Genome-wide association identifies a common variant in the reelin gene that increases the risk of schizophrenia only in women.
Sex differences in schizophrenia are well known, but their genetic basis has not been identified. We performed a genome-wide association scan for schizophrenia in an Ashkenazi Jewish population using DNA pooling. We found a female-specific association with rs7341475, a SNP in the fourth intron of the reelin (RELN) gene (p = 2.9 x 10(-5) in women), with a significant gene-sex effect (p = 1.8 x 10(-4)). We studied rs7341475 in four additional populations, totaling 2,274 cases and 4,401 controls. A significant effect was observed only in women, replicating the initial result (p = 2.1 x 10(-3) in women; p = 4.2 x 10(-3) for gene-sex interaction). Based on all populations the estimated relative risk of women carrying the common genotype is 1.58 (p = 8.8 x 10(-7); p = 1.6 x 10(-5) for gene-sex interaction). The female-specific association between RELN and schizophrenia is one of the few examples of a replicated sex-specific genetic association in any disease.
Shifman
Sagiv
S
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kindgdom. sagiv@vms.huji.ac.il
Johannesson
Martina
M
Bronstein
Michal
M
Chen
Sam X
SX
Collier
David A
DA
Craddock
Nicholas J
NJ
Kendler
Kenneth S
KS
Li
Tao
T
O'Donovan
Michael
M
O'Neill
F Anthony
FA
Owen
Michael J
MJ
Walsh
Dermot
D
Weinberger
Daniel R
DR
Sun
Cuie
C
Flint
Jonathan
J
Darvasi
Ariel
A
D000328:Adult; D000483:Alleles; D044466:Asian People / Q000235:genetics; D016022:Case-Control Studies; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics*; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D015894:Genome, Human; D006801:Humans; D007438:Introns; D007585:Jews / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D000091042:Reelin Protein; D012307:Risk Factors; D012559:Schizophrenia / Q000209:etiology / Q000235:genetics*; D012697:Serine Endopeptidases / Q000235:genetics*; D012727:Sex Characteristics; D044465:White People / Q000235:genetics
D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D000091042:Reelin Protein; C000717127:RELN protein, human; D012697:Serine Endopeptidases