Scalable and accurate polygenic risk profiling with low-pass whole genome sequencing

Abstract Over the last ten yearsthe field of human genomics has made substantial progress in identifying genetic variants that influence disease riskThe emerging consensus is that many individuals at high risk for diseases like heart disease or breast cancer have high risk because of the combined action of many thousands of genetic variants across the genome in a polygenic mannerIdentifying individuals at high polygenic risk of disease may lead to interventions of large public health importanceIn this proposalwe will develop a low pass sequencing assay that allows screening of an individual s polygenic risk of disease in a cost effectivescalableand highly accurate mannerwith an initial application to heart diseaseAs a proof of conceptwe will perform both low pass sequencingto bothx andx coverageand genotypingusing the Illumina Global Screening Arrayofindividuals and compare the estimated risk scores to those computed from gold standard genomesIn summarywe will develop a sequencing based assay to calculate polygenic risk scores that is appropriate for population scale application Narrative The field of human genomics has made substantial progress in identifying genetic variants that influence disease riskA challenge is how to translate this knowledge into effective population scale screening toolsWe will develop a low pass sequencing assay that allows estimation of an individual s risk of disease in a cost effectivescalableand highly accurate manner