Investigation of associations between NR1D1, RORA and RORB genes and bipolar disorder

PLoS One. 2015 Mar 19;10(3):e0121245. doi: 10.1371/journal.pone.0121245. eCollection 2015.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Biomarkers / metabolism
  • Bipolar Disorder / genetics*
  • Epistasis, Genetic
  • Female
  • Humans
  • Male
  • Middle Aged
  • Nuclear Receptor Subfamily 1, Group D, Member 1 / genetics*
  • Nuclear Receptor Subfamily 1, Group F, Member 1 / genetics*
  • Nuclear Receptor Subfamily 1, Group F, Member 2 / genetics*
  • Polymorphism, Single Nucleotide


  • Biomarkers
  • NR1D1 protein, human
  • Nuclear Receptor Subfamily 1, Group D, Member 1
  • Nuclear Receptor Subfamily 1, Group F, Member 1
  • Nuclear Receptor Subfamily 1, Group F, Member 2
  • RORA protein, human
  • RORB protein, human

Grant support

This research was supported by National Science Council (NSC 99-2314-B-002-140-MY3, NSC 102-2314-B-002-117-MY3) and National Health Research Institute (NHRI-EX101-9918NC) Grants to Dr. P.-H. Kuo (PI). The funding sources had no further role in the study design, collection, analysis, or interpretation of data; in writing of the report; and in the decision to submit the paper for publication.