Summarizing polygenic risks for complex diseases in a clinical whole-genome report.

Journal Article (Journal Article)


Disease-causing mutations and pharmacogenomic variants are of primary interest for clinical whole-genome sequencing. However, estimating genetic liability for common complex diseases using established risk alleles might one day prove clinically useful.


We compared polygenic scoring methods using a case-control data set with independently discovered risk alleles in the MedSeq Project. For eight traits of clinical relevance in both the primary-care and cardiomyopathy study cohorts, we estimated multiplicative polygenic risk scores using 161 published risk alleles and then normalized them using the population median estimated from the 1000 Genomes Project.


Our polygenic score approach identified the overrepresentation of independently discovered risk alleles in cases as compared with controls using a large-scale genome-wide association study data set. In addition to normalized multiplicative polygenic risk scores and rank in a population, the disease prevalence and proportion of heritability explained by known common risk variants provide important context in the interpretation of modern multilocus disease risk models.


Our approach in the MedSeq Project demonstrates how complex trait risk variants from an individual genome can be summarized and reported for the general clinician and also highlights the need for definitive clinical studies to obtain reference data for such estimates and to establish clinical utility.

Full Text

Duke Authors

Cited Authors

  • Kong, SW; Lee, I-H; Leshchiner, I; Krier, J; Kraft, P; Rehm, HL; Green, RC; Kohane, IS; MacRae, CA; MedSeq Project,

Published Date

  • July 2015

Published In

Volume / Issue

  • 17 / 7

Start / End Page

  • 536 - 544

PubMed ID

  • 25341114

Pubmed Central ID

  • PMC4547452

Electronic International Standard Serial Number (EISSN)

  • 1530-0366

International Standard Serial Number (ISSN)

  • 1098-3600

Digital Object Identifier (DOI)

  • 10.1038/gim.2014.143


  • eng