Open AccessGenome-wide meta-analysis, fine-mapping and integrative prioritization implicate new Alzheimer’s disease risk genes
Author(s) -
Jeremy Schwartzentruber,
Sarah Cooper,
Yushi Liu,
Iñigo Barrio-Hernandez,
Erica Bello,
Natsuhiko Kumasaka,
Adam M. H. Young,
R. J. M. Franklin,
Toby Johnson,
Karol Estrada,
Daniel Gaffney,
Pedro Beltrão,
Andrew Bassett
Publication year - 2021
Publication title -
nature genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 18.861
H-Index - 573
eISSN - 1546-1718
pISSN - 1061-4036
DOI - 10.1038/s41588-020-00776-w
Subject(s) - biology , expression quantitative trait loci , genome wide association study , quantitative trait locus , genetics , genome , gene , single nucleotide polymorphism , computational biology , genetic association , snp , genotype
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 BIN1, APH1B, PTK2B, PILRA and CASS4.