Association analysis of a functional variant in ATXN2 with schizophrenia.

Schizophrenia (SZ) is a severe mental disorder characterized by multiple neurodevelopmental dysfunctions including a breakdown of thinking process and a deficit of typical emotional responses. Ataxin-2 (ATXN2) plays vital roles in cell proliferation and growth, and functional mutations of ATXN2 cause neurodegenerative phenotypes, including spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS). To explore the possible role of ATXN2 in SZ, we conducted a two-stage study to examine the association of ATXN2 polymorphisms with SZ in the Han Chinese population. Association analysis of seven SNPs in 768 patients and 1348 controls revealed two associated SNPs, including rs630511 (P=1.76E-4) and rs7969300 (P=5.08E-4). We examined these two SNPs in a validation sample of 1957 patients and 1509 controls, and observed an association of rs7969300 with SZ (P=5.03E-3). The SNP rs7969300 is a non-synonymous SNP causing a Ser to Asn substitution, which is predicted to increase the protein stability of ATXN2. Our data suggest that the ATXN2 gene may confer vulnerability for SZ, adding further evidence for the genetic variants within the developmental pathway in the illness.

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.