Genome-wide association study of bipolar disorder in European American and African American individuals

Abstract

To identify bipolar disorder (BD) genetic susceptibility factors, we conducted two genome-wide association (GWA) studies: one involving a sample of individuals of European ancestry (EA; n = 1001 cases; n = 1033 controls), and one involving a sample of individuals of African ancestry (AA; n = 345 cases; n = 670 controls). For the EA sample, single-nucleotide polymorphisms (SNPs) with the strongest statistical evidence for association included rs5907577 in an intergenic region at Xq27.1 (P = 1.6 Â 10 À6) and rs10193871 in NAP5 at 2q21.2 (P = 9.8 Â 10 À6). For the AA sample, SNPs with the strongest statistical evidence for association included rs2111504 in DPY19L3 at 19q13.11 (P = 1.5 Â 10 À6) and rs2769605 in NTRK2 at 9q21.33 (P = 4.5 Â 10 À5 ). We also investigated whether we could provide support for three regions previously associated with BD, and we showed that the ANK3 region replicates in our sample, along with some support for C15Orf53; other evidence implicates BD candidate genes such as SLITRK2. We also tested the hypothesis that BD susceptibility variants exhibit genetic background-dependent effects. SNPs with the strongest statistical evidence for genetic background effects included rs11208285 in ROR1 at 1p31.3 (P = 1.4 Â 10 À6 ), rs4657247 in RGS5 at 1q23.3 (P = 4.1 Â 10 À6 ), and rs7078071 in BTBD16 at 10q26.13 (P = 4.5 Â 10 À6). This study is the first to conduct GWA of BD in individuals of AA and suggests that genetic variations that contribute to BD may vary as a function of ancestry.

Genome-wide association study of bipolar I disorder in the Han Chinese population

“…This may suggest that there are common and population-specific susceptibility genes for bipolar I disorder. As reported in the recent GWA study, 22 differential associations were found in EuropeanAmerican and African-American populations.…”

“…22 Only one region harboring rs7078071 showed nominal association (P = 5.22 Â 10 À4 ) in our Han-Chinese sample (Supplementary Table 5). …”

Slitrks control excitatory and inhibitory synapse formation with LAR receptor protein tyrosine phosphatases

“…Intriguingly, Slitrk isoforms have been associated with multiple neuropsychiatric disorders. For example, Slitrk1 variants are linked to the spectrum of obsessive-compulsive disorders (OCDs), Tourette syndrome, and trichotillomania (7,8), and Slitrk2 is associated with schizophrenia and bipolar disorder (9,10). Moreover, Slitrk1 mutant mice show anxiety-like behaviors and Slitrk5-deficient mice display OCD-like behaviors (11,12).…”

Assessment of first and second degree relatives of individuals with bipolar disorder shows increased genetic risk scores in both affected relatives and young At‐Risk Individuals

“…The first comprised adult subjects of European ancestry (n = 1,947) drawn from the NIMH Genetics Initiative bipolar disorder family samples (waves I–IV European American families, n = 249 families, average of 6–7 subjects across three generations per family) [Nurnberger et al, 1997; Smith et al, 2009]. Subject diagnoses were obtained via standard best estimate (BEFD) procedure (details in supplementary information), and were diagnosed as having bipolar disorder type I (BPI, n = 561); schizoaffective disorder‐bipolar type (SAB, n = 40); bipolar disorder type II (BPII, n = 119); recurrent unipolar depressive disorder (UPR, n = 155); or single episode unipolar depressive disorder (UPS, n = 107).…”

“…Methods for ascertainment and diagnoses for the NIMH Genetics Initiative family dataset have been described extensively elsewhere [Nurnberger et al, 1997; Smith et al, 2009] and are summarized in supplementary information.…”