Open AccessIntegrating human brain proteomes with genome-wide association data implicates new proteins in Alzheimer’s disease pathogenesis
Author(s) -
Aliza P. Wingo,
Yue Liu,
Ekaterina S. Gerasimov,
Jake Gockley,
Benjamin A. Logsdon,
Duc M. Duong,
Eric B. Dammer,
Chloe Robins,
Thomas G. Beach,
Eric M. Reiman,
Michael P. Epstein,
Philip L. De Jager,
James J. Lah,
David A. Bennett,
Nicholas T. Seyfried,
Aĺlan I. Levey
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/s41588-020-00773-z
Subject(s) - genome wide association study , mendelian randomization , biology , proteome , pathogenesis , genetic association , disease , genetics , computational biology , human genome , gene , genome , bioinformatics , single nucleotide polymorphism , medicine , immunology , genetic variants , genotype , pathology
Genome-wide association studies (GWAS) have identified many risk loci for Alzheimer's disease (AD) 1,2 , but how these loci confer AD risk is unclear. Here, we aimed to identify loci that confer AD risk through their effects on brain protein abundance to provide new insights into AD pathogenesis. To that end, we integrated AD GWAS results with human brain proteomes to perform a proteome-wide association study (PWAS) of AD, followed by Mendelian randomization and colocalization analysis. We identified 11 genes that are consistent with being causal in AD, acting via their cis-regulated brain protein abundance. Nine replicated in a confirmation PWAS and eight represent new AD risk genes not identified before by AD GWAS. Furthermore, we demonstrated that our results were independent of APOE e4. Together, our findings provide new insights into AD pathogenesis and promising targets for further mechanistic and therapeutic studies.