Association study in a Sardinian sample between bipolar disorder and the nuclear receptor REV-ERBalpha gene, a critical component of the circadian clock system.
OBJECTIVE
The aim of our study was to investigate the association between REV-ERBalpha gene (NR1D1) single nucleotide polymorphisms (SNPs) and bipolar disorder (BP) in a case-control sample of Sardinian ancestry and evaluate its effect on age at onset (AAO) of BP.


METHODS
We genotyped SNPs rs12941497 (SNP1) and rs939347 (SNP2), located, respectively, in the first intron and in the 5'UTR region of the gene, in a sample comprised of 300 bipolar patients and 300 healthy controls of Sardinian ancestry. We also studied AAO by means of admixture analysis, obtaining a cutoff point of age 22 and then carrying out association analysis between the two AAO groups.


RESULTS
In the case-control comparison, single marker analysis showed no association for any of the SNPs tested. Haplotype analysis showed a nominally significant association for two haplotypes of SNPs 1-2. Comparing the early- and later-onset groups, nominal association was found for SNP1. Haplotype analysis showed that one haplotype was nominally associated with the later-onset group.


CONCLUSIONS
Our results, indicating a nominal association of the REV-ERBalpha gene with BP, suggest a possible role of REV-ERBalpha in the pathogenesis of BP. Further investigation of larger independent samples and different populations is warranted.
Severino
Giovanni
G
Section of Clinical Pharmacology, Department of Neurosciences, University of Cagliari, P.O. San Giovanni di Dio, Via Ospedale 46, Cagliari, Italy. severino@unica.it
Manchia
Mirko
M
Contu
Paolo
P
Squassina
Alessio
A
Lampus
Simona
S
Ardau
Raffaella
R
Chillotti
Caterina
C
Del Zompo
Maria
M
D000328:Adult; D017668:Age of Onset; D001714:Bipolar Disorder / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology*; D016022:Case-Control Studies; D002940:Circadian Rhythm / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007438:Introns / Q000235:genetics; D007558:Italy / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*
D004268:DNA-Binding Proteins; C064353:NR1D1 protein, human; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D018160:Receptors, Cytoplasmic and Nuclear