Xavier Vanhoye (France)
GHE Hospices Civils of Lyon Department of Biochemistry and Molecular BiologyAuthor Of 1 Presentation
O012 - Evaluation of new Polygenic Risk Scores in the diagnosis of Familial Hypercholesterolemia (ID 830)
Abstract
Background and Aims
Whereas the identification of causal mutations leads to a molecular diagnosis of familial hypercholesterolemia (FH), it is now established that the cumulative effects of common SNPs on LDL-cholesterol (LDL-c) can phenocopy the FH conditions. Polygenic Risk Scores (PRSs) have been developed using few to millions of SNPs to identify patients with polygenic-FH. We here set up and compared the performance of several PRSs for the diagnosis of polygenic-FH.
Methods
Four PRSs for LDL-c were set up using PLINK, PRSice2, Lassossum and LDpred2 softwares, including 165 to 1633 SNPs sequenced using the Dysliseq panel. These PRSs were tested in 758 hypercholesterolemic patients, and 1082 French healthy controls and then compared with previously described PRSs. The fraction of LDL-c variance explained by PRSs was defined in controls and the ability of PRS to discriminate mutation negative patients (FH/M-) vs. healthy individuals was determined using ROC curves. Patients with PRSs > 95th percentile of controls were considered as polygenic-FH.
Results
The 165-SNP PRS developed with PLINK explains the highest part of LCL-c variance (adjusted R²: 0.187) and shows the best diagnosis ability (AUC: 0.759, significantly over performing previously-published PRSs: p-value < 1x10-5). Within FH/M- patients, 22% of polygenic forms were detected using this 165-SNP PRS versus 14% with the previously-published 12-SNP PRS (p-value: 5.41x10-5).
Conclusions
Notably, this new PRS improves the diagnosis ability and is compatible with routine genetic diagnosis. Indeed, the identification of polygenic-FH allows the etiologic diagnosis in FH/M- and the identification of an additional cause of hypercholesterolemia in FH/M+.
Presenter of 1 Presentation
O012 - Evaluation of new Polygenic Risk Scores in the diagnosis of Familial Hypercholesterolemia (ID 830)
Abstract
Background and Aims
Whereas the identification of causal mutations leads to a molecular diagnosis of familial hypercholesterolemia (FH), it is now established that the cumulative effects of common SNPs on LDL-cholesterol (LDL-c) can phenocopy the FH conditions. Polygenic Risk Scores (PRSs) have been developed using few to millions of SNPs to identify patients with polygenic-FH. We here set up and compared the performance of several PRSs for the diagnosis of polygenic-FH.
Methods
Four PRSs for LDL-c were set up using PLINK, PRSice2, Lassossum and LDpred2 softwares, including 165 to 1633 SNPs sequenced using the Dysliseq panel. These PRSs were tested in 758 hypercholesterolemic patients, and 1082 French healthy controls and then compared with previously described PRSs. The fraction of LDL-c variance explained by PRSs was defined in controls and the ability of PRS to discriminate mutation negative patients (FH/M-) vs. healthy individuals was determined using ROC curves. Patients with PRSs > 95th percentile of controls were considered as polygenic-FH.
Results
The 165-SNP PRS developed with PLINK explains the highest part of LCL-c variance (adjusted R²: 0.187) and shows the best diagnosis ability (AUC: 0.759, significantly over performing previously-published PRSs: p-value < 1x10-5). Within FH/M- patients, 22% of polygenic forms were detected using this 165-SNP PRS versus 14% with the previously-published 12-SNP PRS (p-value: 5.41x10-5).
Conclusions
Notably, this new PRS improves the diagnosis ability and is compatible with routine genetic diagnosis. Indeed, the identification of polygenic-FH allows the etiologic diagnosis in FH/M- and the identification of an additional cause of hypercholesterolemia in FH/M+.