Gene variants associated with schizophrenia in a Norwegian genome-wide study are replicated in a large European cohort.
We have performed a genome-wide association study (GWAS) of schizophrenia in a Norwegian discovery sample of 201 cases and 305 controls (TOP study) with a focused replication analysis in a larger European sample of 2663 cases and 13,780 control subjects (SGENE-plus study). Firstly, the discovery sample was genotyped with Affymetrix Genome-Wide Human SNP Array 6.0 and 572,888 markers were tested for schizophrenia association. No SNPs in the discovery sample attained genome-wide significance (P<8.7 x 10(-8)). Secondly, based on the GWAS data, we selected 1000 markers with the lowest P values in the discovery TOP sample, and tested these (or HapMap-based surrogates) for association in the replication sample. Sixteen loci were associated with schizophrenia (nominal P value<0.05 and concurring OR) in the replication sample. As a next step, we performed a combined analysis of the findings from these two studies, and the strongest evidence for association with schizophrenia was provided for markers rs7045881 on 9p21, rs433598 on 16p12 and rs10761482 on 10q21. The markers are located in PLAA, ACSM1 and ANK3, respectively. PLAA has not previously been described as a susceptibility gene, but 9p21 is implied as a schizophrenia linkage region. ACSM1 has been identified as a susceptibility gene in a previous schizophrenia GWAS study. The association of ANK3 with schizophrenia is intriguing in light of recent associations of ANK3 with bipolar disorder, thereby supporting the hypothesis of an overlap in genetic susceptibility between these psychopathological entities.
Athanasiu
Lavinia
L
Institute of Psychiatry, University of Oslo, P.O. 1130, Blindern, N-0318 Oslo, Norway
Mattingsdal
Morten
M
Kähler
Anna K
AK
Brown
Andrew
A
Gustafsson
Omar
O
Agartz
Ingrid
I
Giegling
Ina
I
Muglia
Pierandrea
P
Cichon
Sven
S
Rietschel
Marcella
M
Pietiläinen
Olli P H
OP
Peltonen
Leena
L
Bramon
Elvira
E
Collier
David
D
Clair
David St
DS
Sigurdsson
Engilbert
E
Petursson
Hannes
H
Rujescu
Dan
D
Melle
Ingrid
I
Steen
Vidar M
VM
Djurovic
Srdjan
S
Andreassen
Ole A
OA
D017487:Ankyrins / Q000235:genetics*; D003066:Coenzyme A Ligases / Q000235:genetics; D015331:Cohort Studies; D005060:Europe / Q000453:epidemiology; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D009664:Norway / Q000453:epidemiology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011506:Proteins / Q000235:genetics; D012016:Reference Values; D012189:Retrospective Studies; D012559:Schizophrenia / Q000453:epidemiology* / Q000235:genetics*; D044465:White People
C490613:ANK3 protein, human; D017487:Ankyrins; D011506:Proteins; C055324:phospholipase A2-activating protein; C437335:ACSM1 protein, human; D003066:Coenzyme A Ligases