Convergent lines of evidence support BIN1 as a risk gene of Alzheimer's disease.

Genome-wide association studies (GWAS) have identified several susceptibility loci of Alzheimer's disease (AD), which were mainly located in noncoding regions of the genome. Meanwhile, the putative biological mechanisms underlying AD susceptibility loci were still unclear. At present, identifying the functional variants of AD pathogenesis remains a major challenge. Herein, we first used summary data-based Mendelian randomization (SMR) with AD GWAS summary and expression quantitative trait loci (eQTL) data to identify variants who affects expression levels of nearby genes and contributed to the risk of AD. Using the SMR integrative analysis, we totally identified 14 SNPs significantly affected the expression level of 16 nearby genes in blood or brain tissues and contributed to the AD risk. Then, to confirm the results, we replicated the GWAS and eQTL results across multiple samples. Totally, four risk SNP (rs11682128, rs601945, rs3935067, and rs679515) were validated to be associated with AD and affected the expression level of nearby genes (BIN1, HLA-DRA, EPHA1-AS1, and CR1). Besides, our differential expression analysis showed that the BIN1 gene was significantly downregulated in the hippocampus (P = 2.0 × 10-3) and survived after multiple comparisons. These convergent lines of evidence suggest that the BIN1 gene identified by SMR has potential roles in the pathogenesis of AD. Further investigation of the roles of the BIN1 gene in the pathogenesis of AD is warranted.