title: Summarizing polygenic risks for complex diseases in a clinical whole-genome report.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 1] Children's Hospital Informatics Program, Department of Medicine, Boston Children's Hospital, Boston, Massachusetts, USA [2] Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Sek Won
authors.identifier: 0000000348777567
authors.initials: SW
authors.lastname: Kong
authors.affiliation: 1] Children's Hospital Informatics Program, Department of Medicine, Boston Children's Hospital, Boston, Massachusetts, USA [2] Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: In-Hee
authors.initials: IH
authors.lastname: Lee
authors.affiliation: 1] Harvard Medical School, Boston, Massachusetts, USA [2] Genetics Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Ignaty
authors.identifier: 0000000189429265
authors.initials: I
authors.lastname: Leshchiner
authors.affiliation: 1] Harvard Medical School, Boston, Massachusetts, USA [2] Genetics Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Joel
authors.initials: J
authors.lastname: Krier
authors.affiliation: 1] Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA [2] Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA.
authors.forename: Peter
authors.identifier: 0000000179813618
authors.initials: P
authors.lastname: Kraft
authors.affiliation: 1] Harvard Medical School, Boston, Massachusetts, USA [2] Laboratory for Molecular Medicine, Partners Personalized Medicine, Cambridge, Massachusetts, USA [3] Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Heidi L
authors.initials: HL
authors.lastname: Rehm
authors.affiliation: 1] Harvard Medical School, Boston, Massachusetts, USA [2] Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Green
authors.affiliation: 1] Children's Hospital Informatics Program, Department of Medicine, Boston Children's Hospital, Boston, Massachusetts, USA [2] Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Isaac S
authors.initials: IS
authors.lastname: Kohane
authors.affiliation: 1] Harvard Medical School, Boston, Massachusetts, USA [2] Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA [3] Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Calum A
authors.initials: CA
authors.lastname: MacRae
mesh_terms: D000483:Alleles; D009202:Cardiomyopathies / Q000235:genetics; D016022:Case-Control Studies; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods*; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D020412:Multifactorial Inheritance / Q000235:genetics*; D015203:Reproducibility of Results