Author:
Ohlei Olena,Sommerer Yasmine,Dobricic Valerija,Homann Jan,Deecke Laura,Schilling Marcel,Bartrés-Faz David,Cattaneo Gabriele,Düzel Sandra,Fjell Anders M.,Lindenberger Ulman,Pascual-Leone Álvaro,Sabet Sanaz Sedghpour,Solé-Padullés Cristina,Tormos Josep M.,Vetter Valentin M.,Walhovd Kristine B.,Wesse Tanja,Wittig Michael,Franke Andre,Demuth Ilja,Lill Christina M.,Bertram Lars
Abstract
AbstractDNA methylation (DNAm) is an epigenetic mark with essential roles in disease development and predisposition. Here, we created genome-wide maps of methylation quantitative trait loci (meQTL) in three peripheral tissues and used Mendelian randomization (MR) analyses to assess the potential causal relationships between DNAm and risk for two common neurodegenerative disorders, i.e. Alzheimer’s disease (AD) and Parkinson’s disease (PD). Genome-wide single nucleotide polymorphism (SNP; ∼5.5M sites) and DNAm (∼850K CpG sites) data were generated from whole blood (n=1,058), buccal (n=1,527) and saliva (n=837) specimens. We identified between 11 and 15 million genome-wide significant (p<10-14) SNP-CpG associations in each tissue. Combining these meQTL GWAS results with recent AD/PD GWAS summary statistics by MR strongly suggests that the previously described associations betweenPSMC3,PICALM, andTSPAN14and AD may be founded on differential DNAm in or near these genes. In addition, there is strong, albeit less unequivocal, support for causal links between DNAm atPRDM7in AD as well as atKANSL1/MAPTin AD and PD. Our study adds valuable insights on AD/PD pathogenesis by combining two high-resolution “omics” domains, and the meQTL data shared along with this publication will allow like-minded analyses in other diseases.
Publisher
Cold Spring Harbor Laboratory