Integration of polygenic and gut metagenomic risk prediction for common diseases

Multi-omics has opened new avenues for non-invasive risk profiling and early detection of complex diseases. Both polygenic risk scores (PRSs) and the human microbiome have shown promise in improving risk assessment of various common diseases. Here, in a prospective population-based cohort (FINRISK 2002; n=5,676) with ∼18 years of e-health record follow-up, we assess the incremental and combined value of PRSs and gut metagenomic sequencing as compared to conventional risk factors for predicting incident coronary artery disease (CAD), type 2 diabetes (T2D), Alzheimer’s disease (AD) and prostate cancer. We found that PRSs improved predictive capacity over conventional risk factors for all diseases (ΔC-indices between 0.010 – 0.027). In sex-stratified analyses, gut metagenomics improved predictive capacity over baseline age for CAD, T2D and prostate cancer; however, improvement over all conventional risk factors was only observed for T2D (ΔC-index 0.004) and prostate cancer (ΔC-index 0.005). Integrated risk models of PRSs, gut metagenomic scores and conventional risk factors achieved the highest predictive performance for all diseases studied as compared to models based on conventional risk factors alone. We make our integrated risk models available for the wider research community. This study demonstrates that integrated PRS and gut metagenomic risk models improve the predictive value over conventional risk factors for common chronic diseases. ### Competing Interest Statement VS has had research collaboration with Bayer Ltd (Outside this study). TN has received speaking honoraria from Servier Finland and AstraZeneca (not related to this study). The rest of the authors declare that they have no relevant conflicts of interest. ### Funding Statement YL was supported by funding from the Cambridge Baker Centre for Systems Genomics. SR was supported by a British Health Foundation programme grant (RG/18/13/33946). MOR was funded by the Research Council of Finland (grant no. 338818). LL was supported by the European Union's Horizon 2020 research and innovation program (grant no. 952914). TN was supported by the Finnish Foundation for Cardiovascular Research, the Sigrid Juselius Foundation, the Southwestern Finland Hospital District, and the Research Council of Finland (grants no. 321351 and 354447). VS was supported by the Finnish Foundation for Cardiovascular Research and by the Juho Vainio Foundation. ASH was supported by the Research Council of Finland, grant no. 321356. MI was supported by the Munz Chair of Cardiovascular Prediction and Prevention and the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014; NIHR203312) [*]. MI was also supported by the UK Economic and Social Research 878 Council (ES/T013192/1). This study was supported by the Victorian Government's Operational Infrastructure Support (OIS) program and by core funding from the British Heart Foundation (RG/18/13/33946) and the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014; NIHR203312) [*]. *The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. This work was supported by Health Data Research UK, which is funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation and Wellcome. ### 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: All participants gave written informed consent, and the study protocol was approved by the Coordinating Ethics Committee of the Helsinki University Hospital District (Ref. 558/E3/2001). 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, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes