Improved Detection of Common Variants Associated with Schizophrenia by Leveraging Pleiotropy with Cardiovascular-Disease Risk Factors

Abstract

Several lines of evidence suggest that genome-wide association studies (GWASs) have the potential to explain more of the "missing heritability" of common complex phenotypes. However, reliable methods for identifying a larger proportion of SNPs are currently lacking. Here, we present a genetic-pleiotropy-informed method for improving gene discovery with the use of GWAS summary-statistics data. We applied this methodology to identify additional loci associated with schizophrenia (SCZ), a highly heritable disorder with significant missing heritability. Epidemiological and clinical studies suggest comorbidity between SCZ and cardiovascular-disease (CVD) risk factors, including systolic blood pressure, triglycerides, low- and high-density lipoprotein, body mass index, waist-to-hip ratio, and type 2 diabetes. Using stratified quantile-quantile plots, we show enrichment of SNPs associated with SCZ as a function of the association with several CVD risk factors and a corresponding reduction in false discovery rate (FDR). We validate this "pleiotropic enrichment" by demonstrating increased replication rate across independent SCZ substudies. Applying the stratified FDR method, we identified 25 loci associated with SCZ at a conditional FDR level of 0.01. Of these, ten loci are associated with both SCZ and CVD risk factors, mainly triglycerides and low- and high-density lipoproteins but also waist-to-hip ratio, systolic blood pressure, and body mass index. Together, these findings suggest the feasibility of using genetic-pleiotropy-informed methods for improving gene discovery in SCZ and identifying potential mechanistic relationships with various CVD risk factors.

Genetic studies of schizophrenia: an update

“…MIR137 targets multiple genes involved in SCZ, bipolar disorder, and autism [86][87][88] . While the extent of sharing between these disorders may differ, the pleiotropic effects seem to extend beyond these traditional psychiatric disorders [89][90][91][92] .…”

Common susceptibility variants are shared between schizophrenia and psoriasis in the Han Chinese population

“…19,25,26 We estimated that 21% of the genomic contribution to both schizophrenia and psoriasis could be attributed to the shared genetic variants. This finding was validated using a polygenic scoring profile analysis and replicated in our independent Singa pore data sets.…”

“…Recently, evidence has been found for genetic pleiotropy between many complex human diseases, especially immune-mediated disorders. 19,21,22,[24][25][26]29 Schizophrenia has been shown to share a common genetic basis not only with other psychiatric diseases (e.g.. bipolar disorder), but also with metabolic (e.g., type 2 diabetes) and The right Y axis represents the odds ratio. Group 0 = the genetic risk score is less than the 25% quartile of that in controls.…”

“…[16][17][18] Given that most common disorders and traits have been shown to have a polygenic basis, many researchers have explored the possibility that many complex disorders and traits, including schizophrenia and psoriasis, actually share genetic determinants (i.e., are genetically correlated to some degree). [19][20][21][22][23][24][25][26] This trend appears to be even more pronounced in diseases of autoimmune origin. 27 In this light, we tested our hypothesis of a shared genetic basis of schizophrenia and psoriasis using large cohorts previously studied in independent GWAS.…”

A Penalized Regression Approach for Integrative Analysis in Gen ome- Wide Association Studies

“…We propose a penalized proposed approach is that genetically related traits can share common genetic bases [18,20], which enables us to borrow information from some related GWAS when analyzing the trait of primary interest.…”