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Genome-wide polygenic score to identify a monogenic risk-equivalent for coronary disease

By Amit V Khera, Mark Chaffin, Krishna G. Aragam, Connor A Emdin, Derek Klarin, Mary E. Haas, Carolina Roselli, Pradeep Natarajan, Sekar Kathiresan

Posted 15 Nov 2017
bioRxiv DOI: 10.1101/218388 (published DOI: 10.1038/s41588-018-0183-z)

Identification of individuals at increased genetic risk for a complex disorder such as coronary disease can facilitate treatments or enhanced screening strategies. A rare monogenic mutation associated with increased cholesterol is present in ~1:250 carriers and confers an up to 4-fold increase in coronary risk when compared with non-carriers. Although individual common polymorphisms have modest predictive capacity, their cumulative impact can be aggregated into a polygenic score. Here, we develop a new, genome-wide polygenic score that aggregates information from 6.6 million common polymorphisms and show that this score can similarly identify individuals with a 4-fold increased risk for coronary disease. In >400,000 participants from UK Biobank, the score conforms to a normal distribution and those in the top 2.5% of the distribution are at 4-fold increased risk compared to the remaining 97.5%. Similar patterns are observed with genome-wide polygenic scores for two additional diseases, breast cancer and severe obesity.

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