Genome-wide association analysis identifies 13 new risk loci for schizophrenia

Abstract

Schizophrenia is an idiopathic mental disorder with a heritable component and a substantial public health impact. We conducted a multi-stage genome-wide association study (GWAS) for schizophrenia beginning with a Swedish national sample (5,001 cases and 6,243 controls) followed by meta-analysis with previous schizophrenia GWAS (8,832 cases and 12,067 controls) and finally by replication of SNPs in 168 genomic regions in independent samples (7,413 cases, 19,762 controls and 581 parent-offspring trios). We identified 22 loci associated at genome-wide significance; 13 of these are new, and 1 was previously implicated in bipolar disorder. Examination of candidate genes at these loci suggests the involvement of neuronal calcium signaling. We estimate that 8,300 independent, mostly common SNPs (95% credible interval of 6,300-10,200 SNPs) contribute to risk for schizophrenia and that these collectively account for at least 32% of the variance in liability. Common genetic variation has an important role in the etiology of schizophrenia, and larger studies will allow more detailed understanding of this disorder.

Figure 1

Manhattan plot of the Swedish and PGC schizophrenia meta-analysis results. The x-axis is chromosomal position and the y-axis is –log₁₀(P). The red line is the genome-wide significance level (5×10⁻⁸). Gene locations are indicated.

Figure 2

Risk score profiling results using the PGC schizophrenia results as the discovery set and the Sweden data as the testing set. The x-axis shows ten P value thresholds (P_T = 10⁻⁴, 10⁻³, …, 1). The y-axis is the Nagelkerke pseudo R², the proportion of variance in case-control status explained by the risk score profile. The number atop each vertical bar is the P value for the capacity of the risk score profile to predict case-control status for that P_T.

Figure 3

The main figure shows the results of ABPA modeling based on the Sweden + PGC results (population risk 0.01). The x-axis is the estimated number of SNPs on a log₁₀ scale, and the y-axis estimates the total variance in liability explained. The results for five conditions are shown: schizophrenia (this analysis, red) and, for comparison, results from a published analysis of myocardial infarction (MI, purple), type 2 diabetes mellitus (T2D, blue), celiac disease (green), and rheumatoid arthritis (RA, teal). The schizophrenia results are based on 1000 Genomes imputation, and the others on HapMap3 imputation. Color intensity reflects the probability density with darker colors indicating higher density. Contour lines show 50% and 95% credible regions for SCZ, and 95% credible regions for the other diseases. The insets depict estimated SNP distributions for the five disorders: (a) distribution of SNPs in terms of the variance in liability explained per SNP and (b) the estimated distribution of SNP genotypic relative risks (GRR). We again stress that multiple qualifiers are essential in interpreting these estimates.