Abstract
Individual sensitivity to environmental exposures may be genetically influenced. This genotype-by-environment interplay implies differences in phenotypic variance across genotypes, but these variants have proven challenging to detect. Genome-wide association studies of monozygotic twin differences are conducted through family-based variance analyses, which are more robust to the systemic biases that impact population-based methods. We combined data from 21,792 monozygotic twins (10,896 pairs) from 11 studies to conduct one of the largest genome-wide association study meta-analyses of monozygotic phenotypic differences, in children, adolescents and adults separately, for seven psychiatric and neurodevelopmental phenotypes: attention deficit hyperactivity disorder symptoms, autistic traits, anxiety and depression symptoms, psychotic-like experiences, neuroticism and wellbeing. The proportions of phenotypic variance explained by single-nucleotide polymorphisms in these phenotypes were estimated (h2 = 0–18%), but were imprecise. We identified 13 genome-wide significant associations (single-nucleotide polymorphisms, genes and gene sets), including genes related to stress reactivity for depression, growth factor-related genes for autistic traits and catecholamine uptake-related genes for psychotic-like experiences. This is the largest genetic study of monozygotic twins to date by an order of magnitude, evidencing an alternative method to study the genetic architecture of environmental sensitivity. The statistical power was limited for some analyses, calling for better-powered future studies.
| Original language | English |
|---|---|
| Pages (from-to) | 1683-1696 |
| Number of pages | 14 |
| Journal | Nature Human Behaviour |
| Volume | 9 |
| Issue number | 8 |
| Early online date | 10 Jun 2025 |
| DOIs | |
| Publication status | Published - Aug 2025 |
Bibliographical note
Publisher Copyright:© The Author(s) 2025.
Funding
We dedicate this paper to Robert Keers, a wonderful friend, colleague, mentor and scientist, whom we lost too soon. This project continued in his absence, with contributions from many colleagues who helped to complete the work that he started. We especially thank P.B.M. for stepping in to lead the project following Rob\u2019s passing. This project was funded by: a Wellcome Trust grant (project number 208881/Z/17/Z awarded to R.K.); the National Institute for Health and Care Research (NIHR) Barts Biomedical Research Centre\u2014a delivery partnership of Barts Health NHS Trust, Queen Mary University of London, St George\u2019s University Hospitals NHS Foundation Trust and St George\u2019s University of London (NIHR203330 awarded to P.B.M.); the Norwegian Research Council (grant number 295989), Division of Psychiatry at University College London, Medical Research Council (MRC; MR/V002147/1) and National Institute of Mental Health (MH130448) (all awarded to N.M.D.); a grant from the Wellcome Trust and Royal Society (208806/Z/17/Z) and grants from the MRC (MC_UU_00011/1 and MC_UU_00032/1 to the MRC Integrative Epidemiology Unit at the University of Bristol) (all awarded to G.H.); the Australian National Health and Medical Research Council (NHMRC) (grant APP1173025 awarded to K.L.G.); NHMRC grant APP1172990 (awarded to N.G.M.); NHMRC grant APP1172917 (awarded to S.E.M.); National Institutes of Health (NIH) grants R01AG060470, R01AG059329, R01AG050595 and R01AG046938 (awarded to C.A.R.); NIH grants R01AG04563, R01AG10175 and R01AG08861 (awarded to N.L.P.); Riksbankens Jubileumsfond (P18-0782:1) and the Swedish Research Council (2019-00244) (both awarded to S.O.); a King\u2019s International Postgraduate Research Scholarship (awarded to K.L.); the Research Council of Norway (288083) and Jacobs Foundation (2023-1510-00) (both awarded to R.C.); the European Research Council (ERC-2017-COG 771057 (WELL-BEING) awarded to MPVDW and M.B.); the Academy of Finland (grants 265240 and 263278) and Sigrid Jus\u00E9lius Foundation (all awarded to J.K.); Academy of Finland grant 308698 (awarded to A.L.); Academy of Finland grant 314639 (awarded to E.V.); and the NIHR Maudsley Biomedical Research Centre (awarded to J.R.I.C.). The Danish Twin Registry has received support from the National Program for Research Infrastructure 2007 (09-063256), Danish Agency for Science, Technology and Innovation, and NIH (P01 AG08761). Genotyping at the Danish Twin Registry was conducted by the SNP&SEQ Technology Platform\u2019s Science for Life Laboratory (http://snpseq.medsci.uu.se/genotyping/snp-services/) and supported by NIH grant R01AG037985 (to N.L.P.). The Finnish Twin Cohort\u2019s phenotype and genotype data collection has received support from the Wellcome Sanger Institute, Broad Institute, European Network for Genetic and Genomic Epidemiology (FP7-HEALTH-F4-2007; grant agreement 201413), National Institute on Alcohol Abuse and Alcoholism (grants AA-12502, AA-00145 and AA-09203 to R. J. Rose, AA15416 and K02AA018755 to D. M. Dick and R01AA015416 to J. Salvatore) and Academy of Finland (grants 100499, 205585, 118555, 141054, 264146, 308248, 312073, 336823 and 352792 to J.K.). The Murcia Twin Registry is funded by the Spanish Ministerio de Ciencia, Innovaci\u00F3n y Universidades (RTI2018-095185-B-I00), co-funded by the European Regional Development Fund. The Netherlands Twin Register is funded by the Netherlands Organisation for Scientific Research (NWO-GROOT 480-15-001/674). The OATS has received funding from an NHMRC and Australian Research Council Strategic Award Grant (part of the Ageing Well, Ageing Productively programme; 401162), NHMRC Project (seed) Grants (1024224 and 1025243), NHMRC Project Grants (1045325 and 1085606) and NHMRC Program Grants (568969 and 1093083). The OATS was facilitated through access to Twins Research Australia, a national resource supported by a Centres of Research Excellence Grant (1079102) from the NHMRC. DNA was extracted by Genetic Repositories Australia, which was funded by NHMRC Enabling Grant 401184. OATS genotyping was partly funded by a Commonwealth Scientific and Industrial Research Organisation Flagships Collaboration Fund grant. QIMR studies have received support from the following sources: the NHMRC (901061, 950998, 241944, 389875, 389891, 552485, 496682, 1009064, 552485, 496739, 1031119, 1049894, 1069141, 1086683 and 1095227), Australian Research Council (A79600334, A79801419, A79906588, DP0212016 and DP0343921), Human Frontiers Science Program (RG0154/1998-B) and Young and Well Cooperative Research Centre, which was established and funded under the Australian Government\u2019s Cooperative Research Centres programme. The Swedish Twin Registry is funded by the Swedish Research Council (2017-0064 and 421-2013-1061) and Ragnar S\u00F6derberg Foundation (E9/11). PsychChip GWAS genotyping and collaborative work at the Swedish Twin Registry was supported in part by NIH/National Institute on Aging grants R01AG037985, R01AG059329 and R01AG060470; DNA extraction was supported by grants R01AG17561 and R01AG028555; HARMONY was supported by grant R01AG08724; OCTO-Twin was supported by grant R01AG08861; gender was supported by the MacArthur Foundation Research Network on Successful Aging, Axel and Margaret Ax:son Johnson Foundation, Swedish Council for Social Research and Swedish Foundation for Health Care Sciences and Allergy Research; the Swedish Adoption/Twin Study of Aging was supported by grants R01AG04563 and R01AG10175, the MacArthur Foundation Research Network on Successful Aging, the Swedish Council For Working Life and Social Research (97:0147:1B, 2009-0795) and the Swedish Research Council (825-2007-7460 and 825-2009-6141). Research at the