Genome-wide association identifies a common variant in the reelin gene that increases the risk of schizophrenia only in women

• Published in: PLoS genetics Vol. 4; no. 2; p. e28
• Main Authors: Shifman, Sagiv, Johannesson, Martina, Bronstein, Michal, Chen, Sam X, Collier, David A, Craddock, Nicholas J, Kendler, Kenneth S, Li, Tao, O'Donovan, Michael, O'Neill, F Anthony, Owen, Michael J, Walsh, Dermot, Weinberger, Daniel R, Sun, Cuie, Flint, Jonathan, Darvasi, Ariel
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.02.2008; Public Library of Science (PLoS)
• Subjects: Adult; Alleles; Asians - genetics; Case-Control Studies; Cell Adhesion Molecules, Neuronal - genetics; Extracellular Matrix Proteins - genetics; Female; Gender differences; Gene Frequency; Genes; Genetic Predisposition to Disease; Genetic Variation; Genetics; Genetics and Genomics; Genome, Human; Homo (Human); Humans; Introns; Jews - genetics; Male; Middle Aged; Nerve Tissue Proteins - genetics; Neurological Disorders; Odds Ratio; Polymorphism, Single Nucleotide; Reelin Protein; Risk Factors; Schizophrenia - etiology; Schizophrenia - genetics; Serine Endopeptidases - genetics; Sex Characteristics; Studies; Whites - genetics; Womens health
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.0040028

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.