{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T23:51:08Z","timestamp":1788997868374,"version":"build-2803163510"},"reference-count":74,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T00:00:00Z","timestamp":1780358400000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000051","name":"U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute","doi-asserted-by":"publisher","award":["1R01HG010480"],"award-info":[{"award-number":["1R01HG010480"]}],"id":[{"id":"10.13039\/100000051","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000051","name":"U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute","doi-asserted-by":"publisher","award":["U01HG011719"],"award-info":[{"award-number":["U01HG011719"]}],"id":[{"id":"10.13039\/100000051","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000051","name":"U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute","doi-asserted-by":"publisher","award":["R00HG013674"],"award-info":[{"award-number":["R00HG013674"]}],"id":[{"id":"10.13039\/100000051","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011541","name":"U.S. Department of Health & Human Services | NIH | NCI | Division of Cancer Epidemiology and Genetics, National Cancer Institute","doi-asserted-by":"publisher","award":["U01CA249866"],"award-info":[{"award-number":["U01CA249866"]}],"id":[{"id":"10.13039\/100011541","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000052","name":"U.S. Department of Health & Human Services | NIH | NIH Office of the Director","doi-asserted-by":"publisher","award":["1U24OD023382"],"award-info":[{"award-number":["1U24OD023382"]}],"id":[{"id":"10.13039\/100000052","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R35GM150836"],"award-info":[{"award-number":["R35GM150836"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000072","name":"U.S. Department of Health & Human Services | NIH | National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["R01DE031855"],"award-info":[{"award-number":["R01DE031855"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000072","name":"U.S. Department of Health & Human Services | NIH | National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["R01DE031855"],"award-info":[{"award-number":["R01DE031855"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000066","name":"U.S. Department of Health & Human Services | NIH | National Institute of Environmental Health Sciences","doi-asserted-by":"publisher","award":["R01ES034554"],"award-info":[{"award-number":["R01ES034554"]}],"id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000066","name":"U.S. Department of Health & Human Services | NIH | National Institute of Environmental Health Sciences","doi-asserted-by":"publisher","award":["R01ES034554"],"award-info":[{"award-number":["R01ES034554"]}],"id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Genet"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    We have proposed PGS-TRI, a framework for analyzing polygenic scores (PGSs) in case\u2013parent trio studies that estimate the risk of an index condition associated with direct PGS effects, gene\u2013environment interactions and asymmetrical maternal and paternal indirect effects. Simulations confirm its robustness in the presence of complex population structure and assortative mating. Applied to multi-ancestry autism spectrum disorders (ASD) trios (\n                    <jats:italic>n<\/jats:italic>\n                    <jats:sub>trio<\/jats:sub>\n                    \u2009=\u200918,383), PGS-TRI yielded transmission-based direct effects of PGSs for ASD and other neurocognitive traits along a genetic ancestry continuum, and identified asymmetrical indirect effects of parental PGSs for body mass index and neurocognitive traits on children\u2019s ASD risk. In a trio study of European and Asian orofacial clefts (OFCs) (\n                    <jats:italic>n<\/jats:italic>\n                    <jats:sub>trio<\/jats:sub>\n                    \u2009=\u20091,904), PGS-TRI estimated direct and indirect effects of an established PGS and its interaction with maternal risk factors. Finally, we applied PGS-TRI to large-scale, transcriptome-wide and metabolome-wide traits to examine their direct and indirect effects on ASD and OFC risk.\n                  <\/jats:p>","DOI":"10.1038\/s41588-026-02601-2","type":"journal-article","created":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T09:04:13Z","timestamp":1780391053000},"page":"1237-1247","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Estimation of direct and indirect polygenic effects and gene\u2013environment interactions using polygenic scores in case\u2013parent trio studies"],"prefix":"10.1038","volume":"58","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3383-8670","authenticated-orcid":false,"given":"Ziqiao","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8643-5894","authenticated-orcid":false,"given":"Luke","family":"Grosvenor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0979-2935","authenticated-orcid":false,"given":"Debashree","family":"Ray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1353-731X","authenticated-orcid":false,"given":"Tianyuan","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3278-6274","authenticated-orcid":false,"given":"Ingo","family":"Ruczinski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7644-1705","authenticated-orcid":false,"given":"Terri H.","family":"Beaty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather","family":"Volk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7697-3998","authenticated-orcid":false,"given":"Christine","family":"Ladd-Acosta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9060-008X","authenticated-orcid":false,"given":"Nilanjan","family":"Chatterjee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,2]]},"reference":[{"key":"2601_CR1","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1016\/j.ajhg.2019.05.001","volume":"104","author":"S Kerminen","year":"2019","unstructured":"Kerminen, S. et al. Geographic variation and bias in the polygenic scores of complex diseases and traits in Finland. Am. J. Hum. Genet. 104, 1169\u20131181 (2019).","journal-title":"Am. J. Hum. Genet."},{"key":"2601_CR2","doi-asserted-by":"publisher","unstructured":"Berg, J. J. et al. Reduced signal for polygenic adaptation of height in UK Biobank. Elife https:\/\/doi.org\/10.7554\/eLife.39725 (2019).","DOI":"10.7554\/eLife.39725"},{"key":"2601_CR3","doi-asserted-by":"publisher","unstructured":"Sohail, M. et al. Polygenic adaptation on height is overestimated due to uncorrected stratification in genome-wide association studies. Elife https:\/\/doi.org\/10.7554\/eLife.39702 (2019).","DOI":"10.7554\/eLife.39702"},{"key":"2601_CR4","doi-asserted-by":"crossref","first-page":"eaay0328","DOI":"10.1126\/sciadv.aay0328","volume":"6","author":"TT Morris","year":"2020","unstructured":"Morris, T. T., Davies, N. M., Hemani, G. & Smith, G. D. Population phenomena inflate genetic associations of complex social traits. Sci. Adv. 6, eaay0328 (2020).","journal-title":"Sci. Adv."},{"key":"2601_CR5","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1038\/s41588-022-01158-0","volume":"54","author":"A Abdellaoui","year":"2022","unstructured":"Abdellaoui, A., Dolan, C. V., Verweij, K. J. H. & Nivard, M. G. Gene-environment correlations across geographic regions affect genome-wide association studies. Nat. Genet. 54, 1345\u20131354 (2022).","journal-title":"Nat. Genet."},{"key":"2601_CR6","doi-asserted-by":"crossref","first-page":"R170","DOI":"10.1093\/hmg\/ddz204","volume":"28","author":"NM Davies","year":"2019","unstructured":"Davies, N. M. et al. Within family Mendelian randomization studies. Hum. Mol. Genet. 28, R170\u2013R179 (2019).","journal-title":"Hum. Mol. Genet."},{"key":"2601_CR7","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1038\/s41588-022-01062-7","volume":"54","author":"LJ Howe","year":"2022","unstructured":"Howe, L. J. et al. Within-sibship genome-wide association analyses decrease bias in estimates of direct genetic effects. Nat. Genet. 54, 581\u2013592 (2022).","journal-title":"Nat. Genet."