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

Genome-wide association studies have discovered numerous genomic loci associated with Alzheimer's disease (AD); yet the causal genes and variants are incompletely identified. We performed an updated genome-wide AD meta-analysis, which identified 37 risk loci, including new associations near CCDC6, TSPAN14, NCK2 and SPRED2. Using three SNP-level fine-mapping methods, we identified 21 SNPs with >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 datasets and prioritization of genes by using protein interaction networks and tissue-specific expression. Combining this information into a quantitative score, we found that evidence converged on likely causal genes, including the above four genes, and those at previously discovered AD loci, including BINI, APHIB, PTK2B, PILRA and CASS4.

Automated summary

A genome-wide AD meta-analysis identified 37 risk loci, including new associations near CCDC6, TSPAN14, NCK2, and SPRED2. By fine-mapping SNPs and using functional annotation, 21 SNPs with >50% probability of being causally involved in AD risk were identified. Protein interaction networks and tissue-specific expression helped prioritize genes, leading to the discovery of likely causal genes.