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

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.


Population characteristics
Of the 100,453 participants included in the GWAS, the mean age (SD) was 53.7 (11) years, mean BMI was 23.7 (3.5) kg/m2, 57.2% were women and 4.2% reported a prior history of CVD.Overall, men had a higher prevalence of hypertension (i.e.SBP ≥140 mmHg or DBP ≥90 mmHg at baseline recruitment, or self-reported prior diagnosis by a physician) than women (41.5% vs 36.6%).Among those with self-reported hypertension, approximately one-third reported the use of blood-pressurelowering medication.

Recruitment
CKB recruitment is described in Chen et al., PMID: 22158673.

Ethics oversight
Ethical approval was obtained from the Ethical Review Committee of the Chinese Centre for Disease Control and Prevention (Beijing, China, 005/2004) and the Oxford Tropical Research Ethics Committee, University of Oxford (UK, 025-04), and all participants provided written informed consent.
Note that full information on the approval of the study protocol must also be provided in the manuscript.

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Sample size
The sample size of 100,453 CKB participants were used in GWAS, and the sample size of 90,415 participants were used in Mendelian randomization analyses Data exclusions Participants were excluded if they were not genotyped, BMI measurements were missing, any blood pressure trait data points were more than 5 SDs from the mean, and more then 5 SDs from the mean residuals.Genetic outliers within each study region and individuals with selfreported prior CVD were excluded from Mendelian randomization

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The genetic associations with different blood pressure measurements were replicated using publicly available summary statistics from independent cohorts of European ancestry (International Consortium of Blood Pressure) and Japanese ancestry (Biobank Japan).Novel associations were independently replicated by Biobank Japan using study design implemented in present study Randomization Randomization was not relevant to this study.Covariates were adjusted for in statistical models, and genetic analyses (Mendelian randomization) were performed to minimize potential residual confounding and reverse causation

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