Separating direct, indirect, and parent-of-origin genetic effects in the human population
Krätschmer I, Hegemann L, Hofmeister RJ, Corfield EC, Mahmoudi M, Delaneau O, Andreassen OA, Campbell A, Hayward C, Marioni RE, Ystrom E, Havdahl A, Robinson MR. Separating direct, indirect, and parent-of-origin genetic effects in the human population. Cell Genomics., 101277.
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Author
Krätschmer, IlseISTA 
;
Hegemann, Laura;
Hofmeister, Robin J.;
Corfield, Elizabeth C.;
Mahmoudi, Mahdi;
Delaneau, Olivier;
Andreassen, Ole A.;
Campbell, Archie;
Hayward, Caroline;
Marioni, Riccardo E.;
Ystrom, Eivind;
Havdahl, Alexandra
All
;
Hegemann, Laura;
Hofmeister, Robin J.;
Corfield, Elizabeth C.;
Mahmoudi, Mahdi;
Delaneau, Olivier;
Andreassen, Ole A.;
Campbell, Archie;
Hayward, Caroline;
Marioni, Riccardo E.;
Ystrom, Eivind;
Havdahl, Alexandra
All
Corresponding author has ISTA affiliation
Department
Abstract
We introduce JODIE, a genetic joint modeling approach that estimates how DNA loci influence human traits by partitioning genetic effects into four components: direct effects (from a child’s alleles), indirect maternal and paternal effects (from parents’ alleles), and parent-of-origin (PofO) effects (dependent on parental transmission of alleles), while uniquely accounting for assortative mating. We analyze 30,000 child-mother-father trios from the Estonian Biobank and the Norwegian Mother, Father, and Child Cohort, focusing on height, body mass index, and childhood educational test scores. We find direct effects to be the largest contributor to trait variation, but combined, indirect parental and PofO effects are similarly substantial. We support our results by within-family genome-wide association testing and identify 276 independently associated DNA regions with a complex interplay between direct, indirect, and PofO effects. By joint modeling, we show that direct, indirect, and PofO effects collectively shape human phenotypic variation across loci genome-wide.
Publishing Year
Date Published
2026-06-09
Journal Title
Cell Genomics
Publisher
Elsevier
Acknowledgement
We thank Zoltan Kutalik, Peter Visscher, and members of the Robinson group at ISTA for their comments, which improved this manuscript. This work was funded by an SNSF Eccellenza Grant to M.R.R. (PCEGP3-181181) and by core funding from the Institute of Science and Technology Austria.
The Norwegian Mother, Father, and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research. We are grateful to all the participating families in Norway who take part in this on-going cohort study. We thank the Norwegian Institute of Public Health (NIPH) for generating high-quality genomic data. The research is part of the HARVEST collaboration, supported by the Research Council of Norway (#229624). We also thank the NORMENT Center for providing genotype data, funded by the Research Council of Norway (#223273), South East Norway Health Authorities, and Stiftelsen Kristian Gerhard Jebsen, and in collaboration with deCODE Genetics. We further thank the Center for Diabetes Research, the University of Bergen for providing genotype data funded by the ERC AdG project SELECTionPREDISPOSED, Stiftelsen Kristian Gerhard Jebsen, Trond Mohn Foundation, the Research Council of Norway, the Novo Nordisk Foundation, the University of Bergen, and the Western Norway Health Authorities. The MoBa work was performed on the TSD (Tjeneste for Sensitive Data) facilities, owned by the University of Oslo, operated and developed by the TSD service group at the University of Oslo, IT Department (USIT, tsd-drift@usit.uio.no). E.Y. is supported by the European Union (grant numbers 101045526 and 101073237) and the Research Council of Norway (grant numbers 336078, 288083, and 331640).
We would like to acknowledge the participants and investigators of the Generation Scotland Cohort study. Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates (CZD/16/6) and the Scottish Funding Council (HR03006). Genotyping and methylation typing of the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Wellcome Trust Clinical Research Facility, Edinburgh, Scotland and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award “STratifying Resilience and Depression Longitudinally” [STRADL] ref. 104036/Z/14/Z).
We would like to thank and acknowledge the participants and investigators of the Estonian Biobank (EstBB) study. The research was conducted using the Estonian Center of Genomics/Roadmap II funded by the Estonian Research Council (project number TT17).
Norwegian analyses were performed on resources provided by Sigma2 - the National Infrastructure for High-Performance Computing and Data Storage in Norway. Estonian Data analysis was carried out in the High-Performance Computing Center cloud provided by University of Tartu. Analysis of the Generation Scotland data and the summary statistics obtained from the other analyses was conducted at IST Austria and is supported by the Scientific Service Units (SSU) of IST Austria through resources provided by Scientific Computing (SciComp).
Acknowledged SSUs
Article Number
101277
eISSN
IST-REx-ID
Cite this
Krätschmer I, Hegemann L, Hofmeister RJ, et al. Separating direct, indirect, and parent-of-origin genetic effects in the human population. Cell Genomics. doi:10.1016/j.xgen.2026.101277
Krätschmer, I., Hegemann, L., Hofmeister, R. J., Corfield, E. C., Mahmoudi, M., Delaneau, O., … Robinson, M. R. (n.d.). Separating direct, indirect, and parent-of-origin genetic effects in the human population. Cell Genomics. Elsevier. https://doi.org/10.1016/j.xgen.2026.101277
Krätschmer, Ilse, Laura Hegemann, Robin J. Hofmeister, Elizabeth C. Corfield, Mahdi Mahmoudi, Olivier Delaneau, Ole A. Andreassen, et al. “Separating Direct, Indirect, and Parent-of-Origin Genetic Effects in the Human Population.” Cell Genomics. Elsevier, n.d. https://doi.org/10.1016/j.xgen.2026.101277.
I. Krätschmer et al., “Separating direct, indirect, and parent-of-origin genetic effects in the human population,” Cell Genomics. Elsevier.
Krätschmer I, Hegemann L, Hofmeister RJ, Corfield EC, Mahmoudi M, Delaneau O, Andreassen OA, Campbell A, Hayward C, Marioni RE, Ystrom E, Havdahl A, Robinson MR. Separating direct, indirect, and parent-of-origin genetic effects in the human population. Cell Genomics., 101277.
Krätschmer, Ilse, et al. “Separating Direct, Indirect, and Parent-of-Origin Genetic Effects in the Human Population.” Cell Genomics, 101277, Elsevier, doi:10.1016/j.xgen.2026.101277.
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