@article {Abraham041483, author = {Gad Abraham and Aki S. Havulinna and Oneil G. Bhalala and Sean G. Byars and Alysha M. De Livera and Laxman Yetukuri and Emmi Tikkanen and Markus Perola and Heribert Schunkert and Eric J. Sijbrands and Aarno Palotie and Nilesh J. Samani and Veikko Salomaa and Samuli Ripatti and Michael Inouye}, title = {Genomic prediction of coronary heart disease}, elocation-id = {041483}, year = {2016}, doi = {10.1101/041483}, publisher = {Cold Spring Harbor Laboratory}, abstract = {Background Genetics plays an important role in coronary heart disease (CHD) but the clinical utility of a genomic risk score (GRS) relative to clinical risk scores, such as the Framingham Risk Score (FRS), is unclear.Methods We generated a GRS of 49,310 SNPs based on a CARDIoGRAMplusC4D Consortium meta-analysis of CHD, then independently tested this using five prospective population cohorts (three FINRISK cohorts, combined n=12,676, 757 incident CHD events; two Framingham Heart Study cohorts (FHS), combined n=3,406, 587 incident CHD events).Results The GRS was strongly associated with time to CHD event (FINRISK HR=1.74, 95\% CI 1.61-1.86 per S.D. of GRS; Framingham HR=1.28, 95\% CI 1.18-1.38), and was largely unchanged by adjustment for clinical risk scores or individual risk factors, including family history. Integration of the GRS with clinical risk scores (FRS and ACC/AHA13 score) improved prediction of CHD events within 10 years (meta-analysis C-index: +1.5-1.6\%, P\<0.001), particularly for individuals >=60 years old (meta-analysis C-index: +4.6-5.1\%, P\<0.001). Men in the top 20\% of the GRS had 3-fold higher risk of CHD by age 75 in FINRISK and 2-fold in FHS, and attaining 10\% cumulative CHD risk 18y earlier in FINRISK and 12y earlier in FHS than those in the bottom 20\%. Furthermore, high genomic risk was partially compensated for by low systolic blood pressure, low cholesterol level, and non-smoking.Conclusions A GRS based on a large number of SNPs substantially improves CHD risk prediction and encodes decades of variation in CHD risk not captured by traditional clinical risk scores.}, URL = {https://www.biorxiv.org/content/early/2016/02/26/041483}, eprint = {https://www.biorxiv.org/content/early/2016/02/26/041483.full.pdf}, journal = {bioRxiv} }