Uncovering the Heritable Components of Multimorbidities and Disease Trajectories: A Nationwide Cohort Study

Quantifying the contribution of genetics and environmental effects on disease initiation and progression, as well as the shared genetics of different diseases, is vital for the understanding of the disease etiology of multimorbidities. In this study, we leverage nationwide Danish registries to provide a granular atlas of the genetic origin of disease phenotypes for a cohort of all Danes 1978-2018 with partially known pedigree (n = 6.3 million). We estimate the heritability and genetic correlation between thousands of disease phenotypes using a novel approach that can be scaled to nationwide data. Our findings confirm the importance of genetics for a number of known associations and increase the resolution of heritability by adding numerous novel associations, some of which point to shared biologically origin of different phenotypes. We also establish the heritability of disease trajectories and the importance of sex-specific genetic contributions. ### Competing Interest Statement S. Brunak has ownerships in Hoba Therapeutics Aps, Novo Nordisk A/S, Lundbeck A/S, and managing board memberships in Proscion A/S. ### Funding Statement The study was supported by funding from the Novo Nordisk Foundation (grant agreements NNF14CC0001 and NNF17OC0027594). The work was also carried out as a part of the BRIDGE Translational Excellence Programme (bridge.ku.dk) at the Faculty of Health and Medical Sciences, University of Copenhagen, funded by the Novo Nordisk Foundation (NNF18SA0034956). ### 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 use of data from the MultiGeneration Registry-Lite was approved by the Danish National Archives (journal 19/04085). Informed consent or evaluation by a research ethics committee is not required for registry-based research in Denmark. The Danish Blood Donor Study (DBDS) was approved by the National Danish Committee on Health Research Ethics (1-10-72-95-13),the Zealand Regional Committee on Health Research Ethics (SJ-740), and the Data Protection Agency (P-2019-99). Genetic research within the DBDS was approved by the Danish National Committee on Health Research Ethics (1700407). 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 All data produced will be made available online at https://h2.cpr.ku.dk