Investigation of associations between NR1D1, RORA and RORB genes and bipolar disorder
Journal
PLoS ONE
Journal Volume
10
Journal Issue
3
Pages
e0121245
Date Issued
2015
Author(s)
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 genebased 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 genegene 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 1.6x10 -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. ? 2015 Lai et al.
SDGs
Other Subjects
nuclear receptor NR1D1; retinoid related orphan receptor alpha; retinoid related orphan receptor beta; biological marker; NR1D1 protein, human; nuclear receptor NR1D1; retinoid related orphan receptor alpha; retinoid related orphan receptor beta; RORA protein, human; RORB protein, human; adult; Affymetrix Genome Wide CHB Array; aged; Article; bipolar I disorder; bipolar II disorder; case control study; Chinese; controlled study; female; gene gene interaction; gene interaction; gene linkage disequilibrium; genetic analysis; genetic association; genetic marker; genetic variability; genotyping technique; GoldenGate VeraCode assay; Hardy Weinberg equilibrium; human; major clinical study; male; model; multifactor dimension reduction; nonparametric test; NR1D1 gene; RORA gene; RORB gene; single nucleotide polymorphism; statistical model; Taiwan; bipolar disorder; epistasis; genetics; metabolism; middle aged; Adult; Biomarkers; Bipolar Disorder; Epistasis, Genetic; Female; Humans; Male; Middle Aged; Nuclear Receptor Subfamily 1, Group D, Member 1; Nuclear Receptor Subfamily 1, Group F, Member 1; Nuclear Receptor Subfamily 1, Group F, Member 2; Polymorphism, Single Nucleotide
Type
journal article