Common variants on chromosome 6p22.1 are associated with schizophrenia.
Schizophrenia, a devastating psychiatric disorder, has a prevalence of 0.5-1%, with high heritability (80-85%) and complex transmission. Recent studies implicate rare, large, high-penetrance copy number variants in some cases, but the genes or biological mechanisms that underlie susceptibility are not known. Here we show that schizophrenia is significantly associated with single nucleotide polymorphisms (SNPs) in the extended major histocompatibility complex region on chromosome 6. We carried out a genome-wide association study of common SNPs in the Molecular Genetics of Schizophrenia (MGS) case-control sample, and then a meta-analysis of data from the MGS, International Schizophrenia Consortium and SGENE data sets. No MGS finding achieved genome-wide statistical significance. In the meta-analysis of European-ancestry subjects (8,008 cases, 19,077 controls), significant association with schizophrenia was observed in a region of linkage disequilibrium on chromosome 6p22.1 (P = 9.54 x 10(-9)). This region includes a histone gene cluster and several immunity-related genes--possibly implicating aetiological mechanisms involving chromatin modification, transcriptional regulation, autoimmunity and/or infection. These results demonstrate that common schizophrenia susceptibility alleles can be detected. The characterization of these signals will suggest important directions for research on susceptibility mechanisms.
Shi
Jianxin
J
Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California 94304, USA.
Levinson
Douglas F
DF
Duan
Jubao
J
Sanders
Alan R
AR
Zheng
Yonglan
Y
Pe'er
Itsik
I
Dudbridge
Frank
F
Holmans
Peter A
PA
Whittemore
Alice S
AS
Mowry
Bryan J
BJ
Olincy
Ann
A
Amin
Farooq
F
Cloninger
C Robert
CR
Silverman
Jeremy M
JM
Buccola
Nancy G
NG
Byerley
William F
WF
Black
Donald W
DW
Crowe
Raymond R
RR
Oksenberg
Jorge R
JR
Mirel
Daniel B
DB
Kendler
Kenneth S
KS
Freedman
Robert
R
Gejman
Pablo V
PV
D000483:Alleles; D016022:Case-Control Studies; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D005060:Europe / Q000208:ethnology; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008285:Major Histocompatibility Complex / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics* / Q000276:immunology