Predictive Utility of Polygenic Risk Scores for Coronary Heart Disease in Three Major Racial and Ethnic Groups

Abstract

Because polygenic risk scores (PRSs) for coronary heart disease (CHD) are derived from mainly European ancestry (EA) cohorts, their validity in African ancestry (AA) and Hispanic ethnicity (HE) individuals is unclear. We investigated associations of "restricted" and genome-wide PRSs with CHD in three major racial and ethnic groups in the U.S. The eMERGE cohort (mean age 48 ± 14 years, 58% female) included 45,645 EA, 7,597 AA, and 2,493 HE individuals. We assessed two restricted PRSs (PRS_Tikkanen and PRS_Tada; 28 and 50 variants, respectively) and two genome-wide PRSs (PRS_metaGRS and PRS_LDPred; 1.7 M and 6.6 M variants, respectively) derived from EA cohorts. Over a median follow-up of 11.1 years, 2,652 incident CHD events occurred. Hazard and odds ratios for the association of PRSs with CHD were similar in EA and HE cohorts but lower in AA cohorts. Genome-wide PRSs were more strongly associated with CHD than restricted PRSs were. PRS_metaGRS, the best performing PRS, was associated with CHD in all three cohorts; hazard ratios (95% CI) per 1 SD increase were 1.53 (1.46-1.60), 1.53 (1.23-1.90), and 1.27 (1.13-1.43) for incident CHD in EA, HE, and AA individuals, respectively. The hazard ratios were comparable in the EA and HE cohorts (p_interaction = 0.77) but were significantly attenuated in AA individuals (p_interaction= 2.9 × 10^-3). These results highlight the potential clinical utility of PRSs for CHD as well as the need to assemble diverse cohorts to generate ancestry- and ethnicity PRSs.

Keywords: African American; coronary artery disease; coronary heart disease; genome-wide polygenic score; hispanic; ischemic heart disease; multiethnic; polygenic risk scores; risk prediction.

Figure 1

Cumulative Risk of CHD by PRS_metaGRS in Three Racial and Ethnic Groups Cumulative risk of CHD by tertiles of PRS_metaGRS in European ancestry (EA), African ancestry (AA), and Hispanic ethnicity (HE) cohorts, represented by the colors blue (left), orange (middle), and purple (right), respectively. Shaded regions denote 95% confidence intervals.

Figure 2

Distributions of the Absolute CHD Risk Predicted by PRS_metaGRS in EA and AA Individuals Distributions of predicted 10-year absolute risk of MI based on PRS_metaGRS in EA and AA participants aged 35–74 years. (A) shows distribution of risk in men, whereas (B) shows the distribution of risk in women. Dotted vertical lines represent commonly accepted risk thresholds for statin therapy (≥7.5% and ≥10% 10-year absolute CHD risk).

Figure 3

Reclassification of CHD Risk Category by PRS_metaGRS in EA and AA Individuals Reclassification rates after incorporating PRS_metaGRS in individuals aged 35–74 and at intermediate 10-year risk of MI (5%–7.5%) calculated on the basis of age, sex, race- and ethnicity-specific incidence of MI, and corresponding non-CHD mortality rates as competing risks. Note: Conventional CHD risk factors (other than age and sex) were not included in the risk estimates.