Assary Elham, Coleman Jonathan R I, Hemani Gibran, van de Weijer Margot P, Howe Laurence J, Palviainen Teemu, Grasby Katrina L, Ahlskog Rafael, Nygaard Marianne, Cheesman Rosa, Lim Kai, Reynolds Chandra A, Ordoñana Juan R, Colodro-Conde Lucia, Gordon Scott, Madrid-Valero Juan J, Thalamuthu Anbupalam, Hottenga Jouke-Jan, Mengel-From Jonas, Armstrong Nicola J, Sachdev Perminder S, Lee Teresa, Brodaty Henry, Trollor Julian N, Wright Margaret, Ames David, Catts Vibeke S, Latvala Antti, Vuoksimaa Eero, Mallard Travis, Paige Harden K, Tucker-Drob Elliot M, Oskarsson Sven, Hammond Christopher J, Christensen Kaare, Taylor Mark, Lundström Sebastian, Larsson Henrik, Karlsson Robert, Pedersen Nancy L, Mather Karen A, Medland Sarah E, Boomsma Dorret I, Martin Nicholas G, Plomin Robert, Bartels Meike, Lichtenstein Paul, Kaprio Jaakko, Eley Thalia C, Davies Neil M, Munroe Patricia B, Keers Robert
School of Biological and Behavioural Sciences, Queen Mary University of London, London, UK.
Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Nat Hum Behav. 2025 Jun 10. doi: 10.1038/s41562-025-02193-7.
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 (h = 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.
个体对环境暴露的敏感性可能受到遗传影响。这种基因型与环境的相互作用意味着不同基因型在表型方差上存在差异，但事实证明，检测这些变异具有挑战性。通过基于家系的方差分析对同卵双胞胎差异进行全基因组关联研究，这种方法对影响基于人群方法的系统偏差更具稳健性。我们整合了来自11项研究的21792名同卵双胞胎（10896对）的数据，分别针对儿童、青少年和成年人，对七种精神和神经发育表型进行了最大规模之一的全基因组关联研究荟萃分析，这些表型包括注意力缺陷多动障碍症状、自闭症特征、焦虑和抑郁症状、类精神病体验、神经质和幸福感。我们估计了这些表型中由单核苷酸多态性解释的表型方差比例（h = 0 - 18%），但结果并不精确。我们确定了13个全基因组显著关联（单核苷酸多态性、基因和基因集），包括与抑郁症应激反应相关的基因、与自闭症特征相关的生长因子相关基因以及与类精神病体验相关的儿茶酚胺摄取相关基因。这是迄今为止规模最大的同卵双胞胎基因研究，比以往同类研究大一个数量级，证明了一种研究环境敏感性遗传结构的替代方法。某些分析的统计效力有限，需要未来开展更具效力的研究。
