The relationship between genotype- and phenotype-based estimates of genetic liability to psychiatric disorders, in practice and in theory

Genetics as a science has roots in studying phenotypes of relatives, but molecular approaches facilitate direct measurements of genomic variation within individuals. Agricultural and human biomedical research are both emphasizing genotype-based instruments, like polygenic scores, as the future of breeding programs or precision medicine and genetic epidemiology. However, unlike in agriculture, there is an emerging consensus that family variables act nearly independent of genotypes in models of human disease. To advance our understanding of this phenomenon, we use 2,066,057 family records of 99,645 genotyped probands from the iPSYCH2015 case-cohort study to show that state-of-the-field genotype- and phenotype-based genetic instruments explain largely independent components of liability to psychiatric disorders. We support these empirical results with novel theoretical analysis and simulations to describe, in a human biomedical context, parameters affecting current and future performance of the two approaches, their expected interrelationships, and consistency of observed results with expectations under simple additive, polygenic liability models of disease. We conclude, at least for psychiatric disorders, that phenotype- and genotype-based genetic instruments are likely noisy measures of the same underlying additive genetic liability, should be seen for the near future as complementary, and integrated to a greater extent. ### Competing Interest Statement B.J.V. is a member of Allelica's scientific advisory board. ### Funding Statement Lundbeckfonden Fellowship R335-2019-2318; National Institute of Mental Health R01MH130581; National Institute of Health 1R01HG011345-01; National Institute of Health R01GM142112; National Institute of Health 2R01HG006399; Lundbeck Foundation Fellowship (R335-2019-2339); The iPSYCH team was supported by grants from the Lundbeck Foundation (R102-A9118, R155-2014-1724, and R248-2017-2003), NIH/NIMH (1U01MH109514-01 and 1R01MH124851-01 to ADB) and the Universities and University Hospitals of Aarhus and Copenhagen. The Danish National Biobank resource was supported by the Novo Nordisk Foundation. High-performance computer capacity for handling and statistical analysis of iPSYCH data on the GenomeDK HPC facility was provided by the Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing, iSEQ, Aarhus University, Denmark (grant to ADB) ### 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 this data is according the guidelines provided by the Danish Scientific Ethics Committee, the Danish Health Data Authority, the Danish data protection agency and the Danish Neonatal Screening Biobank Steering Committee. 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 All data produced in the present study are available upon reasonable request to the authors and in accordance with Danish legislation