The Contribution of GWAS Loci in Familial Dyslipidemias

Abstract

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.

Fig 1. Distributions of lipid levels in subsets of the Finnish general population and the FCH samples.

Distributions of (a) LDL-C and (b) TG are shown for the Finnish FINRISK population cohort (FINRISK all, blue), hyperlipidemic Finnish population samples (FINRISK hyperlipidemic, green), all FCH family members (FCH all, brown), affected family members (FCH affected, red), and proband individuals (FCH probands, purple). Hyperlipidemia in the population samples is defined as TC or TG ≥ 90^th age- and sex-specific population percentile, analogously with the FCH diagnostic criteria. In (b) the x-axis is cut at 9 mmol/l. FCH, familial combined hyperlipidemia; FINRISK, The National FINRISK Study.

Fig 2. Enrichment of LDL-C or TG associated SNPs in FCH affected individuals by their frequency and effect on LDL-C and TG levels.

Enrichment ratio is the ratio of the allele frequencies in the affected individuals (n = 234) to the allele frequencies in the Finnish FINRISK population cohort (n = 18,715). Only individuals without diabetes or other relevant confounders were included (S1 Text). Under the null hypothesis of no enrichment, a 95% credible interval (shaded area) was estimated by calculating the enrichment statistic (enrichment ratio) for all variants with MAF > 0.001% across the genome excluding the loci of the 212 SNPs. Variants are designated as either lipid level elevating (red) or lowering (blue) for (a) LDL-C and (b) TG based on β estimates from linear regression in the FINRISK samples. Point size and color intensity reflect the magnitude of the effect. Only SNPs with at least one heterozygous carrier are shown (n = 194). *The enrichment ratio for LPL rs1801177 fell within the 95% credible interval.

Fig 3. Number of affected and unaffected individuals with high polygenic lipid scores or carriers of high-impact Mendelian variants.

The black shading presents the number of (a) affected, and (b) unaffected individuals with high polygenic lipid scores (LDL-C, TG, or both polygenic scores over the 90^th percentile in the population) or carriers of a high-impact Mendelian variant (APOE ɛ2ɛ2, n = 2; or homozygosity for APOA5 rs3135506). The families are sorted by the number of affected individuals with high polygenic lipid scores or a high-impact Mendelian variant in (a). The grey shading presents the number of other (a) affected, and (b) unaffected individuals in the family.