135. Genetic Correlation Analysis of Schizophrenia Mirrors Known Epidemiological Relationships and Suggests Novel Associations.

Abstract

Background: In 2015, a new method made it possible to determine shared genetic infuences across phenotypes on a scale far greater than ever before. Linkage Disequilibrium Score Regression (LDSR) allows estimation of genetic correlation, revealing the magnitude and direction of shared genetic effects between pairs of phenotypes. Genetic correlation results for a particular phenotype-such as schizophrenia-are similar to epidemiological results. They reveal fundamental information relevant to patterns of comorbid-ity-but are even more informative because the cause (polygenic variation) is known. Here we report genetic correlation analysis of schizophrenia with 172 diverse phenotypes (psychiatric, medical, personality, and metabolic). Methods: This was an analytic study design, which leverages large-scale data resources. In all, approximately 1.5 million individuals participated in the genome-wide association studies (GWAS) that make these analyses possible. We used linkage disequilibrium score regression (LDSR) as implemented in LDHub, and report results with original P values, Bonferroni correction, and Benjamani-Hochberg false discovery rates to address multiple testing. The main outcomes and measures are genetic correlations between schizophrenia and 172 phenotypes. Results: As has been previously published, there are positive genetic correlations between schizophrenia and other psychiatric disorders; the stron-gest genetic correlation is with bipolar disorder (rg = 0.8312, se = 0.0369, P = 2.3e-112). Novel fndings reveal genetic effects shared between schizophrenia and the personality traits of neuroticism (rg = 0.1815, se = 0.067, P =.0065) and openness to experience (rg = 0.2108, se = 0.075, P =.0046), the latter of which contradicts epidemiological observations. All other genetic correlations were consistent with epidemiological evidence. Findings suggest that long recognized comorbidity between various immune processes and schizophrenia, and also cigarette smoking and schizophrenia, are at least partly due to shared genetic infuences. Conclusion: In the future, the pattern of genetic correlation results for each phe-notype-a “genetic correlation profle”-will be common knowledge. These results provide a reasonable frst draft of the genetic correlation profle for schizophrenia. They affrmatively answer long-standing questions about the possibility of shared genetic effects on immune, metabolic, and other classes of phenotypes, with schizophrenia. These results also clarify reading of the epide-miological literature, highlighting the lower than average body mass index of individuals prior to developing schizophrenia and prior to taking antipsychotic medications. Results that initially appear surprising may prove to be most useful. These results suggest tractable hypotheses that may lead to major cross-trait discoveries and to reconceptualization of underlying biological processes.