title: Investigation of associations between NR1D1, RORA and RORB genes and bipolar disorder.
abstract: Several genes that are involved in the regulation of circadian rhythms are implicated in the susceptibility to bipolar disorder (BD). The current study aimed to investigate the relationships between genetic variants in NR1D1 RORA, and RORB genes and BD in the Han Chinese population. We conducted a case-control genetic association study with two samples of BD patients and healthy controls. Sample I consisted of 280 BD patients and 200 controls. Sample II consisted of 448 BD patients and 1770 healthy controls. 27 single nucleotide polymorphisms in the NR1D1, RORA, and RORB genes were genotyped using GoldenGate VeraCode assays in sample I, and 492 markers in the three genes were genotyped using Affymetrix Genome-Wide CHB Array in sample II. Single marker and gene-based association analyses were performed using PLINK. A combined p-value for the joining effects of all markers within a gene was calculated using the rank truncated product method. Multifactor dimensionality reduction (MDR) method was also applied to test gene-gene interactions in sample I. All markers were in Hardy-Weinberg equilibrium (P>0.001). In sample I, the associations with BD were observed for rs4774388 in RORA (OR = 1.53, empirical p-value, P = 0.024), and rs1327836 in RORB (OR = 1.75, P = 0.003). In Sample II, there were 45 SNPs showed associations with BD, and the most significant marker in RORA was rs11639084 (OR = 0.69, P = 0.002), and in RORB was rs17611535 (OR = 3.15, P = 0.027). A combined p-value of 1.6×10-6, 0.7, and 1.0 was obtained for RORA, RORB and NR1D1, respectively, indicting a strong association for RORA with the risk of developing BD. A four way interaction was found among markers in NR1D1, RORA, and RORB with the testing accuracy 53.25% and a cross-validation consistency of 8 out of 10. In sample II, 45 markers had empirical p-values less than 0.05. The most significant markers in RORA and RORB genes were rs11639084 (OR = 0.69, P = 0.002), and rs17611535 (OR = 3.15, P = 0.027), respectively. Gene-based association was significant for RORA gene (P = 0.0007). Our results support for the involvement of RORs genes in the risk of developing BD. Investigation of the functional properties of genes in the circadian pathway may further enhance our understanding about the pathogenesis of bipolar illness.
authors: Department of Public Health & Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
authors: Yin-Chieh
authors: YC
authors: Lai
authors: Department of Public Health & Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
authors: Chung-Feng
authors: CF
authors: Kao
authors: Department of Psychiatry, Taipei Medical University-Wan Fang Medical Center, Taipei, Taiwan.
authors: Mong-Liang
authors: ML
authors: Lu
authors: Department of Psychiatry & Center of Sleep Disorders, National Taiwan University Hospital, Taipei, Taiwan.
authors: Hsi-Chung
authors: HC
authors: Chen
authors: Department of Psychiatry, Taipei City Psychiatric Center, Taipei City Hospital, Taipei, Taiwan.
authors: Po-Yu
authors: PY
authors: Chen
authors: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors: Chien-Hsiun
authors: CH
authors: Chen
authors: Department of Psychiatry, Taipei Medical University-Wan Fang Medical Center, Taipei, Taiwan.
authors: Winston W
authors: WW
authors: Shen
authors: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors: Jer-Yuarn
authors: JY
authors: Wu
authors: Department of Psychiatry, National Cheng Kung University Hospital, Tainan, Taiwan.
authors: Ru-Band
authors: RB
authors: Lu
authors: Department of Public Health & 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.
authors: Po-Hsiu
authors: PH
authors: Kuo
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000378:metabolism; D001714:Bipolar Disorder / Q000235:genetics*; D004843:Epistasis, Genetic; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000235:genetics*; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000235:genetics*; D057095:Nuclear Receptor Subfamily 1, Group F, Member 2 / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: D015415:Biomarkers; C064353:NR1D1 protein, human; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D057095:Nuclear Receptor Subfamily 1, Group F, Member 2; C539738:RORA protein, human; C539740:RORB protein, human