},{"key":"2601_CR8","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1080\/19485565.2019.1681257","volume":"64","author":"S Trejo","year":"2018","unstructured":"Trejo, S. & Domingue, B. W. Genetic nature or genetic nurture? Introducing social genetic parameters to quantify bias in polygenic score analyses. Biodemography Soc. Biol. 64, 187\u2013215 (2018).","journal-title":"Biodemography Soc. Biol."},{"key":"2601_CR9","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1038\/s41588-019-0403-1","volume":"51","author":"NM Warrington","year":"2019","unstructured":"Warrington, N. M. et al. Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors. Nat. Genet. 51, 804\u2013814 (2019).","journal-title":"Nat. Genet."},{"key":"2601_CR10","volume":"118","author":"Y Wu","year":"2021","unstructured":"Wu, Y. et al. Estimating genetic nurture with summary statistics of multigenerational genome-wide association studies. Proc. Natl Acad. Sci. USA 118, e2023184118 (2021).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2601_CR11","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1126\/science.aan6877","volume":"359","author":"A Kong","year":"2018","unstructured":"Kong, A. et al. The nature of nurture: effects of parental genotypes. Science 359, 424\u2013428 (2018).","journal-title":"Science"},{"key":"2601_CR12","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1038\/ng.3863","volume":"49","author":"DJ Weiner","year":"2017","unstructured":"Weiner, D. J. et al. Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders. Nat. Genet. 49, 978\u2013985 (2017).","journal-title":"Nat. Genet."},{"key":"2601_CR13","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1016\/j.neuron.2018.01.015","volume":"97","author":"SPARK Consortium","year":"2018","unstructured":"SPARK Consortium SPARK: a US cohort of 50,000 families to accelerate autism research. Neuron 97, 488\u2013493 (2018).","journal-title":"Neuron"},{"key":"2601_CR14","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1038\/ng.580","volume":"42","author":"TH Beaty","year":"2010","unstructured":"Beaty, T. H. et al. A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4. Nat. Genet. 42, 525\u2013529 (2010).","journal-title":"Nat. Genet."},{"key":"2601_CR15","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1002\/gepi.20492","volume":"34","author":"MC Cornelis","year":"2010","unstructured":"Cornelis, M. C. et al. The gene, environment association studies consortium (GENEVA): maximizing the knowledge obtained from GWAS by collaboration across studies of multiple conditions. Genet. Epidemiol. 34, 364\u2013372 (2010).","journal-title":"Genet. Epidemiol."},{"key":"2601_CR16","doi-asserted-by":"crossref","first-page":"1236","DOI":"10.1038\/ng.3406","volume":"47","author":"B Bulik-Sullivan","year":"2015","unstructured":"Bulik-Sullivan, B. et al. An atlas of genetic correlations across human diseases and traits. Nat. Genet. 47, 1236\u20131241 (2015).","journal-title":"Nat. Genet."},{"key":"2601_CR17","doi-asserted-by":"crossref","unstructured":"Guan, J. et al. Family-based genome-wide association study designs for increased power and robustness. Nat. Genet. 57, 1044\u20131052 (2025).","DOI":"10.1038\/s41588-025-02118-0"},{"key":"2601_CR18","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1038\/s41588-019-0344-8","volume":"51","author":"J Grove","year":"2019","unstructured":"Grove, J. et al. Identification of common genetic risk variants for autism spectrum disorder. Nat. Genet. 51, 431\u2013444 (2019).","journal-title":"Nat. Genet."},{"key":"2601_CR19","doi-asserted-by":"crossref","DOI":"10.1038\/s41398-023-02453-y","volume":"13","author":"S Sanchez-Roige","year":"2023","unstructured":"Sanchez-Roige, S. et al. CADM2 is implicated in impulsive personality and numerous other traits by genome- and phenome-wide association studies in humans and mice. Transl. Psychiatry 13, 167 (2023).","journal-title":"Transl. Psychiatry"},{"key":"2601_CR20","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1007\/s00439-011-1094-6","volume":"131","author":"JP Casey","year":"2012","unstructured":"Casey, J. P. et al. A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder. Hum. Genet. 131, 565\u2013579 (2012).","journal-title":"Hum. Genet."