A polygenic biomarker to identify patients with severe hypercholesterolemia of polygenic origin

Mol Genet Genomic Med. 2020 Jun;8(6):e1248. doi: 10.1002/mgg3.1248. Epub 2020 Apr 19.


Background: Severe hypercholesterolemia (HC, LDL-C > 4.9 mmol/L) affects over 30 million people worldwide. In this study, we validated a new polygenic risk score (PRS) for LDL-C.

Methods: Summary statistics from the Global Lipid Genome Consortium and genotype data from two large populations were used.

Results: A 36-SNP PRS was generated using data for 2,197 white Americans. In a replication cohort of 4,787 Finns, the PRS was strongly associated with the LDL-C trait and explained 8% of its variability (p = 10-41 ). After risk categorization, the risk of having HC was higher in the high- versus low-risk group (RR = 4.17, p < 1 × 10-7 ). Compared to a 12-SNP LDL-C raising score (currently used in the United Kingdom), the PRS explained more LDL-C variability (8% vs. 6%). Among Finns with severe HC, 53% (66/124) versus 44% (55/124) were classified as high risk by the PRS and LDL-C raising score, respectively. Moreover, 54% of individuals with severe HC defined as low risk by the LDL-C raising score were reclassified to intermediate or high risk by the new PRS.

Conclusion: The new PRS has a better predictive role in identifying HC of polygenic origin compared to the currently available method and can better stratify patients into diagnostic and therapeutic algorithms.

Keywords: hypercholesterolemia; lipids; polygenic risk score; risk stratification.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Cholesterol, LDL / genetics
  • Female
  • Finland
  • Humans
  • Hypercholesterolemia / genetics*
  • Male
  • Middle Aged
  • Multifactorial Inheritance*
  • Polymorphism, Single Nucleotide*
  • United States


  • Cholesterol, LDL