Variants in LPA are associated with familial hypercholesterolaemia: whole genome sequencing analysis in the 100 000 Genomes Project

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.