Carotid intima-media thickness in UK Biobank: Identification of novel genome-wide loci, sex-specific effects and genetic correlations with obesity and glucometabolic traits

Abstract

Objectives: Atherosclerosis is the underlying cause of most cardiovascular disease, but mechanisms underlying atherosclerosis are incompletely understood. Ultrasound measurement of the carotid artery intima-media thickness (cIMT) can be used to measure vascular remodelling, which is indicative of atherosclerosis. Genomewide association studies have identified a number of genetic loci associated with cIMT, but heterogeneity of measurements collected by many small cohorts have been a major limitation in these efforts. Here we conducted genome-wide association analyses in UK Biobank (N=22,179), the largest single study with consistent cIMT measurements.Approach and results: We used BOLT-LMM to run linear regression of cIMT in UK Biobank, adjusted for age, sex, genotyping platform and population structure. In white British participants, we identified 4 novel loci associated with cIMT and replicated most previously reported loci. In the first sex-specific analyses of cIMT, we identified a female-specific locus on Chromosome 5, associated with cIMT in women only and highlight VCAN as a good candidate gene at this locus. Genetic correlations with body-mass index and glucometabolic traits were also observed.Conclusion: These findings replicate previously reported associations, highlight novel biology and provide new directions for investigating the sex differences observed in cardiovascular disease presentation and progression.Genotyping DNA was extracted from blood samples provided by participants, using standard protocols. Details of the UKB genotyping and imputation procedures have been described previously 12,13 . Briefly, the full genetic data release (March 2018) was used for this study. Genotyping, pre-imputation quality control, imputation and post-imputation quality control were conducted centrally by UKB, according to standard procedures. Statistical analysesDescriptive statistics and Spearmans rank correlations were conducted using Stata.Only individuals of white British ancestry were included in the GWAS to maximise homogeneity. BOLT-LMM was used to conduct genetic association analyses, to calculate heritability estimates and estimates of λGC. IMTmean and IMTmax values were natural logarithm-transformed for normality and genetic association analyses were conducted, adjusted for age, sex and genotyping array (primary analysis) or age and genotyping array (secondary analyses). SNPs were excluded if minor allele frequency <0.01, Hardy-Weinberg equilibrium p<1x10 -6 or imputation score <0.3. Genome-wide significance was set at p<5x10 -8 , with suggestive evidence of association being set at p<1x10 -5 . After quality control there were 22,179 participants with IMT and genetic data for analysis.Genetic association results were visualised using FUMA 14 and LocusZoom 15 . Linkage disequilibrium and genetic correlationsLinkage disequilibrium (LD) between analysed SNPs in each GWAS-significant locus was calculated and visualised in a random subset of 10000 white British individuals (or 5000 individuals where the locus ...

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

“…We replicated all SNPs associated with cIMT mean , and all except one (rs11025608) for cIMT max in a previous GWAS that used a proportion of the current UK Biobank samples. 13 We also confirmed 7 of 11 loci that were identified in the CHARGE/UCLEB consortia meta-analysis, including 31 studies with various study designs. 12 These include variants at ATP6AP1L, MCPH1, SGK223 (moderate LD of 0.267 between the 2 lead variants rs11785239 and rs2980478 near ZNF705B identified in the current analysis), ZHX2 , PINX1, CBFA2T3 , and APOE.…”

“…Two loci 5q14.2 ( VCAN, HAPLN1 ) and 8p23.1 ( MCPH1 ) have been reported in previous sex-stratified analysis on cIMT mean. 13 Among the 5 new loci, 17p12 ( MAP2K4 / MYOCD ) were significantly associated with cIMT mean and cIMT max in females only, whereas associations at 14q32.13 ( SYNE3 ) and the 3 loci at 8p23.1 ( SOX7, GATA4/C8orf49, ZNF705B ) were only significant in males.…”

“…Summary data-based Mendelian randomization analysis also identified SVIL which was first reported in a previous GWAS. 13…”

Association Study of Genetic Variants in Calcium Signaling-Related Genes With Cardiovascular Diseases

“…Moreover, participants with GG genotype had a prolonged QRS duration compared to those with CC genotype (89.00 ± 14.01 vs. 88.48 ± 14.44 ms) ( Supplementary Table 7 ), which was in accordance with the notion that each copy of C allele in rs4074536 was associated with less than 1 ms shortening of QRS duration ( Sotoodehnia et al, 2010 ). Interestingly, our PheWAS approach revealed that rs4484922 showed nominal evidence of association with multiple parameters of carotid intima-medial thickness (cIMT) ultrasound measurement ( Supplementary Table 7 ), and the elevated cIMT observed in individuals with CC genotype may increase the risk of atherosclerosis, which is an underlying cause of multiple CVDs ( Strawbridge et al, 2020 ).…”

Comparison Analysis of Childhood Body Mass Index Cut-offs in Predicting Adulthood Carotid Intima Media Thickness: Tehran Lipid and Glucose Study

“…Carotid intima-media thickness (CIMT) evaluation is a noninvasive and sensitive technique in detection and quantification of subclinical atherosclerosis (7). Also, CIMT is considered as a predictive factor of cardiovascular incidents.…”