Identification of the primate-specific gene BTN3A2 as an additional schizophrenia risk gene in the MHC loci.

Background: Schizophrenia is a complex mental disorder resulting in poor life quality and high social and economic burden. Despite the fact that genome-wide association studies (GWASs) have successfully identified a number of risk loci for schizophrenia, identifying the causal genes at the risk loci and elucidating their roles in disease pathogenesis remain major challenges.

Methods: The summary data-based Mendelian randomization analysis (SMR) was used to integrate a large-scale GWAS of schizophrenia with brain expression quantitative trait loci (eQTL) data and brain methylation expression quantitative trait loci (meQTL) data, to identify novel risk gene(s) for schizophrenia. We then analyzed the mRNA expression and methylation statuses of the gene hit BTN3A2 during the early brain development. Electrophysiological analyses of CA1 pyramidal neurons were performed to evaluate the excitatory and inhibitory synaptic activity after overexpression of BTN3A2 in rat hippocampal slices. Cell surface binding assay was used to test the interaction of BTN3A2 and neurexins.

Findings: We identified BTN3A2 as a potential risk gene for schizophrenia. The mRNA expression and methylation data showed that BTN3A2 expression in human brain is highest post-natally. Further electrophysiological analyses of rat hippocampal slices showed that BTN3A2 overexpression specifically suppressed the excitatory synaptic activity onto CA1 pyramidal neurons, most likely through its interaction with the presynaptic adhesion molecule neurexins.

Interpretation: Increased expression of BTN3A2 might confer risk for schizophrenia by altering excitatory synaptic function. Our result constitutes a paradigm for distilling risk gene using an integrative analysis and functional characterization in the post-GWAS era. FUND: This study was supported by the Strategic Priority Research Program (B) of the Chinese Academy of Sciences (XDB02020003 to Y-GY), the National Natural Science Foundation of China (31730037 to Y-GY), and the Bureau of Frontier Sciences and Education, Chinese Academy of Sciences (QYZDJ-SSW-SMC005 to Y-GY).