Genome-wide association study meta-analysis of European and Asian-ancestry samples identifies three novel loci associated with bipolar disorder

• Published in: Molecular psychiatry Vol. 18; no. 2; pp. 195 - 205
• Main Authors: Chen, D T, Jiang, X, Akula, N, Shugart, Y Y, Wendland, J R, Steele, C J M, Kassem, L, Park, J-H, Chatterjee, N, Jamain, S, Cheng, A, Leboyer, M, Muglia, P, Schulze, T G, Cichon, S, Nöthen, M M, Rietschel, M, McMahon, F J
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2013; Nature Publishing Group
• Subjects: 631/208/205/2138; 692/699/476/1333; 692/700/478/174; Adult and adolescent clinical studies; Ankyrins - genetics; Ankyrins - metabolism; Antidepressive Agents - pharmacology; Asian Continental Ancestry Group - genetics; Behavioral Sciences; Biological and medical sciences; Biological Psychology; Bipolar disorder; Bipolar Disorder - ethnology; Bipolar Disorder - genetics; Bipolar disorders; Cell Line, Transformed; Chromosome 3; Cytokines - genetics; Dose-Response Relationship, Drug; European Continental Ancestry Group - genetics; Female; Gene Expression Regulation - drug effects; Gene Expression Regulation - genetics; Gene Frequency; Genetic analysis; Genetic aspects; Genetic markers; Genetic Predisposition to Disease; Genome-wide association studies; Genome-Wide Association Study; Genomes; Health aspects; Human health and pathology; Humans; Lectins - genetics; Lectins - metabolism; Life Sciences; Lithium Chloride - pharmacology; Male; Medical sciences; Medicine; Medicine & Public Health; Membrane Transport Proteins - genetics; Membrane Transport Proteins - metabolism; Meta-analysis; Meta-Analysis as Topic; Mood disorders; Neurosciences; original-article; Pharmacotherapy; Polymorphism, Single Nucleotide; Psychiatrics and mental health; Psychiatry; Psychological aspects; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Receptors, Prostaglandin - genetics; Receptors, Prostaglandin - metabolism; RNA, Messenger - metabolism; Single-nucleotide polymorphism; Size distribution; Systematic review; Time Factors; Valproic Acid - pharmacology; Canada; France; United States; Germany; meta-analysis; TRANK1; bipolar disorder; ANK3; 3p21; LBA1; Mood disorder; Concomitant disease; Asiatic; Bipolar disorder; Review; Ethnic group; Metaanalysis
• ISSN: 1359-4184; 1476-5578; 1476-5578
• DOI: 10.1038/mp.2011.157

Meta-analyses of bipolar disorder (BD) genome-wide association studies (GWAS) have identified several genome-wide significant signals in European-ancestry samples, but so far account for little of the inherited risk. We performed a meta-analysis of ∼750 000 high-quality genetic markers on a combined sample of ∼14 000 subjects of European and Asian-ancestry (phase I). The most significant findings were further tested in an extended sample of ∼17 700 cases and controls (phase II). The results suggest novel association findings near the genes TRANK1 ( LBA1 ), LMAN2L and PTGFR . In phase I, the most significant single nucleotide polymorphism (SNP), rs9834970 near TRANK1 , was significant at the P =2.4 × 10 −11 level, with no heterogeneity. Supportive evidence for prior association findings near ANK3 and a locus on chromosome 3p21.1 was also observed. The phase II results were similar, although the heterogeneity test became significant for several SNPs. On the basis of these results and other established risk loci, we used the method developed by Park et al. to estimate the number, and the effect size distribution, of BD risk loci that could still be found by GWAS methods. We estimate that >63 000 case–control samples would be needed to identify the ∼105 BD risk loci discoverable by GWAS, and that these will together explain <6% of the inherited risk. These results support previous GWAS findings and identify three new candidate genes for BD. Further studies are needed to replicate these findings and may potentially lead to identification of functional variants. Sample size will remain a limiting factor in the discovery of common alleles associated with BD.