August 13, 2020Open Access
Genome-wide association analysis of pulse wave velocity traits provide new insights into the causal relationship between arterial stiffness and blood pressure
Key Result
A genome-wide association analysis identified a new locus for arterial stiffness near SLC4A7 on cytoband 3p24.1 (rs939834, p = 2.05x10-8) and demonstrated via Mendelian randomization that systolic blood pressure causally affects pulse wave velocity.
Study Design
Type
Observational (n=6,758)
Structured PICO
P
Population
6,758 adults aged 18 to 79 from a randomly sampled population-based study in Germany, assessed for pulse wave velocity and genetic associations.
O
Outcome
Genetic loci associated with carotid-femoral PWV (cfPWV), brachial-ankle (baPWV) and brachial-femoral (bfPWV), and causal relationship between PWV and blood pressuresurrogate
This GWAS identifies a novel genetic locus for arterial stiffness and uses Mendelian Randomization to demonstrate that systolic blood pressure causally increases pulse wave velocity.
Main Result
Effect estimate: β 0.058
p-value: p=2.05x10-8
Limitations
- Comparability of results with other studies is hampered by different technologies used for PWV assessment
- Power differs between phenotypes due to different sample sizes
- Further GWAS and meta-GWAS are required to identify further robust associations and corroborate candidates
Abstract
BACKGROUND: The pathophysiology of arterial stiffness is not completely understood. Pulse wave velocity (PWV) is an established marker for arterial stiffness. We compare genetics of three PWV modes, namely carotid-femoral PWV (cfPWV), brachial-ankle (baPWV) and brachial-femoral (bfPWV), reflecting different vascular segments to analyse association with genetic variants, heritability and genetic correlation with other biological traits. Furthermore we searched for shared genetic architecture concerning PWV, blood pressure (BP) and coronary artery disease (CAD) and examined the causal relationship between PWV and BP. METHODS AND RESULTS: We performed a genome-wide association study (GWAS) for cfPWV, baPWV and bfPWV in LIFE-Adult (N = 3,643-6,734). We analysed the overlap of detected genetic loci with those of BP and CAD and performed genetic correlation analyses. By bidirectional Mendelian Randomization, we assessed the causal relationships between PWV and BP. For cfPWV we identified a new locus with genome-wide significance near SLC4A7 on cytoband 3p24.1 (lead SNP rs939834: p = 2.05x10-8). We replicated a known PWV locus on cytoband 14q32.2 near RP11-61O1.1 (lead SNPs: rs17773233, p = 1.38x10-4; rs1381289, p = 1.91x10-4) For baPWV we estimated a heritability of 28% and significant genetic correlation with hypertension (rg = 0.27, p = 6.65x10-8). We showed a positive causal effect of systolic blood pressure on PWV modes (cfPWV: p = 1.51x10-4; bfPWV: p = 1.45x10-3; baPWV: p = 6.82x10-15). CONCLUSIONS: We identified a new locus for arterial stiffness and successfully replicated an earlier proposed locus. PWV shares common genetic architecture with BP and CAD. BP causally affects PWV. Larger studies are required to further unravel the genetic determinants and effects of PWV.