},{"key":"2601_CR21","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1007\/s10519-022-10109-8","volume":"52","author":"JA Pasman","year":"2022","unstructured":"Pasman, J. A. et al. The CADM2 gene and behavior: a phenome-wide scan in UK-Biobank. Behav. Genet. 52, 306\u2013314 (2022).","journal-title":"Behav. Genet."},{"key":"2601_CR22","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1038\/s41588-018-0147-3","volume":"50","author":"JJ Lee","year":"2018","unstructured":"Lee, J. J. et al. Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals. Nat. Genet. 50, 1112\u20131121 (2018).","journal-title":"Nat. Genet."},{"key":"2601_CR23","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1038\/nature14177","volume":"518","author":"AE Locke","year":"2015","unstructured":"Locke, A. E. et al. Genetic studies of body mass index yield new insights for obesity biology. Nature 518, 197\u2013206 (2015).","journal-title":"Nature"},{"key":"2601_CR24","doi-asserted-by":"crossref","first-page":"7339","DOI":"10.1038\/s41598-019-43861-9","volume":"9","author":"J Morris","year":"2019","unstructured":"Morris, J. et al. Genetic variation in CADM2 as a link between psychological traits and obesity. Sci. Rep. 9, 7339 (2019).","journal-title":"Sci. Rep."},{"key":"2601_CR25","doi-asserted-by":"crossref","unstructured":"Sakic, B. et al. Unravelling the joint genetic architecture between psychiatic and insulin-related traits in the general population. Preprint at medRxiv https:\/\/doi.org\/2024.10.04.24314905 (2024).","DOI":"10.1101\/2024.10.04.24314905"},{"key":"2601_CR26","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1038\/ng.3506","volume":"48","author":"A Gusev","year":"2016","unstructured":"Gusev, A. et al. Integrative approaches for large-scale transcriptome-wide association studies. Nat. Genet. 48, 245\u2013252 (2016).","journal-title":"Nat. Genet."},{"key":"2601_CR27","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1038\/s41588-021-00783-5","volume":"53","author":"SA Lambert","year":"2021","unstructured":"Lambert, S. A. et al. The Polygenic Score Catalog as an open database for reproducibility and systematic evaluation. Nat. Genet. 53, 420\u2013425 (2021).","journal-title":"Nat. Genet."},{"key":"2601_CR28","doi-asserted-by":"crossref","first-page":"2348","DOI":"10.1093\/hmg\/ddac037","volume":"31","author":"Y Yu","year":"2022","unstructured":"Yu, Y. et al. Polygenic risk impacts PDGFRA mutation penetrance in non-syndromic cleft lip and palate. Hum. Mol. Genet. 31, 2348\u20132357 (2022).","journal-title":"Hum. Mol. Genet."},{"key":"2601_CR29","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1038\/s41586-023-05844-9","volume":"616","author":"Y Xu","year":"2023","unstructured":"Xu, Y. et al. An atlas of genetic scores to predict multi-omic traits. Nature 616, 123\u2013131 (2023).","journal-title":"Nature"},{"key":"2601_CR30","doi-asserted-by":"crossref","first-page":"1280","DOI":"10.3390\/genes11111280","volume":"11","author":"Y Yang","year":"2020","unstructured":"Yang, Y., Suzuki, A., Iwata, J. & Jun, G. Secondary genome-wide association study using novel analytical strategies disentangle genetic components of cleft lip and\/or cleft palate in 1q32.2. Genes 11, 1280 (2020).","journal-title":"Genes"},{"key":"2601_CR31","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1111\/j.1541-0420.2011.01713.x","volume":"68","author":"H Schwender","year":"2012","unstructured":"Schwender, H., Taub, M. A., Beaty, T. H., Marazita, M. L. & Ruczinski, I. Rapid testing of SNPs and gene\u2013environment interactions in case\u2013parent trio data based on exact analytic parameter estimation. Biometrics 68, 766\u2013773 (2012).","journal-title":"Biometrics"},{"key":"2601_CR32","first-page":"506","volume":"52","author":"RS Spielman","year":"1993","unstructured":"Spielman, R. S., McGinnis, R. E. & Ewens, W. J. Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am. J. Hum. Genet. 52, 506\u2013516 (1993).","journal-title":"Am. J. Hum. Genet."