P295: Detection of copy number variants by chromosome microarray vs exome sequencing at a single clinic over an eight year period

Methods: We develop a novel method to quantify individuals' total number of KIV-2 repeats from exome data, validate this quantification against measured Lp(a) levels, and then use this method, combined with a SNV-based genetic risk score, to genotype an entire all-comers cohort of individuals from health systems across the United States (Helix Research Network; N = 76,147) for an estimated Lp(a) level.Results: Our combined genotyping strategy improved prediction of those with clinically elevated Lp(a) measurements across the genetically diverse cohort, especially for individuals not genetically similar to European reference populations, where GRS-based estimates fall short (r2= 0.04 for GRS, r2 = 0.34 KIV2+GRS in non-European).Importantly, high combined genetic risk of high Lp(a) genotypes are significantly associated with earlier onset and increased incidence in ASCVD, compared to average and low combined genetic risk genotypes in a retrospective analysis of atherosclerotic diagnoses derived from electronic health records (EHRs).This holds in the cohort at large (CAD HRs=1.29,1.58), in the European subcohort (HRs=1.30,1.61)as well as at trending levels of significance in individuals not genetically similar to Europeans (HRs=1.22,1.31).In addition, high combined genetic risk for high Lp(a) genotypes are at least 2-fold enriched amongst individuals with ASCVD diagnosis despite a lack of EHR-based evidence of traditional risk factors for cardiovascular disease.Conclusion: Our study demonstrates that genetically predicted Lp(a) levels, incorporating both SNV and our novel KIV-2 repeat estimate, may be a practical method to predict clinically elevated Lp(a).Supporting this, individuals with high combined genetic risk for high Lp(a) have an increased risk for ASCVD, as evidenced across data from seven US-based health systems.