Open AccessGenome‐ and epigenome‐wide studies of plasma protein biomarkers for Alzheimer's disease implicate TBCA and TREM2 in disease risk
Author(s) -
Hillary Robert F.,
Gadd Danni A.,
McCartney Daniel L.,
Shi Liu,
Campbell Archie,
Walker Rosie M.,
Ritchie Craig W.,
Deary Ian J.,
Evans Kathryn L.,
NevadoHolgado Alejo J.,
Hayward Caroline,
Porteous David J.,
McIntosh Andrew M.,
Lovestone Simon,
Robinson Matthew R.,
Marioni Riccardo E.
Publication year - 2022
Publication title -
alzheimer's and dementia: diagnosis, assessment and disease monitoring
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.497
H-Index - 37
ISSN - 2352-8729
DOI - 10.1002/dad2.12280
Subject(s) - epigenetics , trem2 , epigenome , mendelian randomization , biology , disease , biomarker , dna methylation , genome wide association study , genetics , microvesicles , clusterin , bioinformatics , single nucleotide polymorphism , microrna , receptor , medicine , genotype , gene , gene expression , genetic variants , apoptosis , myeloid cells
The levels of many blood proteins are associated with Alzheimer's disease (AD) or its pathological hallmarks. Elucidating the molecular factors that control circulating levels of these proteins may help to identify proteins associated with disease risk mechanisms. Methods Genome‐wide and epigenome‐wide studies (n individuals ≤1064) were performed on plasma levels of 282 AD‐associated proteins, identified by a structured literature review. Bayesian penalized regression estimated contributions of genetic and epigenetic variation toward inter‐individual differences in plasma protein levels. Mendelian randomization (MR) and co‐localization tested associations between proteins and disease‐related phenotypes. Results Sixty‐four independent genetic and 26 epigenetic loci were associated with 45 proteins. Novel findings included an association between plasma triggering receptor expressed on myeloid cells 2 (TREM2) levels and a polymorphism and cytosine‐phosphate‐guanine (CpG) site within the MS4A4A locus. Higher plasma tubulin‐specific chaperone A (TBCA) and TREM2 levels were significantly associated with lower AD risk. Discussion Our data inform the regulation of biomarker levels and their relationships with AD.