title: Two variants in Ankyrin 3 (ANK3) are independent genetic risk factors for bipolar disorder.
abstract: Two recent reports have highlighted ANK3 as a susceptibility gene for bipolar disorder (BD). We first reported association between BD and the ANK3 marker rs9804190 in a genome-wide association study (GWAS) of two independent samples (Baum et al., 2008). Subsequently, a meta-analysis of GWAS data based on samples from the US and the UK reported association with a different ANK3 marker, rs10994336 (Ferreira et al., 2008). The markers lie about 340 kb apart in the gene. Here, we test both markers in additional samples and characterize the contribution of each marker to BD risk. Our previously reported findings at rs9804190, which had been based on DNA pooling, were confirmed by individual genotyping in the National Institute of Mental Health (NIMH) waves 1-4 (P=0.05; odds ratio (OR)=1.24) and German (P=0.0006; OR=1.34) samples. This association was replicated in an independent US sample known as NIMH wave 5 (466 cases, 212 controls; P=0.017; OR=1.38). A random-effects meta-analysis of all three samples was significant (P=3 x 10(-6); OR=1.32), with no heterogeneity. Individual genotyping of rs10994336 revealed a significant association in the German sample (P=0.0001; OR=1.70), and similar ORs in the NIMH 1-4 and NIMH 5 samples that were not significant at the P<0.05 level. Meta-analysis of all three samples supported an association with rs10994336 (P=1.7 x 10(-5); OR=1.54), again with no heterogeneity. There was little linkage disequilibrium between the two markers. Further analysis suggested that each marker contributed independently to BD, with no significant marker x marker interaction. Our findings strongly support ANK3 as a BD susceptibility gene and suggest true allelic heterogeneity.
authors.affiliation: Unit on the Genetic Basis of Mood and Anxiety Disorders, National Institute of Mental Health, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD 20892-3719, USA. schulzet@mail.nih.gov
authors.forename: T G
authors.initials: TG
authors.lastname: Schulze
authors.forename: S D
authors.initials: SD
authors.lastname: Detera-Wadleigh
authors.forename: N
authors.initials: N
authors.lastname: Akula
authors.forename: A
authors.initials: A
authors.lastname: Gupta
authors.forename: L
authors.initials: L
authors.lastname: Kassem
authors.forename: J
authors.initials: J
authors.lastname: Steele
authors.forename: J
authors.initials: J
authors.lastname: Pearl
authors.forename: J
authors.initials: J
authors.lastname: Strohmaier
authors.forename: R
authors.initials: R
authors.lastname: Breuer
authors.forename: M
authors.initials: M
authors.lastname: Schwarz
authors.forename: P
authors.initials: P
authors.lastname: Propping
authors.forename: M M
authors.initials: MM
authors.lastname: Nöthen
authors.forename: S
authors.initials: S
authors.lastname: Cichon
authors.forename: J
authors.initials: J
authors.lastname: Schumacher
authors.forename: M
authors.initials: M
authors.lastname: Rietschel
authors.forename: F J
authors.initials: FJ
authors.lastname: McMahon
mesh_terms: D000328:Adult; D017487:Ankyrins / Q000235:genetics*; D001714:Bipolar Disorder / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D005858:Germany; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D009315:National Institute of Mental Health (U.S.); D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors; D014481:United States; D055815:Young Adult
chemical_list: C490613:ANK3 protein, human; D017487:Ankyrins