Identification of novel loci for bipolar I disorder in a multi-stage genome-wide association study.
OBJECTIVE
Identification of genetic variants that influence bipolar I disorder (BPD-I) through genome-wide association (GWA) studies is limited in Asian populations. The current study aimed to identify novel common variants for BPD-I in an ethnically homogeneous Taiwanese sample using a multi-stage GWA study design.


METHODS
At the discovery stage, 200 BPD-I patients and 200 controls that combined to form 16 pools were genotyped with 1 million markers. Utilizing a newly developed rank-based method, top-ranked markers were selected. After validation with individual genotyping, a fine-mapping association study was conducted to identify associated loci using 240 patients and 240 controls. At the last stage, independent samples were collected (351 cases and 341 controls) for replication.


RESULTS
Among the top-ranked markers from the discovery stage, eight genes and 15 individual SNPs were evaluated in the fine-mapping stage. At this stage, rs7619173, which is not in a gene coding region, showed the most significant association (P = 2 ∗ 10(-5)) with BPD-I. Four genes had empirical P-values<0.05, including KCNH7 (P = 0.0047), MYST4 (P = 0.0047), NRXN3 (P = 0.0095), and SEMA3D (P = 0.037). For markers genotyped in replication samples, rs7619173 exhibited a significant association (P(combined) = 2 ∗ 10(-4)) after multiple testing correction, while markers rs11001178 (MYST4) and rs2217887 (NRXN3) showed weak associations (P(combined) = 0.02) with BPD-I.


CONCLUSIONS
A multi-stage GWA design has the potential to uncover the underlying pathogenesis of a complex trait. Findings in the present study highlight three loci that warrant further investigation for bipolar.
Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan; Research Center for Genes, Environment and Human Health, National Taiwan University, Taipei, Taiwan. Electronic address: phkuo@ntu.edu.tw.
P H
PH
Kuo
Department of Nursing, Cardinal Tien College of Healthcare & Management, I-Lan, Taiwan.
L C
LC
Chuang
Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
J R
JR
Liu
Department of Psychiatry, National Taiwan University Hospital, Taipei, Taiwan.
C M
CM
Liu
Department of Psychiatry, Taipei City Psychiatric Center, Taipei City Hospital, Taipei, Taiwan; Department of Psychiatry, School of Medicine, Taipei Medical University, Taipei, Taiwan.
M C
MC
Huang
Department of Psychiatry, Taipei City Psychiatric Center, Taipei City Hospital, Taipei, Taiwan.
S K
SK
Lin
Institute of Molecular Medicine, National Cheng Kung University, Taiwan.
H
H
Sunny Sun
Department of Psychiatry, National Taiwan University Hospital, Taipei, Taiwan.
M H
MH
Hsieh
Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan; Research Center for Genes, Environment and Human Health, National Taiwan University, Taipei, Taiwan.
H
H
Hung
Department of Psychiatry, National Cheng Kung University Hospital, Tainan, Taiwan.
R B
RB
Lu
D000293:Adolescent; D000328:Adult; D000368:Aged; D001714:Bipolar Disorder / Q000235:genetics*; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D051548:Histone Acetyltransferases / Q000235:genetics*; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D039961:Semaphorins / Q000235:genetics; D013624:Taiwan; D055815:Young Adult
D051638:Ether-A-Go-Go Potassium Channels; C486376:KCNH7 protein, human; D009419:Nerve Tissue Proteins; C000592402:Sema3D protein, human; D039961:Semaphorins; C082354:neurexin IIIalpha; D051548:Histone Acetyltransferases; C487137:KAT6B protein, human
Bipolar disorder; Genome-wide association; Rank-based method