Association study of 21 circadian genes with bipolar I disorder, schizoaffective disorder, and schizophrenia.
OBJECTIVE
Published studies suggest associations between circadian gene polymorphisms and bipolar I disorder (BPI), as well as schizoaffective disorder (SZA) and schizophrenia (SZ). The results are plausible, based on prior studies of circadian abnormalities. As replications have not been attempted uniformly, we evaluated representative, common polymorphisms in all three disorders.


METHODS
We assayed 276 publicly available 'tag' single nucleotide polymorphisms (SNPs) at 21 circadian genes among 523 patients with BPI, 527 patients with SZ/SZA, and 477 screened adult controls. Detected associations were evaluated in relation to two published genome-wide association studies (GWAS).


RESULTS
Using gene-based tests, suggestive associations were noted between EGR3 and BPI (p = 0.017), and between NPAS2 and SZ/SZA (p = 0.034). Three SNPs were associated with both sets of disorders (NPAS2: rs13025524 and rs11123857; RORB: rs10491929; p < 0.05). None of the associations remained significant following corrections for multiple comparisons. Approximately 15% of the analyzed SNPs overlapped with an independent study that conducted GWAS for BPI; suggestive overlap between the GWAS analyses and ours was noted at ARNTL.


CONCLUSIONS
Several suggestive, novel associations were detected with circadian genes and BPI and SZ/SZA, but the present analyses do not support associations with common polymorphisms that confer risk with odds ratios greater than 1.5. Additional analyses using adequately powered samples are warranted to further evaluate these results.
Department of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, PA 15213, USA.
Hader A
HA
Mansour
Michael E
ME
Talkowski
Joel
J
Wood
Kodavali V
KV
Chowdari
Lora
L
McClain
Konasale
K
Prasad
Debra
D
Montrose
Andrea
A
Fagiolini
Edward S
ES
Friedman
Michael H
MH
Allen
Charles L
CL
Bowden
Joseph
J
Calabrese
Rif S
RS
El-Mallakh
Michael
M
Escamilla
Stephen V
SV
Faraone
Mark D
MD
Fossey
Laszlo
L
Gyulai
Jennifer M
JM
Loftis
Peter
P
Hauser
Terence A
TA
Ketter
Lauren B
LB
Marangell
David J
DJ
Miklowitz
Andrew A
AA
Nierenberg
Jayendra
J
Patel
Gary S
GS
Sachs
Pamela
P
Sklar
Jordan W
JW
Smoller
Nan
N
Laird
Matcheri
M
Keshavan
Michael E
ME
Thase
David
D
Axelson
Boris
B
Birmaher
David
D
Lewis
Tim
T
Monk
Ellen
E
Frank
David J
DJ
Kupfer
Bernie
B
Devlin
Vishwajit L
VL
Nimgaonkar
D000328:Adult; D001714:Bipolar Disorder / Q000235:genetics*; D002940:Circadian Rhythm / Q000235:genetics; D056925:Circadian Rhythm Signaling Peptides and Proteins / Q000235:genetics*; D030541:Databases, Genetic; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011569:Psychiatric Status Rating Scales; D011618:Psychotic Disorders / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics*; D055815:Young Adult
D056925:Circadian Rhythm Signaling Peptides and Proteins