Abstract

Aims Familial hypercholesterolaemia (FH) is an inherited disease of high LDL cholesterol (LDL-C) caused by defects in LDLR, APOB, APOE, and PCSK9 genes. A pathogenic variant cannot be found in ∼60% of clinical FH patients. Using whole genome sequencing (WGS), we examined genetic determinants of FH. Methods and results Whole genome sequencing data generated by the 100 000 Genomes Project (100KGP) included 536 FH patients diagnosed using the FH Simon–Broome criteria. Rare variants in known FH genes were analysed. Genome-wide association study between 443 FH variant-negative unrelated FH cases and 77 275 control participants of the 100KGP was run using high-coverage WGS data. Polygenic risk scores for LDL-C (LDL PRS) and lipoprotein(a) (Lp(a) PRS) were computed. An FH-causing variant was found in 17.4% of FH cases. Genome-wide association study identified the LPA gene locus being significantly associated (P < 1 × 10−8). Familial hypercholesterolaemia variant-negative participants had higher LDL and Lp(a) PRSs in comparison with the controls (P < 1.0 × 10−16 and P < 4.09 × 10−6, respectively). Similar associations were found in the monogenic FH with both LDL and Lp(a) PRSs being higher than in controls (P < 4.03 × 10−4 and P < 3.01 × 10−3, respectively). High LDL PRS was observed in 36.4% of FH variant-negative cases, whereas high Lp(a) PRS in 18.5%, with 7.0% having both high LDL and Lp(a) PRSs. Conclusion This genome-wide analysis of monogenic and polygenic FH causes confirms a complex and heterogeneous architecture of hypercholesterolaemia, with the LPA gene playing a significant role. Both Lp(a) and LDL-C should be measured for precision FH diagnosis. Specific therapies to lower Lp(a) should be targeted to those who will benefit most.