DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation

Abstract

Genome-wide association studies have identified hundreds of genetic variants associated with blood pressure (BP), but sequence variation accounts for a small fraction of the phenotypic variance. Epigenetic changes may alter the expression of genes involved in BP regulation and explain part of the missing heritability. We therefore conducted a two-stage meta-analysis of the cross-sectional associations of systolic and diastolic BP with blood-derived genome-wide DNA methylation measured on the Infinium HumanMethylation450 BeadChip in 17,010 individuals of European, African American, and Hispanic ancestry. Of 31 discovery-stage cytosine-phosphate-guanine (CpG) dinucleotides, 13 replicated after Bonferroni correction (discovery: N = 9,828, p < 1.0 × 10; replication: N = 7,182, p < 1.6 × 10). The replicated methylation sites are heritable (h > 30%) and independent of known BP genetic variants, explaining an additional 1.4% and 2.0% of the interindividual variation in systolic and diastolic BP, respectively. Bidirectional Mendelian randomization among up to 4,513 individuals of European ancestry from 4 cohorts suggested that methylation at cg08035323 (TAF1B-YWHAQ) influences BP, while BP influences methylation at cg00533891 (ZMIZ1), cg00574958 (CPT1A), and cg02711608 (SLC1A5). Gene expression analyses further identified six genes (TSPAN2, SLC7A11, UNC93B1, CPT1A, PTMS, and LPCAT3) with evidence of triangular associations between methylation, gene expression, and BP. Additional integrative Mendelian randomization analyses of gene expression and DNA methylation suggested that the expression of TSPAN2 is a putative mediator of association between DNA methylation at cg23999170 and BP. These findings suggest that heritable DNA methylation plays a role in regulating BP independently of previously known genetic variants.

Associations between high blood pressure and DNA methylation

“…The effect sizes were heterogeneous for the majority of associations but the magnitude of difference between two studies was small. cg19693031 (near TXNIP) and cg18120259 (in gene body LOC100132354), found within the top hundred CpG sites of the trans-ancestry EWAS of SBP in our analyses, were among the 126 previously reported associations [16]. The direction of effect was consistent with the previous analysis and the magnitude of association was slightly larger in our study.…”

“…We looked up 126 associations reported earlier [16] that also appeared in the trans-ancestry EWAS of SBP and DBP in our study (Table Y in S1 File). The evidence of associations for these sites was generally weaker in our study.…”

DNA methylation modules associate with incident cardiovascular disease and cumulative risk factor exposure

“…Thus, our models replicate previous findings that cumulative risk factor exposure correlates with CVD risk [43] while suggesting that brown methylation module activation may be sensing, rather than mediating, this effect. One concrete example supporting this observation is the DMR near SLC1A5 containing primarily brown CpGs, one of which (cg02711608) was suggested in Mendelian randomization analysis to be causally downstream of blood pressure [30].…”

“…Another region discovered was on chromosome 19 near the transcription start site (TSS) of SLC1A5, which codes for a neutral amino acid transporter. Though strong evidence does not yet exist linking SLC1A5 to cardiovascular mechanisms, its CpGs have shown associations with diabetes, blood pressure, and mortality [29][30][31], and we note that its companion amino acid transporter, SLC7A5, is known to regulate metabolic and inflammatory reprogramming of monocytes in response to stimulation by lipopolysaccharide (LPS). Notably, CpG sites in both SLC9A1 and SLC1A5 were discovered and replicated in a recent EWAS for BMI (including the FHS cohort) [32], though that specific SLC9A1 site was not one of the three constituent CpGs in the region found here.…”

Methylome-Wide Association Study of Central Adiposity Implicate Genes Involved in Immune and Endocrine Systems

“…Interestingly, there are no cardiometabolic GWAS associations for T2D near this CpG and no cis-meQTL (methylation quantitative locus) either [43]. However, recent investigations implicate cg19693031 methylation as a mediator between early life famine and adult metabolic disease [46], indicating the relationship between methylation at this site and cardiometabolic disease may be driven through environmental exposures.…”