A Two-Stage Association Study Suggests BRAP as a Susceptibility Gene for Schizophrenia

Schizophrenia (SZ) is a neurodevelopmental disorder in which altered immune function typically plays an important role in mediating the effect of environmental insults and regulation of inflammation. The breast cancer suppressor protein associated protein (BRAP) is suggested to exert vital effects in neurodevelopment by modulating the mitogen-activated protein kinase cascade and inflammation signaling. To explore the possible role of BRAP in SZ, we conducted a two-stage study to examine the association of BRAP polymorphisms with SZ in the Han Chinese population. In stage one, we screened SNPs in BRAP from our GWAS data, which detected three associated SNPs, with rs3782886 being the most significant one (P = 2.31E-6, OR = 0.67). In stage two, we validated these three SNPs in an independently collected population including 1957 patients and 1509 controls, supporting the association of rs3782886 with SZ (P = 1.43E-6, OR = 0.73). Furthermore, cis-eQTL analysis indicates that rs3782886 genotypes are associated with mRNA levels of aldehyde dehydrogenase 2 family (ALDH2) (P = 0.0039) and myosin regulatory light chain 2 (MYL2) (P < 1.0E-4). Our data suggest that the BRAP gene may confer vulnerability for SZ in Han Chinese population, adding further evidence for the involvement of developmental and/or neuroinflammatory cascades in the illness.