Identification of genetic architecture shared between schizophrenia and Alzheimer's disease

Both schizophrenia (SCZ) and Alzheimer's disease (AD) are highly heritable brain disorders. Despite of the observed comorbidity and shared psychosis and cognitive decline between the two disorders, the genetic risk architecture shared by SCZ and AD remains largely unknown. Based on summary statistics of the currently available largest genome-wide association studies for SCZ (n = 130,644) and AD (n = 455,258) in individuals of European ancestry, we conducted conditional/conjunctional false discovery rate (FDR) analysis to enhance the statistical power for discovering more genetic associations with SCZ or AD and to detect the common genetic variants shared by both disorders. We found shared genetic architecture in SCZ conditioned on AD and vice versa across different levels of significance, indicating polygenic overlap. We found 268 (78 novel) SCZ-only and 125 (55 novel) AD-only SNPs at conditional FDR < 0.01, and 16 lead SNPs shared by SCZ and AD at conjunctional FDR < 0.05. Only half of the shared SNPs showed concordant effect direction, which was consistent with the modest genetic correlation (r = 0.097; P = 0.026) between the two disorders. This study provides evidence for polygenic overlap between SCZ and AD, suggesting the existence of the shared molecular genetic mechanisms, which may inform therapeutic targets that are applicable for both disorders.