Browsing by Subject "family"

Familial combined hyperlipidemia (FCH) is a complex and common familial dyslipidemia characterized by elevated total cholesterol and/or triglyceride levels with over five-fold risk of coronary heart disease. The genetic architecture and contribution of rare Mendelian and common variants to FCH susceptibility is unknown. In 53 Finnish FCH families, we genotyped and imputed nine million variants in 715 family members with DNA available. We studied the enrichment of variants previously implicated with monogenic dyslipidemias and/or lipid levels in the general population by comparing allele frequencies between the FCH families and population samples. We also constructed weighted polygenic scores using 212 lipid-associated SNPs and estimated the relative contributions of Mendelian variants and polygenic scores to the risk of FCH in the families. We identified, across the whole allele frequency spectrum, an enrichment of variants known to elevate, and a deficiency of variants known to lower LDL-C and/or TG levels among both probands and FCH affecteds. The score based on TG associated SNPs was particularly high among affected individuals compared to non-affected family members. Out of 234 FCH affecteds across the families, seven (3 %) carried Mendelian variants and 83 (35 %) showed high accumulation of either known LDL-C or TG elevating variants by having either polygenic score over the 90th percentile in the population. There was large between-family variation in how much the polygenic scores contributed to the FCH phenotype. FCH is highly polygenic, supporting the hypothesis that variants across the whole allele frequency spectrum contribute to this complex familial trait. This reinforces the clinical tenet that FCH is a cluster of overlapping genetic defects instead of an etiologically homogenous disease entity.