A polygenic resilience score moderates the genetic risk for schizophrenia

Abstract

Based on the discovery by the Resilience Project (Chen R. et al. Nat Biotechnol 34:531-538, 2016) of rare variants that confer resistance to Mendelian disease, and protective alleles for some complex diseases, we posited the existence of genetic variants that promote resilience to highly heritable polygenic disorders1,0 such as schizophrenia. Resilience has been traditionally viewed as a psychological construct, although our use of the term resilience refers to a different construct that directly relates to the Resilience Project, namely: heritable variation that promotes resistance to disease by reducing the penetrance of risk loci, wherein resilience and risk loci operate orthogonal to one another. In this study, we established a procedure to identify unaffected individuals with relatively high polygenic risk for schizophrenia, and contrasted them with risk-matched schizophrenia cases to generate the first known "polygenic resilience score" that represents the additive contributions to SZ resistance by variants that are distinct from risk loci. The resilience score was derived from data compiled by the Psychiatric Genomics Consortium, and replicated in three independent samples. This work establishes a generalizable framework for finding resilience variants for any complex, heritable disorder.

Fig. 1

An Illustration of our method for deriving polygenic resilience scores for a complex disorder

Fig. 2

(Top panel) Polygenic resilience scores were computed in our discovery sample (high-risk controls = 3,786, high-risk cases = 18,619) based on results obtained from GWAS meta-analysis of resilience to SZ. The barplot shows the amount of variance in resilience explained by resilience scores (i.e., high-risk controls versus high-risk cases) explained by resilience scores across ten p-value bins. The dot plot shows corresponding Odds Ratios (OR) for resilience scores, wherein OR > 1.0 represents that high-risk controls have higher resilience scores compared with high-risk cases. (Bottom panel) The predictive performance of polygenic resilience scores is shown based on a meta-analysis of results obtained from three independent replication samples (Molecular Genetics of Schizophrenia, iPSYCH, and deCODE Genetics; high-risk controls = 7,653, high-risk cases = 1,903). Average Nagelkerke’s pseudo-R² values calculated using arithmetic means and 95% confidence intervals are shown in the bottom left panel. Meta-analysis was used to pool natural log of OR and standard errors with an inverse-variance fixed effect model using the R package metafor

Fig. 3

A pair of odds ratios and confidence intervals are plotted for the top seven common variants associated with resilience to SZ (p < 1× 10⁻⁰⁵). This demonstrates that variants associated with resilience to SZ were not significantly associated with SZ risk (i.e., p > 0.05). Associations in red are for resilience obtained from the sample of individuals at the upper tail of the distribution of risk scores (i.e., high-risk controls, n = 3,775, and equal-risk cases, n = 18,581), whereas associations in blue were obtained from the full sample of SZ cases and controls in the published PGC-SZ2 data set (51 studies, n cases = 32,838, n controls = 44,357). A dotted line denoted no effect (i.e., OR = 1.0). An OR > 1.0 for red dots indicates that the allele was observed more frequently in high-risk controls than high-risk cases (i.e., increases resilience), whereas a OR > 1.0 for blue dots indicates that the allele was observed more frequently in cases than controls (i.e., increases risk)