FUNCTIONAL IN SILICO ANALYSIS OF GENETIC VARIANTS FROM GENOME-WIDE ASSOCIATION STUDIES OF BLOOD PRESSURE AND HYPERTENSION

Abstract

Objective: Hypertension is a complex disease with a strong genetic component. Genome wide association studies (GWAS) have identified hundreds of variants associated with hypertension and its defining traits [systolic blood pressure(SBP), diastolic blood pressure(DBP), pulse pressure(PP)]. Our goal was to catalogue all sentinel variants identified by GWAS of hypertension and investigate their functional effects on transcription/translation in silico. Design and method: We compiled a list of all common (minor allele frequency >0.05) sentinel variants associated with SBP, DBP and PP in at least one GWAS at genome-wide level of statistical significance (P < 5x10-8). In silico analyses were conducted to characterise putative biological consequences of these variants at mRNA/protein level. All sentinel variants (and their statistical proxies) were characterised using Ensembl variant effect predictor (VEP) GRCh37 release 90 to identify effects on coding and non-coding exons. Data from the University of California Santa Cruz (UCSC) CpG islands was used to map variants to regulatory regions of open chromatin. Combined Annotation Dependent Depletion (CADD) scores quantified the overall genetic deleteriousness of variants. Results: A total of 892 variants were significantly associated with at least one BP-defining trait in GWAS. The effects of each allele copy of these variants on blood pressure ranged from 0.15–1.58mmHg (for SBP) and 0.09–0.81mmHg (for DBP). A total of 599 (67%) variants received at least one functional annotation. Only 92 (10.3%) variants led to missense changes in encoded proteins. A significant number of variants directly mapped to regulatory regions of active chromatin such as active enhancers and transcription start sites [258 (28.9%) and 225 (25.2%), respectively]. Only three variants [rs16859180 in the gene Serine/Threonine Kinase 36(STK36), rs328 in lipoprotein lipase(LPL) and rs11556924 in zinc finger C3HC-type protein 1(ZC3HC1)] had CADD scores >30 (placing them in the top 0.1% of most deleterious variants in the human genome). Conclusions: The majority of BP GWAS variants do not alter the amino-acid content of encoded proteins. A significant proportion are located within regions of regulatory importance to transcription, suggesting that many BP GWAS variants operate through quantitative effect on expression of key genes in specific cells and tissues.