A new 165-SNP low-density lipoprotein cholesterol polygenic risk score based on next generation sequencing outperforms previously published scores in routine diagnostics of familial hypercholesterolemia

Published:December 14, 2022DOI:


      Genetic diagnosis of familial hypercholesterolemia (FH) remains unexplained in 30 to 70% of patients after exclusion of monogenic disease. There is now a growing evidence that a polygenic burden significantly modulates LDL-cholesterol (LDL-c) concentrations. Several LDL-c polygenic risk scores (PRS) have been set up. However, the balance between their diagnosis performance and their practical use in routine practice is not clearly established. Consequently, we set up new PRS based on our routine panel for sequencing and compared their diagnostic performance with previously-published PRS. After a meta-analysis, four new PRS including 165 to 1633 SNP were setup using different softwares. They were established using two French control cohorts (MONA LISA n=1082 and FranceGenRef n=856). Then the explained LDL-c variance and the ability of each PRS to discriminate monogenic negative FH patients (M-) versus healthy controls were compared with 4 previously-described PRS in 785 unrelated FH patients. Between all PRS, the 165-SNP PRS developed with PLINK showed the best LDL-c explained variance (adjusted R²=0.19) and the best diagnosis abilities (AUROC=0.77, 95%CI=0.74-0.79): it significantly outperformed all the previously-published PRS (p<1 × 10−4). By using a cut-off at the 75th percentile, 61% of M- patients exhibited a polygenic hypercholesterolemia with the 165-SNP PRS versus 48% with the previously published 12-SNP PRS (p =3.3 × 10−6). These results were replicated using the UK biobank. This new 165-SNP PRS, usable in routine diagnosis, exhibits better diagnosis abilities for a polygenic hypercholesterolemia diagnosis. It would be a valuable tool to optimize referral for whole genome sequencing.

      List of human genes


      FH (familial hypercholesterolemia), LDL (low density lipoprotein), LDL-c (low density lipoprotein cholesterol), ASCVD (Atherosclerotic Cardiovascular Disease), SNP (single nucleotide polymorphism), GWAS (genome-wide association studies), PRS (polygenic risk scores), 2M-SNP (2 million SNP), NGS (next generation sequencing), FGR (FranceGenRef), CNIL (“Commission Nationale de l'Informatique et des Libertés”), DLCN (Dutch Lipid Clinic Network), ACMG (American College of Medical Genetics and Genomic), M+ (monogenic hypercholesterolemia), VUS (variant of uncertain significance), M- (mutation free patients), GLGC (Global Lipids Genetics Consortium), LD (linkage disequilibrium), ROC (receiver-operating characteristic), AUROC (Area under the ROC curve), WGS (Whole Genome Sequencing), CVD (cardio-vascular disease), Lp(a) (lipoprotein (a))
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