intrinsic earliness, but also possibly differing in their genetic background for other factors controlling this polygenic trait. To do so the lines were grown individually in two temperature regimes (16 and 23 xC) under long days having previously been fully vernalized. Multiple comparisons analyses were carried out among lines of the same allelic group for the Eps-Am1 gene. Results indicated that within each group there were lines that did not differ in their earliness per se, others differed but without exhibiting any linertemperature interaction and finally different types of interaction were shown, including cases where the ranking of lines was altered depending on the growing temperature. It is thus possible that the selection of a genotype based on its earliness per se in an environment might not represent the same performance in another location where temperature varied significantly.

Inference of Evolutionary Forces Acting on Human Biological Pathways.

Because natural selection is likely to act on multiple genes underlying a given phenotypic trait, we study here the potential effect of ongoing and past selection on the genetic diversity of human biological pathways. We first show that genes included in gene sets are generally under stronger selective constraints than other genes and that their evolutionary response is correlated. We then introduce a new procedure to detect selection at the pathway level based on a decomposition of the classical McDonald-Kreitman test extended to multiple genes. This new test, called 2DNS, detects outlier gene sets and takes into account past demographic effects and evolutionary constraints specific to gene sets. Selective forces acting on gene sets can be easily identified by a mere visual inspection of the position of the gene sets relative to their two-dimensional null distribution. We thus find several outlier gene sets that show signals of positive, balancing, or purifying selection but also others showing an ancient relaxation of selective constraints. The principle of the 2DNS test can also be applied to other genomic contrasts. For instance, the comparison of patterns of polymorphisms private to African and non-African populations reveals that most pathways show a higher proportion of nonsynonymous mutations in non-Africans than in Africans, potentially due to different demographic histories and selective pressures.

Structural control on present-day topography of a basement massif: the Central and Eastern Anti-Atlas (Morocco)

The Anti-Atlas basement massif extends South of the High Atlas, and, despite a very mild Cenozoic deformation, its altitude exceeds 1500m in large areas, reaching 3305m in Jbel Sirwa. Structural contours of the present elevation of a polygenic planation surface (the High Erosional surface) and of the base of Cretaceous and Neogene inliers have been performed to characterize the major tectonic structures. Gentle Cenozoic WSW-ENE- and N-Strending folds, of 60 to100km wavelength, reactivate Variscan structures, being the major contributors to the local topography of the Anti-Atlas. Reactivated thrusts of decakilometric to kilometric-scale and E-W trend involving the Neogene rocks exhibit a steep attitude and a small displacement, but they also produce a marked topographic expression. The resulting Cenozoic horizontal shortening along N-S sections across the Anti-Atlas is about 1%. The position of the major anticlinal hinges determines the location of the fluvial divides of the Warzazat basin and the Anti-Atlas, and a structural depression on one of these hinges (Jbel Saghro anticline) allowed the formerly endorheic Warzazat basin to drain southwards. The first Cenozoic structures generating local topography are of pre-mid Miocene age (postdated by 6.7Ma volcanic rocks at the Jbel Saghro), whereas the youngest thrust movements postdate the Pliocene sedimentary and volcanic rocks (involving 2.1Ma volcanic rocks at Jbel Sirwa). In addition to these features, the mean elevation of the Anti-Atlas at the regional scale is also the result of a mantle thermal anomaly reported in previous works for the entire Atlas system.

Association between parental history and genetic risk scores for coronary heart disease prediction: The population-based CoLaus study.

BACKGROUND AND AIMS: Parental history (PH) and genetic risk scores (GRSs) are separately associated with coronary heart disease (CHD), but evidence regarding their combined effects is lacking. We aimed to evaluate the joint associations and predictive ability of PH and GRSs for incident CHD. METHODS: Data for 4283 Caucasians were obtained from the population-based CoLaus Study, over median follow-up time of 5.6 years. CHD was defined as incident myocardial infarction, angina, percutaneous coronary revascularization or bypass grafting. Single nucleotide polymorphisms for CHD identified by genome-wide association studies were used to construct unweighted and weighted versions of three GRSs, comprising of 38, 53 and 153 SNPs respectively. RESULTS: PH was associated with higher values of all weighted GRSs. After adjustment for age, sex, smoking, diabetes, systolic blood pressure, low and high density lipoprotein cholesterol, PH was significantly associated with CHD [HR 2.61, 95% CI (1.47-4.66)] and further adjustment for GRSs did not change this estimate. Similarly, one standard deviation change of the weighted 153-SNPs GRS was significantly associated with CHD [HR 1.50, 95% CI (1.26-1.80)] and remained so, after further adjustment for PH. The weighted, 153-SNPs GRS, but not PH, modestly improved discrimination [(C-index improvement, 0.016), p = 0.048] and reclassification [(NRI improvement, 8.6%), p = 0.027] beyond cardiovascular risk factors. After including both the GRS and PH, model performance improved further [(C-index improvement, 0.022), p = 0.006]. CONCLUSION: After adjustment for cardiovascular risk factors, PH and a weighted, polygenic GRS were jointly associated with CHD and provided additive information for coronary events prediction.

Impact of a cis-associated gene expression SNP on chromosome 20q11.22 on bipolar disorder susceptibility, hippocampal structure and cognitive performance.

BackgroundBipolar disorder is a highly heritable polygenic disorder. Recent enrichment analyses suggest that there may be true risk variants for bipolar disorder in the expression quantitative trait loci (eQTL) in the brain.AimsWe sought to assess the impact of eQTL variants on bipolar disorder risk by combining data from both bipolar disorder genome-wide association studies (GWAS) and brain eQTL.MethodTo detect single nucleotide polymorphisms (SNPs) that influence expression levels of genes associated with bipolar disorder, we jointly analysed data from a bipolar disorder GWAS (7481 cases and 9250 controls) and a genome-wide brain (cortical) eQTL (193 healthy controls) using a Bayesian statistical method, with independent follow-up replications. The identified risk SNP was then further tested for association with hippocampal volume (n = 5775) and cognitive performance (n = 342) among healthy individuals.ResultsIntegrative analysis revealed a significant association between a brain eQTL rs6088662 on chromosome 20q11.22 and bipolar disorder (log Bayes factor = 5.48; bipolar disorder P = 5.85×10(-5)). Follow-up studies across multiple independent samples confirmed the association of the risk SNP (rs6088662) with gene expression and bipolar disorder susceptibility (P = 3.54×10(-8)). Further exploratory analysis revealed that rs6088662 is also associated with hippocampal volume and cognitive performance in healthy individuals.ConclusionsOur findings suggest that 20q11.22 is likely a risk region for bipolar disorder; they also highlight the informative value of integrating functional annotation of genetic variants for gene expression in advancing our understanding of the biological basis underlying complex disorders, such as bipolar disorder.