| Title: | 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 |
| Journal: | Arteriosclerosis Thrombosis and Vascular Biology |
| Published: | 2 Dec 2021 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/34852643/ |
| DOI: | https://doi.org/10.1161/atvbaha.121.317007 |
| URL: | https://www.ahajournals.org/doi/pdf/10.1161/ATVBAHA.121.317007 |
Publication 13822
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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.</p>
APPROACH AND RESULTS: We performed 3 genome-wide association studies in 45 185 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).</p>
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.</p>
10 Keywords
- Carotid Intima-Media Thickness
- Female
- Genetic Predisposition to Disease
- Genome-Wide Association Study
- Humans
- Male
- Polymorphism, Single Nucleotide
- Protein-Lysine 6-Oxidase
- Risk Factors
- Transcription Factors
9 Authors
- Ming Wai Yeung
- Siqi Wang
- Yordi J. van de Vegte
- Oleg Borisov
- Jessica van Setten
- Harold Snieder
- Niek Verweij
- M. Abdullah Said
- Pim van der Harst
1 Application
| Application ID | Title |
|---|---|
| 15031 | Genetic dissection of cardiovascular risk factors and their relation to disease to establish causality and identify novel targets of therapy |
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