TY - JOUR T1 - Genomic prediction of coronary heart disease JF - bioRxiv DO - 10.1101/041483 SP - 041483 AU - Gad Abraham AU - Aki S. Havulinna AU - Oneil G. Bhalala AU - Sean G. Byars AU - Alysha M. De Livera AU - Laxman Yetukuri AU - Emmi Tikkanen AU - Markus Perola AU - Heribert Schunkert AU - Eric J. Sijbrands AU - Aarno Palotie AU - Nilesh J. Samani AU - Veikko Salomaa AU - Samuli Ripatti AU - Michael Inouye Y1 - 2016/01/01 UR - http://biorxiv.org/content/early/2016/02/26/041483.abstract N2 - 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. ER -