Twenty-Five Novel Loci for Carotid Intima-Media Thickness: A Genome-Wide Association Study in >45 000 Individuals and Meta-Analysis of >100 000 Individuals
Wai Yeung, Ming; Wang, Siqi; van de Vegte, Yordi J; Borisov, Oleg; van Setten, Jessica; Snieder, Harold; Verweij, Niek; Said, M Abdullah; van der Harst, Pim
(2022) Arteriosclerosis, Thrombosis, and Vascular Biology, volume 42, issue 4, pp. 484 - 501
(Article)
Abstract
Objective: Carotid artery intima-media thickness (cIMT) is a widely accepted marker of subclinical atherosclerosis. Twenty susceptibility loci for cIMT were previously identified and the identification of additional susceptibility loci furthers our knowledge on the genetic architecture underlying atherosclerosis. Approach and Results: We performed 3 genome-wide association studies in 45 185
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participants from the UK Biobank study who underwent cIMT measurements and had data on minimum, mean, and maximum thickness. We replicated 15 known loci and identified 20 novel loci associated with cIMT at P<5×10-8. Seven novel loci (ZNF385D, ADAMTS9, EDNRA, HAND2, MYOCD, ITCH/EDEM2/MMP24, and MRTFA) were identified in all 3 phenotypes. An additional new locus (LOXL1) was identified in the meta-analysis of the 3 phenotypes. Sex interaction analysis revealed sex differences in 7 loci including a novel locus (SYNE3) in males. Meta-analysis of UK Biobank data with a previous meta-analysis led to identification of three novel loci (APOB, FIP1L1, and LOXL4). Transcriptome-wide association analyses implicated additional genes ARHGAP42, NDRG4, and KANK2. Gene set analysis showed an enrichment in extracellular organization and the PDGF (platelet-derived growth factor) signaling pathway. We found positive genetic correlations of cIMT with coronary artery disease rg=0.21 (P=1.4×10-7), peripheral artery disease rg=0.45 (P=5.3×10-5), and systolic blood pressure rg=0.30 (P=4.0×10-18). A negative genetic correlation between average of maximum cIMT and high-density lipoprotein was found rg=-0.12 (P=7.0×10-4). Conclusions: Genome-wide association meta-analyses in >100 000 individuals identified 25 novel loci associated with cIMT providing insights into genes and tissue-specific regulatory mechanisms of proatherosclerotic processes. We found evidence for shared biological mechanisms with cardiovascular diseases.
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Keywords: Analysis, Carotid intima-media thickness, Genetics, Genome-wide association study, Meta, Population genetics, Cardiology and Cardiovascular Medicine, Journal Article
ISSN: 1079-5642
Publisher: Lippincott Williams and Wilkins
Note: Funding Information: We thank the CARDIoGRAMplusC4D (Coronary Artery Disease Genome-Wide Replication and Meta-Analysis Plus the Coronary Artery Disease Genetics), the GERA study (Genetic Epidemiology Research on Adult Health and Aging), GLGC (Global Lipids Genetics Consortium) and MEGASTROKE investigators for making their data publicly available. The MEGASTROKE project received funding from sources specified at http://www.megastroke.org/acknowledgments.html . We would like to thank the Centre for Information Technology of the University of Groningen for their support and for providing access to the Peregrine high-performance computing cluster. In addition, we thank Ruben N. Eppinga, MD, PhD, Tom Hendriks, MD, PhD, M. Yldau van der Ende, MD, PhD, Hilde E. Groot, MD, Jan Walter Benjamins, BEng, and Yanick Hagemeijer, MSc, University of Groningen, University Medical Center Groningen, Department of Cardiology, for their contributions to the extraction and processing of data in the UK Biobank. None of the mentioned contributors received compensation, except for their employment at the University Medical Center Groningen. Publisher Copyright: © 2022 American Heart Association, Inc.
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