Importance of Genetic Studies of Cardiometabolic Disease in Diverse Populations

Abstract

Genome-wide association studies have revolutionized our understanding of the genetic underpinnings of cardiometabolic disease. Yet, the inadequate representation of individuals of diverse ancestral backgrounds in these studies may undercut their ultimate potential for both public health and precision medicine. The goal of this review is to describe the imperativeness of studying the populations who are most affected by cardiometabolic disease, to the aim of better understanding the genetic underpinnings of the disease. We support this premise by describing the current variation in the global burden of cardiometabolic disease and emphasize the importance of building a globally and ancestrally representative genetics evidence base for the identification of population-specific variants, fine-mapping, and polygenic risk score estimation. We discuss the important ethical, legal, and social implications of increasing ancestral diversity in genetic studies of cardiometabolic disease and the challenges that arise from the (1) lack of diversity in current reference populations and available analytic samples and the (2) unequal generation of health-associated genomic data and their prediction accuracies. Despite these challenges, we conclude that additional, unprecedented opportunities lie ahead for public health genomics and the realization of precision medicine, provided that the gap in diversity can be systematically addressed. Achieving this goal will require concerted efforts by social, academic, professional and regulatory stakeholders and communities, and these efforts must be based on principles of equity and social justice.

Keywords: cardiovascular diseases; genomics; global burden of disease; metabolic diseases; minority health; precision medicine; social justice.

Figure 1.

Participant Diversity in GWAS of Cardiometabolic Traits. Non-Europeans make up just 11% of GWAS of ischemic stroke, 17% of GWAS of chronic kidney disease, 20% of GWAS of Type 2 diabetes, and 24% of GWAS of hypertensive heart disease, and the vast majority of non-European GWAS participants are Asian. Trait definitions note: Ischemic Heart Disease included GWAS traits: Ischemic heart disease. Hypertensive Heart Disease definition included GWAS traits: hypertension, hypertension (young onset), and Medication use (antihypertensives). Ischemic Stroke definition included GWAS traits: Ischemic stroke, Ischemic stroke (cardioembolic), Ischemic stroke (large artery atherosclerosis), Ischemic stroke (non-cardioembolic), Ischemic stroke (small artery occlusion), Ischemic stroke (small-vessel), Ischemic stroke (undetermined subtype). Type 2 Diabetes definition included GWAS traits: Type 2 diabetes, Type 2 diabetes adjusted for BMI, prevalent Type 2 diabetes. Chronic Kidney Disease definition included GWAS traits: Chronic kidney disease, Incident chronic kidney disease, Renal function and chronic kidney disease, Chronic kidney disease and diabetic kidney disease in diabetes, Chronic kidney disease and diabetic kidney disease in type 2 diabetes, Chronic kidney disease in diabetes, Chronic kidney disease in type 2 diabetes, Chronic kidney disease (severe chronic kidney disease vs normal kidney function) in type 1 diabetes, Chronic kidney disease (chronic kidney disease vs normal or mildly reduced eGFR) in type 1 diabetes, Chronic kidney disease (reduced eGFR or end stage renal disease) in type 1 diabetes, Chronic kidney disease (end stage renal disease vs. normal eGFR) in type 1 diabetes. Data from https://gwasdiversitymonitor.com, accessed March 18, 2020.

Figure 2 A-B.

Global burden of ischemic heart disease Colors represent binned values of age-standardized disability adjusted life-years (DALYS) from ischemic heart disease per 100,000 population for females (Panel A) and males (Panel B). Data used for the figure was downloaded from the Institute for Health Metrics and Evaluation's Global Burden of Disease (GBD) Compare Data Visualization tool and is available at http://vizhub.healthdata.org/gbd-compare.

Figure 2 A-B.

Global burden of ischemic heart disease Colors represent binned values of age-standardized disability adjusted life-years (DALYS) from ischemic heart disease per 100,000 population for females (Panel A) and males (Panel B). Data used for the figure was downloaded from the Institute for Health Metrics and Evaluation's Global Burden of Disease (GBD) Compare Data Visualization tool and is available at http://vizhub.healthdata.org/gbd-compare.

Figure 3A-C.

Performance and distribution of Polygenic Risk Score (PRS) for obesity in PAGE participants. (A) The adjusted R² of the PRS developed by Khera and colleagues in PAGE participants, stratified by self-identified race/ethnicity. The risk scores were standardized by self-identified race/ethnicity and outliers beyond 4 standard deviations were removed for these analyses. (B) The performance of the PRS on obesity (BMI≥30kg/m²), stratified by self-identified race/ethnicity. The highest area under the curve was found in East and South Asian participants. (C) The distribution of obesity (BMI≥30kg/m²) by race/ethnicity-stratified decile of the PRS, demonstrating the differential distributions of obesity by race/ethnicity.