Evidence for genetic association of RORB with bipolar disorder

Abstract

Background: Bipolar disorder, particularly in children, is characterized by rapid cycling and switching, making circadian clock genes plausible molecular underpinnings for bipolar disorder. We previously reported work establishing mice lacking the clock gene D-box binding protein (DBP) as a stress-reactive genetic animal model of bipolar disorder. Microarray studies revealed that expression of two closely related clock genes, RAR-related orphan receptors alpha (RORA) and beta (RORB), was altered in these mice. These retinoid-related receptors are involved in a number of pathways including neurogenesis, stress response, and modulation of circadian rhythms. Here we report association studies between bipolar disorder and single-nucleotide polymorphisms (SNPs) in RORA and RORB.

Methods: We genotyped 355 RORA and RORB SNPs in a pediatric cohort consisting of a family-based sample of 153 trios and an independent, non-overlapping case-control sample of 152 cases and 140 controls. Bipolar disorder in children and adolescents is characterized by increased stress reactivity and frequent episodes of shorter duration; thus our cohort provides a potentially enriched sample for identifying genes involved in cycling and switching.

Results: We report that four intronic RORB SNPs showed positive associations with the pediatric bipolar phenotype that survived Bonferroni correction for multiple comparisons in the case-control sample. Three RORB haplotype blocks implicating an additional 11 SNPs were also associated with the disease in the case-control sample. However, these significant associations were not replicated in the sample of trios. There was no evidence for association between pediatric bipolar disorder and any RORA SNPs or haplotype blocks after multiple-test correction. In addition, we found no strong evidence for association between the age-at-onset of bipolar disorder with any RORA or RORB SNPs.

Conclusion: Our findings suggest that clock genes in general and RORB in particular may be important candidates for further investigation in the search for the molecular basis of bipolar disorder.

Figure 1

Genomic Organization of RORB with Association Results. The genomic location and organization of RORB are shown, with exons represented by vertical purple bars. All 43 analyzed RORB SNPs are shown and their positions are indicated. The four SNPs with significant associations to bipolar disorder in the case-control sample are highlighted in red. The haplotype block structure in the case-control sample as defined by the Confidence Intervals algorithm [38] in Haploview [34] is illustrated, with the linkage disequilibrium (LD) structure shown below. The two haplotype blocks with two-tailed permutation-based P-values < 0.001 are highlighted in red, and the block with P < 0.01 is highlighted in orange. Image created using LocusView http://www.broad.mit.edu/mpg/locusview/[51].