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Genetic control of the human brain proteome.

TitleGenetic control of the human brain proteome.
Publication TypeJournal Article
Year of Publication2021
AuthorsRobins C, Liu Y, Fan W, Duong DM, Meigs J, Harerimana NV, Gerasimov ES, Dammer EB, Cutler DJ, Beach TG, Reiman EM, De Jager PL, Bennett DA, Lah JJ, Wingo AP, Levey AI, Seyfried NT, Wingo TS
JournalAm J Hum Genet
Volume108
Issue3
Pagination400-410
Date Published2021 03 04
ISSN1537-6605
KeywordsAutopsy, Brain, Female, Gene Expression Regulation, Genetic Variation, Genome-Wide Association Study, Genotype, Humans, Male, Proteome, Proteomics, Quantitative Trait Loci, RNA, Messenger, Transcriptome
Abstract

We generated an online brain pQTL resource for 7,376 proteins through the analysis of genetic and proteomic data derived from post-mortem samples of the dorsolateral prefrontal cortex of 330 older adults. The identified pQTLs tend to be non-synonymous variation, are over-represented among variants associated with brain diseases, and replicate well (77%) in an independent brain dataset. Comparison to a large study of brain eQTLs revealed that about 75% of pQTLs are also eQTLs. In contrast, about 40% of eQTLs were identified as pQTLs. These results are consistent with lower pQTL mapping power and greater evolutionary constraint on protein abundance. The latter is additionally supported by observations of pQTLs with large effects' tending to be rare, deleterious, and associated with proteins that have evidence for fewer protein-protein interactions. Mediation analyses using matched transcriptomic and proteomic data provided additional evidence that pQTL effects are often, but not always, mediated by mRNA. Specifically, we identified roughly 1.6 times more mRNA-mediated pQTLs than mRNA-independent pQTLs (550 versus 341). Our pQTL resource provides insight into the functional consequences of genetic variation in the human brain and a basis for novel investigations of genetics and disease.

DOI10.1016/j.ajhg.2021.01.012
Pubmed Linkhttps://www.ncbi.nlm.nih.gov/pubmed/33571421?dopt=Abstract
page_expoExternal
Alternate JournalAm J Hum Genet
PubMed ID33571421
PubMed Central IDPMC8008492
Grant ListU01 AG046152 / AG / NIA NIH HHS / United States
U01 MH115484 / MH / NIMH NIH HHS / United States
U01 AG057195 / AG / NIA NIH HHS / United States
R01 AG017917 / AG / NIA NIH HHS / United States
R56 AG062633 / AG / NIA NIH HHS / United States
U01 AG061357 / AG / NIA NIH HHS / United States
T32 NS007480 / NS / NINDS NIH HHS / United States
RF1 AG051633 / AG / NIA NIH HHS / United States
U24 NS072026 / NS / NINDS NIH HHS / United States
P30 AG019610 / AG / NIA NIH HHS / United States
U01 AG061356 / AG / NIA NIH HHS / United States
U01 AG032984 / AG / NIA NIH HHS / United States
R01 AG056533 / AG / NIA NIH HHS / United States
R01 AG030146 / AG / NIA NIH HHS / United States
I01 BX003853 / BX / BLRD VA / United States
R56 AG062256 / AG / NIA NIH HHS / United States
R01 AG036042 / AG / NIA NIH HHS / United States
P30 AG010161 / AG / NIA NIH HHS / United States
R56 AG060757 / AG / NIA NIH HHS / United States
P50 AG025688 / AG / NIA NIH HHS / United States
R01 AG036836 / AG / NIA NIH HHS / United States
R01 AG015819 / AG / NIA NIH HHS / United States

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