},{"key":"2601_CR33","doi-asserted-by":"crossref","first-page":"1516","DOI":"10.1126\/science.273.5281.1516","volume":"273","author":"R Risch","year":"1996","unstructured":"Risch, R. & Merikangas, M. The future of genetic studies of complex human diseases. Science 273, 1516\u20131517 (1996).","journal-title":"Science"},{"key":"2601_CR34","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1007\/s10038-004-0217-5","volume":"50","author":"KL Ayres","year":"2005","unstructured":"Ayres, K. L. & Curnow, R. N. Detecting non-multiplicative genotype relative risks from transmissions of parental alleles to affected children. J. Hum. Genet. 50, 46\u201348 (2005).","journal-title":"J. Hum. Genet."},{"key":"2601_CR35","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1086\/302566","volume":"65","author":"D Clayton","year":"1999","unstructured":"Clayton, D. & Jones, H. Transmission\/disequilibrium tests for extended marker haplotypes. Am. J. Hum. Genet. 65, 1161\u20131169 (1999).","journal-title":"Am. J. Hum. Genet."},{"key":"2601_CR36","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1111\/j.1469-1809.1995.tb00751.x","volume":"59","author":"PC Sham","year":"1995","unstructured":"Sham, P. C. & Curtis, D. An extended transmission\/disequilibrium test (TDT) for multi-allele marker loci. Ann. Hum. Genet. 59, 323\u2013336 (1995).","journal-title":"Ann. Hum. Genet."},{"key":"2601_CR37","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1038\/sj.ejhg.5200494","volume":"8","author":"GR Abecasis","year":"2000","unstructured":"Abecasis, G. R., Cookson, W. O. C. & Cardon, L. R. Pedigree tests of transmission disequilibrium. Eur. J. Hum. Genet. 8, 545\u2013551 (2000).","journal-title":"Eur. J. Hum. Genet."},{"key":"2601_CR38","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1002\/(SICI)1098-2272(1999)16:3<261::AID-GEPI3>3.0.CO;2-M","volume":"16","author":"DJ Schaid","year":"1999","unstructured":"Schaid, D. J. Case-parents design for gene\u2013environment interaction. Genet. Epidemiol. 16, 261\u2013273 (1999).","journal-title":"Genet. Epidemiol."},{"key":"2601_CR39","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1086\/302707","volume":"66","author":"DM Umbach","year":"2000","unstructured":"Umbach, D. M. & Weinberg, C. R. The use of case\u2013parent triads to study joint effects of genotype and exposure. Am. J. Hum. Genet. 66, 251\u2013261 (2000).","journal-title":"Am. J. Hum. Genet."},{"key":"2601_CR40","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1002\/gepi.10307","volume":"26","author":"HJ Cordell","year":"2004","unstructured":"Cordell, H. J., Barratt, B. J. & Clayton, D. G. Case\/pseudocontrol analysis in genetic association studies: a unified framework for detection of genotype and haplotype associations, gene\u2013gene and gene\u2013environment interactions, and parent-of-origin effects. Genet. Epidemiol. 26, 167\u2013185 (2004).","journal-title":"Genet. Epidemiol."},{"key":"2601_CR41","first-page":"1006","volume":"60","author":"LE Mitchell","year":"1997","unstructured":"Mitchell, L. E. Differentiating between fetal and maternal genotypic effects, using the transmission test for linkage disequilibrium. Am. J. Hum. Genet. 60, 1006\u20131007 (1997).","journal-title":"Am. J. Hum. Genet."},{"key":"2601_CR42","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1086\/301802","volume":"62","author":"CR Weinberg","year":"1998","unstructured":"Weinberg, C. R., Wilcox, A. J. & Lie, R. T. A log-linear approach to case-parent-triad data: assessing effects of disease genes that act either directly or through maternal effects and that may be subject to parental imprinting. Am. J. Hum. Genet. 62, 969\u2013978 (1998).","journal-title":"Am. J. Hum. Genet."},{"key":"2601_CR43","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1038\/sj.ejhg.5200625","volume":"9","author":"S Horvath","year":"2001","unstructured":"Horvath, S., Xu, X. & Laird, N. M. The family based association test method: strategies for studying general genotype\u2013phenotype associations. Eur. J. Hum. Genet. 9, 301\u2013306 (2001).","journal-title":"Eur. J. Hum. Genet."