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Dybdahl Krebs, M.* ; Appadurai, V.* ; Georgii Hellberg, K.L.* ; Ohlsson, H.* ; Steinbach, J.* ; Pedersen, E.* ; Werge, T.* ; Sundquist, J.* ; Sundquist, K.* ; Border, R.* ; Cai, N. ; Zaitlen, N.* ; Dahl, A.* ; Vilhjalmsson, B.* ; Flint, J.* ; Bacanu, S.A.* ; Kendler, K.S.* ; Schork, A.J.*

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

Am. J. Hum. Genet. 113, 184-201 (2026)
Postprint DOI PMC
Open Access Green
Genetics as a science has roots in studying phenotypes of relatives, but molecular approaches facilitate direct measurements of genomic variation between individuals. Agricultural and human biomedical research are both emphasizing genotype-based instruments, such as polygenic scores, but unlike in agriculture, there is an emerging consensus that family variables act nearly independently of genotypes in models of human disease. However, there is insufficient theoretical treatment of these scores, especially guiding our understanding of how and why scores derived from different sources of data may combine. To advance our understanding of this phenomenon, we use 2,066,057 family records of 99,645 genotyped probands from the Integrative Psychiatric Research (iPSYCH)2015 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 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 the low correlation between current phenotype- and genotype-based genetic instruments is caused by both being noisy measures of additive genetic liability. We expect they should remain complementary over the near future and therefore expect approaches integrating both sources of information to achieve more power for genetic inference.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Family Genetic Risk Scores ; Genetic Liability ; Genetics ; Polygenic Risk Scores ; Psychiatric Disorders; Environmental Contributions; Missing Heritability; Genomic Selection; R Package; Prediction; Risk; Traits; Inference; Livestock; Sample
ISSN (print) / ISBN 0002-9297
e-ISSN 1537-6605
Zeitschrift American Journal of Human Genetics, The
Quellenangaben Band: 113, Heft: 1, Seiten: 184-201 Artikelnummer: , Supplement: ,
Verlag Elsevier
Verlagsort New York, NY
Begutachtungsstatus Peer reviewed
Institut(e) Helmholtz Pioneer Campus (HPC)
Förderungen Lundbeck Foundation Initia-tive for Integrative Psychiatric Research (iPSYCH)
National Institute of Mental Health
Danish Independent Research Fund
Lundbeck Foundation