Genetic architecture of heart failure with preserved versus reduced ejection fraction

Figures

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  Fig. 1. Study schema. Schematic diagram detailing datasets and analyses used in the study.

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  Fig. 2. Algorithm for phenotyping of cohorts for genetic analyses. Consort diagram describes the methodology utilized to accurately phenotype the case cohorts (unclassified HF, HFrEF, HFpEF, restrictive case definition of HFpEF) and controls included in the study from the Million Veteran Program.

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  Fig. 3. Genome-wide associations of HFrEF and HFpEF. Genome-wide significant loci association studies of HFpEF and HFrEF among non-Hispanic White veterans. Sentinel SNPs and the nearest mapped genes are shown. Y-axis shows chromosomal position. Sentinel SNPs and their nearest genes are shown. All tests were two-sided without adjustment for multiple comparisons. *: novel HF locus; #: unique locus in the HFrEF GWAS but not in the HF meta-analysis; dashed vertical line indicates genome-wide significance threshold (P = 5 × 10−8).

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  Fig. 4. Genetic associations between HFrEF/HFpEF risk variants and HF risk factors. The genetic associations were identified from published GWAS of HF risk factors. All tests were two-sided without adjustment for multiple comparisons. *Beta: beta coefficients for continuous risk factors, log (odds ratio) for binary risk factors, percent change in eGFR. CAD coronary artery disease, AFib atrial fibrillation, T2D type 2 diabetes, BMI body mass index, HDL high-density lipoprotein cholesterol, LDL low-density lipoprotein cholesterol, TC total cholesterol, TG triglycerides, SBP systolic blood pressure, DBP diastolic blood pressure, PP pulse pressure, eGFR estimated glomerular filtration rate.

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  Fig. 5. Mendelian randomization analysis of HF risk factors in relation to HFpEF and HFrEF. X-axis shows odds ratios (ORs), with error bars showing 95% confidence intervals. CAD coronary artery disease, AFib atrial fibrillation, T2D type 2 diabetes, BMI body mass index, HDL high-density lipoprotein cholesterol, LDL low-density lipoprotein cholesterol, TC total cholesterol, TG triglycerides, SBP systolic blood pressure, DBP diastolic blood pressure, PP pulse pressure, eGFR estimated glomerular filtration rate.

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  Fig. 6. Limited genetic discovery in HFpEF due to pathophysiological heterogeneity. All tests were two-sided without adjustment for multiple comparisons.