The Contribution of GWAS Loci in Familial Dyslipidemias

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 affected FCH individuals. The score based on TG associated SNPs was particularly high among affected individuals compared to non-affected family members. Out of 234 affected FCH individuals 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. The positive predictive value of high score was much higher for affected FCH individuals than for similar sporadic cases in the population. FCH is highly polygenic, supporting the hypothesis that variants across the whole allele frequency spectrum contribute to this complex familial trait. Polygenic SNP panels improve identification of individuals affected with FCH, but their clinical utility remains to be defined.
Author Summary Familial combined hyperlipidemia (FCH) is a familial dyslipidemia and the most common familial risk factor for premature coronary heart disease. Its genetic architecture is poorly understood. Rare high-impact variants have been identified in some patients, but have not explained a substantial portion of the trait. FCH has previously been speculated to be a polygenic disorder, but genetic data supporting this hypothesis have so far been incomplete. We provide experimental evidence for the polygenicity and heterogeneity of FCH in a large set of affected families using comprehensive genome-wide variant data. Approximately a third of the affected FCH individuals in our sample had high polygenic burden, and only a minority carried high-impact variants identifiable by genotyping. We show that the polygenic burden of affected FCH family members is comparable to that observed in individuals with similar lipid phenotypes in the general population. Genetic variants identified in large-scale population studies can also underlie the typical phenotypes observed in complex familial diseases such as FCH. Advances in genetic diagnosis based on population samples may thus also benefit FCH families. Families without high polygenic burden are good candidates for sequencing studies to identify rare variants not observable with genotyping.