Causal relevance of different blood pressure traits on risk of cardiovascular diseases: GWAS and Mendelian randomisation in 100,000 Chinese adults

Abstract

Elevated blood pressure (BP) is major risk factor for cardiovascular diseases (CVD). Genome-wide association studies (GWAS) conducted predominantly in populations of European ancestry have identified >2,000 BP-associated loci, but other ancestries have been less well-studied. We conducted GWAS of systolic, diastolic, pulse, and mean arterial BP in 100,453 Chinese adults. We identified 128 non-overlapping loci associated with one or more BP traits, including 74 newly-reported associations. Despite strong genetic correlations between populations, we identified appreciably higher heritability and larger variant effect sizes in Chinese compared with European or Japanese ancestry populations. Using instruments derived from these GWAS, multivariable Mendelian randomisation demonstrated that BP traits contribute differently to the causal associations of BP with CVD. In particular, only pulse pressure was independently causally associated with carotid plaque. These findings reinforce the need for studies in diverse populations to understand the genetic determinants of BP traits and their roles in disease risk.

Fig. 1. Overlap of associations across BMI-adjusted blood pressure traits.

a Venn diagram of associated loci across BMI-adjusted blood pressure traits. The numbers in brackets indicate the total number of loci associated with that BP phenotype. b Genetic correlation between the 4 traits as assessed by LD score regression.

Fig. 2. Comparisons of variant effect sizes of blood pressure traits between CKB and ICBP (BMI-adjusted) and between CKB and BBJ (BMI-unadjusted).

Comparisons of CKB with each of ICBP and BBJ used genome-wide significant variants identified in BBJ and ICBP, respectively. Variant per-allele effects are in mmHg. Dashed diagonal lines are the identity line (y = x). Solid lines are the Deming regression line forced through the origin. Source data are provided as a Source Data file.

Fig. 3. Mendelian randomisation of blood pressure traits with risk of major cardiovascular diseases and subclinical atherosclerosis.

Effects are shown as odds ratios (95% CI) for disease risk per 1 SD higher blood pressure (left panel) or per 5 mmHg higher blood pressure (right panel). F-statistic was calculated as the mean across CKB regions. SBP, systolic blood pressure; DBP, diastolic blood pressure; PP, pulse pressure; MAP, mean arterial pressure. Source data are provided as a Source Data file.

Fig. 4. Multivariable Mendelian randomisation of blood pressure traits with risk of major cardiovascular diseases and subclinical atherosclerosis.

Effects are shown as odds ratios (95% CI) per 1-SD higher blood pressure for (a) ischaemic stroke; (b) major coronary events; (c) intracerebral haemorrhage and (d) carotid plaque. Overlapping loci from two traits were merged and, in cases where there was more than one lead variant at a locus, the association with the lowest P-value was used to determine which variant to include when constructing the genetic scores. SBP systolic blood pressure, DBP diastolic blood pressure, PP pulse pressure, MAP mean arterial pressure, SV single variable MR, MV multi-variable MR. F-statistic was calculated as the mean across CKB regions. F-statistic for MV indicates the conditional F-statistic. Source data are provided as a Source Data file.