title: Risk prediction by genetic risk scores for coronary heart disease is independent of self-reported family history.
abstract: OBJECTIVE
  Genetic risk scores (GRSs) have been associated with coronary heart disease (CHD) in large studies. We asked whether expanding an established 27-variant GRS (GRS27) to a 50-variant GRS (GRS50) improved CHD prediction and whether GRSs are independent of self-reported family history of CHD.
  
  
  RESULTS
  The association between GRSs and incident CHD was assessed in Cox models adjusting for established risk factors in 23 595 participants of the Malmö Diet and Cancer study--a prospective, population-based study. During a median follow-up of 14.4 years, 2213 participants experienced a first CHD event. After adjustment for established risk factors, both GRS27 and GRS50 were associated with incident CHD [hazard ratio (HR) = 1.70 for high (top quintile) vs. low (bottom quintile) of GRS27; 95% confidence interval (CI): 1.48-1.94; Ptrend = 1.6 × 10(-15) and HR = 1.92 for GRS50; 95% CI: 1.67-2.20; Ptrend = 6.2 × 10(-22)]. Adding 23 single nucleotide polymorphisms (SNPs) to GRS27 improved risk prediction (P = 3 × 10(-6)). Further adjustment for self-reported family history did not appreciably change the risk estimates of either GRS27 (HR = 1.65; 95% CI: 1.45-1.89) or GRS50 (HR = 1.87; 95% CI: 1.63-2.14). The addition of GRS50 to established risk factors, including self-reported family history, improved discrimination (P < 0.0001) and reclassification (continuous net reclassification improvement index = 0.17, P < 0.0001). In young participants (below median age), those with high GRS50 had 2.4-fold greater risk (95% CI: 1.85-3.12) than those with low GRS50.
  
  
  CONCLUSIONS
  The addition of 23 SNPs to an existing GRS27 improved CHD risk prediction and was independent of self-reported family history. Coronary heart disease risk assessment by GRS could be particularly useful in young individuals.
authors.affiliation: Center for Human Genetic Research and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA Department of Medicine, Harvard Medical School, Boston, MA, USA.
authors.forename: Hayato
authors.initials: H
authors.lastname: Tada
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden Department of Internal Medicine, Skåne University Hospital, Malmö, Sweden olle.melander@med.lu.se sekar@broad.mit.edu dov.shiffman@questdiagnostics.com.
authors.forename: Olle
authors.initials: O
authors.lastname: Melander
authors.affiliation: Quest Diagnostics, Alameda, CA, USA.
authors.forename: Judy Z
authors.initials: JZ
authors.lastname: Louie
authors.affiliation: Quest Diagnostics, Alameda, CA, USA.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Catanese
authors.affiliation: Quest Diagnostics, Alameda, CA, USA.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rowland
authors.affiliation: Quest Diagnostics, Alameda, CA, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Devlin
authors.affiliation: Center for Human Genetic Research and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA Department of Medicine, Harvard Medical School, Boston, MA, USA olle.melander@med.lu.se sekar@broad.mit.edu dov.shiffman@questdiagnostics.com.
authors.forename: Sekar
authors.initials: S
authors.lastname: Kathiresan
authors.affiliation: Quest Diagnostics, Alameda, CA, USA olle.melander@med.lu.se sekar@broad.mit.edu dov.shiffman@questdiagnostics.com.
authors.forename: Dov
authors.initials: D
authors.lastname: Shiffman
mesh_terms: D017677:Age Distribution; D000368:Aged; D003324:Coronary Artery Disease / Q000453:epidemiology / Q000235:genetics*; D004812:Epidemiologic Methods; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D013548:Sweden / Q000453:epidemiology
keywords: Coronary heart disease risk; Genetic risk scores