Shared polygenic susceptibility to treatment response in severe affective and psychotic disorders: Evidence from GWAS data sets

Abstract

While schizophrenia (SCZ), bipolar disorder (BD) and major depressive disorder (MDD) genetically correlate, the pleiotropy underlying response/resistance to drugs used in these disorders has not been investigated. The aim of this study is to analyze the genetic relationship between treatment-resistant schizophrenia (TRS), response to lithium in BD (respLi) and response to antidepressants in MDD (respAD) using the conditional/conjunctional false discovery rate (cond/conjFDR) methodology, based on the hypothesis that shared mechanisms related to a common psychopathology factor underlie these phenotypes. A cross-trait polygenic enrichment for TRS conditioned on associations with respLi was observed. The conjFDR analysis identified rs11631065 (chr15:66654304) as a shared locus between them. One of the genes at this locus is MAP2K1, previously reported as associated with TRS after conditioning on body mass index genome-wide association study (GWAS). The set of genes at TRS-respLi conjFDR < 0.95 showed enrichment in response to psychotropic drugs in severe mental disorders from GWAS Catalog as well as in neurodevelopment and synaptic pathways. In conclusion, our study constitutes the first evidence of a transdiagnostic genetic signal associated with response to different pharmacological treatments in psychotic and affective disorders. It is necessary to confirm these results when larger GWAS of these phenotypes are available.