Polygenic Health Index, General Health, Pleiotropy, Embryo Selection and Disease Risk

We construct a polygenic health index as a weighted sum of polygenic risk scores for 20 major disease conditions, including, e.g., coronary artery disease, type 1 and 2 diabetes, schizophrenia, etc. Individual weights are determined by population-level estimates of impact on life expectancy. We validate this index in odds ratios and selection experiments using unrelated individuals and siblings (pairs and trios) from the UK Biobank. Individuals with higher index scores have decreased disease risk across almost all 20 diseases (no significant risk increases), and longer calculated life expectancy. When estimated Disability Adjusted Life Years (DALYs) are used as the performance metric, the gain from selection among 10 individuals (highest index score vs average) is found to be roughly 4 DALYs. We find no statistical evidence for antagonistic trade-offs in risk reduction across these diseases. Correlations between genetic disease risks are found to be mostly positive and generally mild. These results have important implications for public health and also for fundamental issues such as pleiotropy and genetic architecture of human disease conditions. ### Competing Interest Statement The authors declare the following competing interests: SH is a founder, shareholder, and serves on the Board of Directors of Genomic Prediction, Inc. (GP). LT is a founder, shareholder, serves on the Board of Directors of Genomic Prediction, Inc. (GP), and is the CEO of GP. EW and LL are employees and shareholders of GP. TR declares no competing interests. ### Funding Statement This study was funded by internal grants at Michigan State University and by Genomic Prediction, Inc. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The UK Biobank has ethical approval from the North West Centre for Research Ethics Committee (Application 11/NW/0382), which covers the UK. UK Biobank obtained informed consent from all participants. Full details can be found at . The generation and use of the data presented in this paper was approved by the UK Biobank access committee under UK Biobank application number 15326. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Access to the UK Biobank resource is available via application ().