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

Abstract

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.

Figure 1. Association Signal on Chromosome 22 in a Sliding-window of Nine Consecutive SNPs

The −log10 values are the negative logarithm (base 10) of the sliding windows ranks divided by the number of windows on Chromosome 22. The combined rank across men and women is based on a silhouette statistic [36]. The inset shows a magnification of the region indicated by a vertical line and the position of DGCR2 and COMT genes within this interval.

Figure 2. Association Signal for Schizophrenia in the Reelin Gene

(I) The −log values are the negative logarithm (base 10) of the rank of each SNP divided by the number of SNPs on the array. The rank is based on a silhouette statistic [36], calculated separately for DNA pools of men (red) and women (blue) using the GenePool software. Arrows indicate the most significant SNPs, genotyped individually. The signal from rs2106173 was found to be an artifact of the DNA pooling experiment. (II) The structure and location of the reelin gene is from the Genome Browser of the University of California, Santa Cruz. Blue boxes represent the gene exons. (III) Similar patterns of linkage disequilibrium (LD) in Ashkenazi Jewish population (ASH) and individuals with European ancestry from HapMap (CEU). The blue arrows indicate the position of SNP rs7341475. Figures were generated using the Haploview software (http://www.broad.mit.edu/mpg/haploview/), with the standard color scheme. Pairwise LD levels between the SNPs in the region are represented by the color of the squares, which increase from white to blue to red (white, disequilibrium coefficient (D') < 1 and LOD score < 2; blue, D' = 1 and LOD score < 2; pink or light red, D' < 1 and LOD score ≥ 2; and bright red, D' = 1 and LOD score ≥ 2).

Figure 3. Risk Effects of the GG Genotype of rs7341475 Estimated by Odds Ratio Separately for Men and Women across Samples

The point estimate of the odds ratio for each sample is represented by a square with a size proportional to the weight of study. The 95% confidence interval (95% CI) for each study is represented by a horizontal line. The confidence interval for the combined data is represented by a diamond.