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Integrating human brain proteomes with genome-wide association data implicates new proteins in Alzheimer's disease pathogenesis.

TitleIntegrating human brain proteomes with genome-wide association data implicates new proteins in Alzheimer's disease pathogenesis.
Publication TypeJournal Article
Year of Publication2021
AuthorsWingo AP, Liu Y, Gerasimov ES, Gockley J, Logsdon BA, Duong DM, Dammer EB, Robins C, Beach TG, Reiman EM, Epstein MP, De Jager PL, Lah JJ, Bennett DA, Seyfried NT, Levey AI, Wingo TS
JournalNat Genet
Volume53
Issue2
Pagination143-146
Date Published2021 02
ISSN1546-1718
KeywordsAlzheimer Disease, Apolipoproteins E, Brain, Epoxide Hydrolases, Genome-Wide Association Study, Humans, Parkinson Disease, Polymorphism, Single Nucleotide, Proteome, Quantitative Trait Loci, Receptors, Virus, Sequence Analysis, RNA, Single-Cell Analysis
Abstract

Genome-wide association studies (GWAS) have identified many risk loci for Alzheimer's disease (AD), 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.

DOI10.1038/s41588-020-00773-z
Pubmed Linkhttps://www.ncbi.nlm.nih.gov/pubmed/33510477?dopt=Abstract
page_expoExternal
Alternate JournalNat Genet
PubMed ID33510477
PubMed Central IDPMC8130821
Grant ListU01 AG046152 / AG / NIA NIH HHS / United States
IK4 BX005219 / BX / BLRD VA / United States
R01 AG061800 / AG / NIA NIH HHS / United States
P30 AG066511 / AG / NIA NIH HHS / United States
U01 AG061356 / AG / NIA NIH HHS / United States
R01 AG053960 / AG / NIA NIH HHS / United States
R01 AG017917 / AG / NIA NIH HHS / United States
U01 AG061357 / AG / NIA NIH HHS / United States
P30 AG010161 / AG / NIA NIH HHS / United States
RC2 AG036547 / AG / NIA NIH HHS / United States
RF1 AG057470 / AG / NIA NIH HHS / United States
U01 MH115484 / MH / NIMH NIH HHS / United States
RF1 AG015819 / AG / NIA NIH HHS / United States
R01 AG056533 / AG / NIA NIH HHS / United States
I01 BX003853 / BX / BLRD VA / United States
R56 AG062256 / AG / NIA NIH HHS / United States
R56 AG062633 / AG / NIA NIH HHS / United States
R01 AG057911 / AG / NIA NIH HHS / United States
R56 AG060757 / AG / NIA NIH HHS / United States
P50 AG025688 / AG / NIA NIH HHS / United States
U24 NS072026 / NS / NINDS NIH HHS / United States
U01 AG046161 / AG / NIA NIH HHS / United States
P30 NS055077 / NS / NINDS NIH HHS / United States
R01 AG015819 / AG / NIA NIH HHS / United States

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