Evidence for genetic association of RORB with bipolar disorder.
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.


CONCLUSIONS
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.
McGrath
Casey L
CL
Department of Psychiatry, Laboratory of Neurophenomics, Indiana University School of Medicine, Indianapolis, IN, USA. mcgrath.casey@gmail.com
Glatt
Stephen J
SJ
Sklar
Pamela
P
Le-Niculescu
Helen
H
Kuczenski
Ronald
R
Doyle
Alysa E
AE
Biederman
Joseph
J
Mick
Eric
E
Faraone
Stephen V
SV
Niculescu
Alexander B
AB
Tsuang
Ming T
MT
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000818:Animals; D001714:Bipolar Disorder / Q000175:diagnosis / Q000235:genetics*; D056926:CLOCK Proteins / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D015331:Cohort Studies; D039721:Diagnostic and Statistical Manual of Mental Disorders; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007438:Introns / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; 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 / Q000235:genetics*; D011569:Psychiatric Status Rating Scales
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; D056926:CLOCK Proteins; C538943:CLOCK protein, human