Whole-Genome Sequencing to Characterize Monogenic and Polygenic Contributions in Patients Hospitalized With Early-Onset Myocardial Infarction

Abstract

Background: The relative prevalence and clinical importance of monogenic mutations related to familial hypercholesterolemia and of high polygenic score (cumulative impact of many common variants) pathways for early-onset myocardial infarction remain uncertain. Whole-genome sequencing enables simultaneous ascertainment of both monogenic mutations and polygenic score for each individual.

Methods: We performed deep-coverage whole-genome sequencing of 2081 patients from 4 racial subgroups hospitalized in the United States with early-onset myocardial infarction (age ≤55 years) recruited with a 2:1 female-to-male enrollment design. We compared these genomes with those of 3761 population-based control subjects. We first identified individuals with a rare, monogenic mutation related to familial hypercholesterolemia. Second, we calculated a recently developed polygenic score of 6.6 million common DNA variants to quantify the cumulative susceptibility conferred by common variants. We defined high polygenic score as the top 5% of the control distribution because this cutoff has previously been shown to confer similar risk to that of familial hypercholesterolemia mutations.

Results: The mean age of the 2081 patients presenting with early-onset myocardial infarction was 48 years, and 66% were female. A familial hypercholesterolemia mutation was present in 36 of these patients (1.7%) and was associated with a 3.8-fold (95% CI, 2.1-6.8; P<0.001) increased odds of myocardial infarction. Of the patients with early-onset myocardial infarction, 359 (17.3%) carried a high polygenic score, associated with a 3.7-fold (95% CI, 3.1-4.6; P<0.001) increased odds. Mean estimated untreated low-density lipoprotein cholesterol was 206 mg/dL in those with a familial hypercholesterolemia mutation, 132 mg/dL in those with high polygenic score, and 122 mg/dL in those in the remainder of the population. Although associated with increased risk in all racial groups, high polygenic score demonstrated the strongest association in white participants ( P for heterogeneity=0.008).

Conclusions: Both familial hypercholesterolemia mutations and high polygenic score are associated with a >3-fold increased odds of early-onset myocardial infarction. However, high polygenic score has a 10-fold higher prevalence among patients presents with early-onset myocardial infarction.

Clinical trial registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00597922.

Keywords: genetics; humans; hypercholesterolemia; myocardial infarction; risk.

Figure 1.

Principal Components of Ancestry According to Race and Myocardial Infarction Status The first two principal components of ancestry are plotted according to race (A) and patient versus control status (B), confirming that the population were well matched with respect to genetic background. Additional details on principal components calculation are provided in the Supplementary Appendix.

Figure 2.. A four-exon deletion of LDLR identified by structural variant analysis of whole genome sequencing.

Visualization of copy-number estimates in 100 base pair sequential bins for 5,842 individuals with whole genome sequencing data available. Background shading represents the range of copy-number estimates from whole genome sequencing for the middle 50% and 90% of samples for the darker and lighter shades of gray, respectively. Points represent copy-number estimates per 100 base pair bin in the individual in whom a 7,889 base pair deletion encompassing four exons of LDLR was noted. The solid black line represents the rolling mean copy-number estimate in 1 kb windows. This variant is predicted to result in loss of function of the low-density lipoprotein receptor gene (LDLR) gene resulting in heterozygous familial hypercholesterolemia.

Figure 3.

Variation in Polygenic Score Distribution and Clinical Importance According to Race The distributions of the polygenic score across racial groups within 3,761 control participants are displayed based on raw values (A) and after adjustment for genetic ancestry using the first four principal components (B). Values were scaled to a mean of 0 and standard deviation of 1 to facilitate interpretation. We next determined the relationship between high polygenic score (top 5% of the distribution) and risk of early-onset myocardial infarction (C). Odds ratios were calculated using a logistic regression model adjusted for the first four principal components of ancestry. The clinical importance of high polygenic score varied across racial groupings (p-heterogeneity = 0.008). MI – myocardial infarction; OR – odds ratio; CI – confidence interval

Figure 4.

Polygenic Score Percentile Among Early-onset Myocardial Infarction Patients Versus Controls A reference distribution for polygenic score percentiles adjusted for genetic ancestry was constructed in the control population. Median polygenic score percentile among patients with early-onset myocardial infarction was in the 72^nd percentile of the distribution. Violin plots display the polygenic score percentile distribution in patients versus controls. Within the white boxplot insets, the horizontal line in each box indicates the median score, and the top and bottom of the boxes indicate the 75th and 25th percentiles, respectively.

Figure 5.

LDL Cholesterol according to Monogenic and Polygenic Risk Strata Among patients presenting with early-onset myocardial infarction, violin plots display the low-density lipoprotein (LDL) cholesterol distribution according to genetic risk category – only high polygenic score, only familial hypercholesterolemia (FH) mutation, both high polygenic score and familial hypercholesterolemia, or neither. Within the white boxplot insets, the horizontal line in each box indicates the median score, and the top and bottom of the boxes indicate the 75th and 25th percentiles, respectively.