Genetics of monozygotic twins reveals the impact of environmental sensitivity on psychiatric and neurodevelopmental phenotypes

Elham Assary (), Jonathan R. I. Coleman, Gibran Hemani, Margot P. Weijer, Laurence J. Howe, Teemu Palviainen, Katrina L. Grasby, Rafael Ahlskog, Marianne Nygaard, Rosa Cheesman, Kai Lim, Chandra A. Reynolds, Juan R. Ordoñana, Lucia Colodro-Conde, Scott Gordon, Juan J. Madrid-Valero, Anbupalam Thalamuthu, Jouke-Jan Hottenga, Jonas Mengel-From, Nicola J. Armstrong, Perminder S. Sachdev, Teresa Lee, Henry Brodaty, Julian N. Trollor, Margaret Wright, David Ames, Vibeke S. Catts, Antti Latvala, Eero Vuoksimaa, Travis Mallard, K. Paige Harden, Elliot M. Tucker-Drob, Sven Oskarsson, Christopher J. Hammond, Kaare Christensen, Mark Taylor, Sebastian Lundström, Henrik Larsson, Robert Karlsson, Nancy L. Pedersen, Karen A. Mather, Sarah E. Medland, Dorret I. Boomsma, Nicholas G. Martin, Robert Plomin, Meike Bartels, Paul Lichtenstein, Jaakko Kaprio, Thalia C. Eley, Neil M. Davies, Patricia B. Munroe and Robert Keers
Additional contact information
Elham Assary: Queen Mary University of London
Jonathan R. I. Coleman: King’s College London
Gibran Hemani: University of Bristol
Margot P. Weijer: Vrije Universiteit Amsterdam
Laurence J. Howe: University of Bristol
Teemu Palviainen: University of Helsinki
Katrina L. Grasby: QIMR Berghofer Medical Research Institute
Rafael Ahlskog: Uppsala University
Marianne Nygaard: University of Southern Denmark
Rosa Cheesman: University of Oslo
Kai Lim: King’s College London
Chandra A. Reynolds: University of Colorado Boulder
Juan R. Ordoñana: University of Murcia
Lucia Colodro-Conde: QIMR Berghofer Medical Research Institute
Scott Gordon: QIMR Berghofer Medical Research Institute
Juan J. Madrid-Valero: University of Murcia
Anbupalam Thalamuthu: UNSW Sydney
Jouke-Jan Hottenga: Vrije Universiteit Amsterdam
Jonas Mengel-From: University of Southern Denmark
Nicola J. Armstrong: UNSW Sydney
Perminder S. Sachdev: UNSW Sydney
Teresa Lee: UNSW Sydney
Henry Brodaty: UNSW Sydney
Julian N. Trollor: UNSW Sydney
Margaret Wright: University of Queensland
David Ames: St George’s Hospital
Vibeke S. Catts: UNSW Sydney
Antti Latvala: University of Helsinki
Eero Vuoksimaa: University of Helsinki
Travis Mallard: Harvard Medical School
K. Paige Harden: University of Texas at Austin
Elliot M. Tucker-Drob: University of Texas at Austin
Sven Oskarsson: Uppsala University
Christopher J. Hammond: King’s College London
Kaare Christensen: University of Southern Denmark
Mark Taylor: Karolinska Institutet
Sebastian Lundström: University of Gothenburg
Henrik Larsson: Karolinska Institutet
Robert Karlsson: Karolinska Institutet
Nancy L. Pedersen: Karolinska Institutet
Karen A. Mather: UNSW Sydney
Sarah E. Medland: QIMR Berghofer Medical Research Institute
Dorret I. Boomsma: Vrije Universiteit Amsterdam
Nicholas G. Martin: QIMR Berghofer Medical Research Institute
Robert Plomin: King’s College London
Meike Bartels: Vrije Universiteit Amsterdam
Paul Lichtenstein: Karolinska Institutet
Jaakko Kaprio: University of Helsinki
Thalia C. Eley: King’s College London
Neil M. Davies: University College London
Patricia B. Munroe: Queen Mary University of London
Robert Keers: Queen Mary University of London

Nature Human Behaviour, 2025, vol. 9, issue 8, 1683-1696

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41562-025-02193-7

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