title: Genome-wide association study meta-analysis of European and Asian-ancestry samples identifies three novel loci associated with bipolar disorder.
abstract: 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.
authors.affiliation: Human Genetics Branch, National Institute of Mental Health, Intramural Research Program, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD 20892, USA. chend4@mail.nih.gov
authors.forename: D T
authors.initials: DT
authors.lastname: Chen
authors.forename: X
authors.initials: X
authors.lastname: Jiang
authors.forename: N
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authors.lastname: Akula
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authors.lastname: Shugart
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authors.lastname: Wendland
authors.forename: C J M
authors.initials: CJ
authors.lastname: Steele
authors.forename: L
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authors.lastname: Kassem
authors.forename: J-H
authors.initials: JH
authors.lastname: Park
authors.forename: N
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authors.lastname: Chatterjee
authors.forename: S
authors.initials: S
authors.lastname: Jamain
authors.forename: A
authors.initials: A
authors.lastname: Cheng
authors.forename: M
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authors.lastname: Leboyer
authors.forename: P
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authors.lastname: Muglia
authors.forename: T G
authors.initials: TG
authors.lastname: Schulze
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authors.lastname: Cichon
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authors.initials: MM
authors.lastname: Nöthen
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authors.lastname: Rietschel
authors.forename: F J
authors.initials: FJ
authors.lastname: McMahon
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authors.lastname: Farmer
authors.forename: P
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authors.lastname: McGuffin
authors.forename: I
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authors.lastname: Craig
authors.forename: C
authors.initials: C
authors.lastname: Lewis
authors.forename: G
authors.initials: G
authors.lastname: Hosang
authors.forename: S
authors.initials: S
authors.lastname: Cohen-Woods
authors.forename: J B
authors.initials: JB
authors.lastname: Vincent
authors.forename: J L
authors.initials: JL
authors.lastname: Kennedy
authors.forename: J
authors.initials: J
authors.lastname: Strauss
mesh_terms: D017487:Ankyrins / Q000235:genetics / Q000378:metabolism; D000928:Antidepressive Agents / Q000494:pharmacology; D044466:Asian People / Q000235:genetics; D001714:Bipolar Disorder / Q000208:ethnology* / Q000235:genetics*; D002461:Cell Line, Transformed; D016207:Cytokines / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D037102:Lectins / Q000235:genetics / Q000378:metabolism; D018021:Lithium Chloride / Q000494:pharmacology; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D015201:Meta-Analysis as Topic; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000378:metabolism; D011982:Receptors, Prostaglandin / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014635:Valproic Acid / Q000494:pharmacology; D044465:White People / Q000235:genetics
chemical_list: C490613:ANK3 protein, human; D017487:Ankyrins; D000928:Antidepressive Agents; D016207:Cytokines; C477344:LMAN2L protein, human; D037102:Lectins; D026901:Membrane Transport Proteins; D012333:RNA, Messenger; D011982:Receptors, Prostaglandin; C112841:TRANK1 protein, human; C034671:prostaglandin F2alpha receptor; D014635:Valproic Acid; D018021:Lithium Chloride