Genome‐wide pleiotropy analysis identifies novel blood pressure variants and improves its polygenic risk scores

Figures

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  Figure 1. Blood pressure (BP) path diagram in Mendelian randomization and horizontal pleiotropic analysis, which corresponds to the model (1). To declare horizontal pleiotropy, we require both γ1≠0 and γ2≠ 0. β and β′ are the mutual direct causal effects between γ1 and γ2. DBP, diastolic BP; G, genetic instrumental variable; SBP, systolic BP; U, confounding factors

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  Figure 2. Manhattan and QQ plots for genome‐wide pleiotropy tests between SBP and DBP using UK Biobank‐ICBP summary statistics. The GWAS of pleiotropy tests is equivalent to performing GWAS for two new traits: BPpleio1 = DBP −β × SBP and BPpleio2 = SBP −β′ × DBP, where β and β′ are the estimated causal effects of SBP on DBPand DBP on SBP, respectively. (a, b) Manhattan and QQ plots for BPpleio2. (c, d) Manhattan and QQ plots for BPpleio1. DBP, diastolic BP; GWAS; genome‐wide association studies; ICBP, International Consortium for Blood Pressure; SBP, systolic BP; The horizontal line in Manhattans represents p = 5 × 10−8. The top and bottom Manhattan plots are highly similar, indicating the consistency of the two‐directional Mendelian Randomization analysis

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  Figure 3. Comparison between the systolic blood pressure (SBP) and Diastolic blood pressure (DBP) effect sizes for mediation (black dots) and pleiotropic (red dots) variants in UK Biobank‐International Consortium for Blood Pressure

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  Figure 4. Comparison between the effect sizes between UKB‐ICBP and MVP. (a) SBP effect sizes of mediation variants. (b) DBP effect sizes of mediation variants. (c) BPpleio1 effect sizes for pleiotropic variants. (d) BPpleio2 effect sizes for pleiotropic variants. The two variants rs113081691 and rs17057329 in the red circles in (a) and (b) represent substantial different effect sizes of SBP and DBP between UKB‐ICBP and MVP, likely driven by multi‐ethnic samples from MVP. DBP, diastolic blood pressure; ICBP, International Consortium for Blood Pressure; MVP, Million Veteran Program; SBP, systolic blood pressure; UKB, UK Biobank.

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  Figure 5. Relationship the core genetic risk score (cGRS) and pleiotropic genetic risk score (pGRS) with blood pressure (BP), risk of hypertension (HTN), and cardiovascular disease (CVD) in UK Biobank. (a) Sex‐adjusted mean systolic BP (SBP); (b) sex‐adjusted mean diastolic BP (DBP); (c) odds ratios of HTN; (d) odds ratios of CVD. cGRS was calculated in every decile and pGRS was calculated in every quintile. Odds ratios were calculated by comparing each of the cGRS deciles and pGRS quintiles with the lowest decile and 20th. The curves with pGRS = 0 represent the models without including pGRS