Fig. 1 | Nature Communications

Fig. 1

From: Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries

Fig. 1

Schema of overall study design Analyses were stratified by phenotype, Lp(a) (mass) and Lp(a)-C, where available. Lp(a)-C analyses were performed using the following individuals with WGS data: 2284 individuals from the Estonian Biobank (EST) and 3418 individuals from Jackson Heart Study (JHS). Lp(a) mass analyses were performed using the same Jackson Heart Study participants, as well as array-derived genotypes from 27,344 Finnish FINRISK (FIN) individuals with imputation performed using 2690 FIN individuals with WGS and 5093 FIN individuals with WES. After quality control filters, 119,401,837 SNPs and 7,207,350 indels were discovered genome-wide across individuals analyzed. Structural variant discovery at the LPA locus was performed, finding KIV2-CN and eight additional rare CNVs. An imputation model was developed to impute KIV2-CN using 60 LPA locus variants. Three overarching analyses were subsequently performed: (1) Common variant analyses, (2) Rare variant analyses, and (3) Mendelian randomization. Among common and low-frequency variants with MAF > 0.1%, we performed single variant analysis, and separately, analyzed genetic modifiers of KIV2-CN’s effect on Lp(a) and Lp(a)-C concentrations. We also performed rare variant analyses, aggregating rare variants (MAF < 1%) in (1) coding sequence and (2) putative functional non-coding sequence, and associated with Lp(a)-C. Lastly, we performed Mendelian randomization, using different classes of variants associated with Lp(a) as genetic instruments and associating these with incident clinical cardiovascular events in FIN and prevalent subclinical atherosclerosis in JHS, MESA, FHS, and OOA. CNV copy number variant, EST Estonian biobank, FHS Framingham heart study, FIN FINRISK, JHS Jackson Heart Study, KIV2-CN kringle IV-2 copy number, Lp(a) lipoprotein(a), Lp(a)-C lipoprotein(a) cholesterol, MAF minor allele frequency, MESA Multi-ethnic study of atherosclerosis, MR Mendelian randomization, OOA Old-Order Amish