Swedish Twin Registry was also supported by Riksbankens Jubileumsfond (P18-0782:1) and the Swedish Research Council (2019-00244). The Twins Early Development Study is supported by a programme grant (MR/V012878/1) to T.C.E. from the UK Medical Research Council (previously MR/M021475/1 awarded to R.P.), with additional support from the NIH (AG046938). TwinsUK is funded by the Wellcome Trust, the Medical Research Council, Versus Arthritis, the European Union\u2019s Horizon 2020 programme, the Chronic Disease Research Foundation, ZOE, the NIHR Clinical Research Network and the Biomedical Research Centre based at Guy\u2019s and St Thomas\u2019 NHS Foundation Trust in partnership with King\u2019s College London. This research utilized the Queen Mary\u2019s Apocrita high-performance computing facility, supported by Queen Mary University of London\u2019s Research-IT services (https://doi.org/10.5281/zenodo.438045)50. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. We dedicate this paper to Robert Keers, a wonderful friend, colleague, mentor and scientist, whom we lost too soon. This project continued in his absence, with contributions from many colleagues who helped to complete the work that he started. We especially thank P.B.M. for stepping in to lead the project following Rob\u2019s passing. This project was funded by: a Wellcome Trust grant (project number 208881/Z/17/Z awarded to R.K.); the National Institute for Health and Care Research (NIHR) Barts Biomedical Research Centre\u2014a delivery partnership of Barts Health NHS Trust, Queen Mary University of London, St George\u2019s University Hospitals NHS Foundation Trust and St George\u2019s University of London (NIHR203330 awarded to P.B.M.); the Norwegian Research Council (grant number 295989), Division of Psychiatry at University College London, Medical Research Council (MRC; MR/V002147/1) and National Institute of Mental Health (MH130448) (all awarded to N.M.D.); a grant from the Wellcome Trust and Royal Society (208806/Z/17/Z) and grants from the MRC (MC_UU_00011/1 and MC_UU_00032/1 to the MRC Integrative Epidemiology Unit at the University of Bristol) (all awarded to G.H.); the Australian National Health and Medical Research Council (NHMRC) (grant APP1173025 awarded to K.L.G.); NHMRC grant APP1172990 (awarded to N.G.M.); NHMRC grant APP1172917 (awarded to S.E.M.); National Institutes of Health (NIH) grants R01AG060470, R01AG059329, R01AG050595 and R01AG046938 (awarded to C.A.R.); NIH grants R01AG04563, R01AG10175 and R01AG08861 (awarded to N.L.P.); Riksbankens Jubileumsfond (P18-0782:1) and the Swedish Research Council (2019-00244) (both awarded to S.O.); a King\u2019s International Postgraduate Research Scholarship (awarded to K.L.); the Research Council of Norway (288083) and Jacobs Foundation (2023-1510-00) (both awarded to R.C.); the European Research Council (ERC-2017-COG 771057 (WELL-BEING) awarded to MPVDW and M.B.); the Academy of Finland (grants 265240 and 263278) and Sigrid Jus\u00E9lius Foundation (all awarded to J.K.); Academy of Finland grant 308698 (awarded to A.L.); Academy of Finland grant 314639 (awarded to E.V.); and the NIHR Maudsley Biomedical Research Centre (awarded to J.R.I.C.). The Danish Twin Registry has received support from the National Program for Research Infrastructure 2007 (09-063256), Danish Agency for Science, Technology and Innovation, and NIH (P01 AG08761). Genotyping at the Danish Twin Registry was conducted by the SNP&SEQ Technology Platform\u2019s Science for Life Laboratory ( http://snpseq.medsci.uu.se/genotyping/snp-services/ ) and supported by NIH grant R01AG037985 (to N.L.P.). The Finnish Twin Cohort\u2019s phenotype and genotype data collection has received support from the Wellcome Sanger Institute, Broad Institute, European Network for Genetic and Genomic Epidemiology (FP7-HEALTH-F4-2007; grant agreement 201413), National Institute on Alcohol Abuse and Alcoholism (grants AA-12502, AA-00145 and AA-09203 to R. J. Rose, AA15416 and K02AA018755 to D. M. Dick and R01AA015416 to J. Salvatore) and Academy of Finland (grants 100499, 205585, 118555, 141054, 264146, 308248, 312073, 336823 and 352792 to J.K.). The Murcia Twin Registry is funded by the Spanish Ministerio de Ciencia, Innovaci\u00F3n y Universidades (RTI2018-095185-B-I00), co-funded by the European Regional Development Fund. The Netherlands Twin Register is funded by the Netherlands Organisation for Scientific Research (NWO-GROOT 480-15-001/674). The OATS has received funding from an NHMRC and Australian Research Council Strategic Award Grant (part of the Ageing Well, Ageing Productively programme; 401162), NHMRC Project (seed) Grants (1024224 and 1025243), NHMRC Project Grants (1045325 and 1085606) and NHMRC Program Grants (568969 and 1093083). The OATS was facilitated through access to Twins Research Australia, a national resource supported by a Centres of Research Excellence Grant (1079102) from the NHMRC. DNA was extracted by Genetic Repositories Australia, which was funded by NHMRC Enabling Grant 401184. OATS genotyping was partly funded by a Commonwealth Scientific and Industrial Research Organisation Flagships Collaboration Fund grant. QIMR studies have received support from the following sources: the NHMRC (901061, 950998, 241944, 389875, 389891, 552485, 496682, 1009064, 552485, 496739, 1031119, 1049894, 1069141, 1086683 and 1095227), Australian Research Council (A79600334, A79801419, A79906588, DP0212016 and DP0343921), Human Frontiers Science Program (RG0154/1998-B) and Young and Well Cooperative Research Centre, which was established and funded under the Australian Government\u2019s Cooperative Research Centres programme. The Swedish Twin Registry is funded by the Swedish Research Council (2017-0064 and 421-2013-1061) and Ragnar S\u00F6derberg Foundation (E9/11). PsychChip GWAS genotyping and collaborative work at the Swedish Twin Registry was supported in part by NIH/National Institute on Aging grants R01AG037985, R01AG059329 and R01AG060470; DNA extraction was supported by grants R01AG17561 and R01AG028555; HARMONY was supported by grant R01AG08724; OCTO-Twin was supported by grant R01AG08861; gender was supported by the MacArthur Foundation Research Network on Successful Aging, Axel and Margaret Ax:son Johnson Foundation, Swedish Council for Social Research and Swedish Foundation for Health Care Sciences and Allergy Research; the Swedish Adoption/Twin Study of Aging was supported by grants R01AG04563 and R01AG10175, the MacArthur Foundation Research Network on Successful Aging, the Swedish Council For Working Life and Social Research (97:0147:1B, 2009-0795) and the Swedish Research Council (825-2007-7460 and 825-2009-6141). Research at the Swedish Twin Registry was also supported by Riksbankens Jubileumsfond (P18-0782:1) and the Swedish Research Council (2019-00244). The Twins Early Development Study is supported by a programme grant (MR/V012878/1) to T.C.E. from the UK Medical Research Council (previously MR/M021475/1 awarded to R.P.), with additional support from the NIH (AG046938). TwinsUK is funded by the Wellcome Trust, the Medical Research Council, Versus Arthritis, the European Union\u2019s Horizon 2020 programme, the Chronic Disease Research Foundation, ZOE, the NIHR Clinical Research Network and the Biomedical Research Centre based at Guy\u2019s and St Thomas\u2019 NHS Foundation Trust in partnership with King\u2019s College London. This research utilized the Queen Mary\u2019s Apocrita high-performance computing facility, supported by Queen Mary University of London\u2019s Research-IT services ( https://doi.org/10.5281/zenodo.438045 ). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.