Genome-wide meta-analysis, fine-mapping, and integrative prioritization implicate new Alzheimer’s disease risk genes

Genome-wide association studies (GWAS) have discovered numerous genomic loci associated with Alzheimer’s disease (AD), yet the causal genes and variants remain incompletely identified. We performed an updated genome-wide AD meta-analysis, which identified 37 risk loci, including novel associations near CCDC6, TSPAN14, NCK2, and SPRED2. Using three SNP-level fine-mapping methods, we identified 21 SNPs with greater than 50% probability each of being causally involved in AD risk, and others strongly suggested by functional annotation. We followed this with colocalization analyses across 109 gene expression quantitative trait loci (eQTL) datasets, and prioritization of genes using protein interaction networks and tissue-specific expression. Combining this information into a quantitative score, we find that evidence converges on likely causal genes, including the above four genes, and those at previously discovered AD loci, including BIN1, APH1B, PTK2B, PILRA, and CASS4.