A genome-wide association analysis of a broad psychosis phenotype identifies three loci for further investigation

Abstract

Background: Genome-wide association studies (GWAS) have identified several loci associated with schizophrenia and/or bipolar disorder. We performed a GWAS of psychosis as a broad syndrome rather than within specific diagnostic categories.

Methods: 1239 cases with schizophrenia, schizoaffective disorder, or psychotic bipolar disorder; 857 of their unaffected relatives, and 2739 healthy controls were genotyped with the Affymetrix 6.0 single nucleotide polymorphism (SNP) array. Analyses of 695,193 SNPs were conducted using UNPHASED, which combines information across families and unrelated individuals. We attempted to replicate signals found in 23 genomic regions using existing data on nonoverlapping samples from the Psychiatric GWAS Consortium and Schizophrenia-GENE-plus cohorts (10,352 schizophrenia patients and 24,474 controls).

Results: No individual SNP showed compelling evidence for association with psychosis in our data. However, we observed a trend for association with same risk alleles at loci previously associated with schizophrenia (one-sided p = .003). A polygenic score analysis found that the Psychiatric GWAS Consortium's panel of SNPs associated with schizophrenia significantly predicted disease status in our sample (p = 5 × 10(-14)) and explained approximately 2% of the phenotypic variance.

Conclusions: Although narrowly defined phenotypes have their advantages, we believe new loci may also be discovered through meta-analysis across broad phenotypes. The novel statistical methodology we introduced to model effect size heterogeneity between studies should help future GWAS that combine association evidence from related phenotypes. Applying these approaches, we highlight three loci that warrant further investigation. We found that SNPs conveying risk for schizophrenia are also predictive of disease status in our data.

Keywords: Bipolar disorder; genome-wide association; meta-analysis; polygenic score analysis; psychosis; schizophrenia.

Figure 1

Replication of previously published associated schizophrenia (SCZ) and bipolar disorder (BPD) loci. Reported odds ratios from the literature (x axis) plotted against the odds ratios estimated from our data as listed in Table 1 (y axis). The dotted line indicates an odds ratio of 1 in our data. Points above the line indicate the same direction of effect in previous studies and our data. Black circles indicate single nucleotide polymorphisms that replicate (p one-sided < .05) in our study. Triangles denote single nucleotide polymorphisms within the major histocompatibility complex region. Sign tests for an enrichment of effect in the same direction are presented for loci previously associated with schizophrenia, bipolar disorder, or both. Additional details on the sign tests are available in Table S4 of Supplement 1.

Figure 2

Quantile-quantile plots of the distribution of observed and expected p value at all autosomal single nucleotide polymorphisms passing quality control. The genomic control lambda value was 1.03. This represents analyses conducted on our entire discovery sample (n = 4835).

Figure 3

Regional association plots for the three single nucleotide polymorphisms (SNPs) reported in Table 2. The plots show the evidence of association in our discovery data at genotyped SNPs. The SNP listed in Table 2 is indicated with a diamond, and flanking SNPs (circles) are colored according to their correlations (r²) with this SNP measured in HapMap. CEU, Utah residents (CEPH) with Northern and Western European ancestry.