},{"key":"2601_CR44","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1002\/gepi.209","volume":"23","author":"C Lange","year":"2002","unstructured":"Lange, C. & Laird, N. M. On a general class of conditional tests for family-based association studies in genetics: the asymptotic distribution, the conditional power, and optimality considerations. Genet. Epidemiol. 23, 165\u2013180 (2002).","journal-title":"Genet. Epidemiol."},{"key":"2601_CR45","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1086\/381563","volume":"74","author":"C Lange","year":"2004","unstructured":"Lange, C., DeMeo, D., Silverman, E. K., Weiss, S. T. & Laird, N. M. PBAT: tools for family-based association studies. Am. J. Hum. Genet. 74, 367\u2013369 (2004).","journal-title":"Am. J. Hum. Genet."},{"key":"2601_CR46","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1038\/s41586-023-06079-4","volume":"618","author":"Y Ding","year":"2023","unstructured":"Ding, Y. et al. Polygenic scoring accuracy varies across the genetic ancestry continuum. Nature 618, 774\u2013781 (2023).","journal-title":"Nature"},{"key":"2601_CR47","doi-asserted-by":"crossref","first-page":"621018","DOI":"10.3389\/fcell.2021.621018","volume":"9","author":"W Zhang","year":"2021","unstructured":"Zhang, W. et al. Detecting gene-environment interaction for maternal exposures using case\u2013parent trios ascertained through a case with non-syndromic orofacial cleft. Front. Cell. Dev. Biol. 9, 621018 (2021).","journal-title":"Front. Cell. Dev. Biol."},{"key":"2601_CR48","doi-asserted-by":"crossref","first-page":"2349","DOI":"10.1056\/NEJMoa1605086","volume":"375","author":"AV Khera","year":"2016","unstructured":"Khera, A. V. et al. Genetic risk, adherence to a healthy lifestyle, and coronary disease. N. Engl. J. Med. 375, 2349\u20132358 (2016).","journal-title":"N. Engl. J. Med."},{"key":"2601_CR49","doi-asserted-by":"crossref","first-page":"1295","DOI":"10.1001\/jamaoncol.2016.1025","volume":"2","author":"P Maas","year":"2016","unstructured":"Maas, P. et al. Breast cancer risk from modifiable and nonmodifiable risk factors among white women in the United States. JAMA Oncol. 2, 1295\u20131302 (2016).","journal-title":"JAMA Oncol."},{"key":"2601_CR50","doi-asserted-by":"crossref","first-page":"2211","DOI":"10.1158\/0008-5472.CAN-12-2388","volume":"73","author":"M Garcia-Closas","year":"2013","unstructured":"Garcia-Closas, M. et al. Common genetic polymorphisms modify the effect of smoking on absolute risk of bladder cancer. Cancer Res. 73, 2211\u20132220 (2013).","journal-title":"Cancer Res."},{"key":"2601_CR51","doi-asserted-by":"crossref","DOI":"10.1186\/s13059-016-0926-z","volume":"17","author":"TR Gaunt","year":"2016","unstructured":"Gaunt, T. R. et al. Systematic identification of genetic influences on methylation across the human life course. Genome Biol. 17, 61\u2013z (2016).","journal-title":"Genome Biol."},{"key":"2601_CR52","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1093\/aje\/kwu283","volume":"181","author":"S Burgess","year":"2015","unstructured":"Burgess, S. & Thompson, S. G. Multivariable Mendelian randomization: the use of pleiotropic genetic variants to estimate causal effects. Am. J. Epidemiol. 181, 251\u2013260 (2015).","journal-title":"Am. J. Epidemiol."},{"key":"2601_CR53","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1038\/s41586-018-0579-z","volume":"562","author":"C Bycroft","year":"2018","unstructured":"Bycroft, C. et al. The UK Biobank resource with deep phenotyping and genomic data. Nature 562, 203\u2013209 (2018).","journal-title":"Nature"},{"key":"2601_CR54","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1093\/oxfordjournals.aje.a010093","volume":"150","author":"S Schmidt","year":"1999","unstructured":"Schmidt, S. & Schaid, D. J. Potential misinterpretation of the case-only study to assess gene\u2013environment interaction. Am. J. Epidemiol. 150, 878\u2013885 (1999).","journal-title":"Am. J. Epidemiol."},{"key":"2601_CR55","unstructured":"Falconer, D. S. & Mackay, T. F. C. Introduction to Quantitative Genetics (Addison Wesley Longman, 1996)."},{"key":"2601_CR56","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1002\/gepi.22250","volume":"43","author":"J An","year":"2019","unstructured":"An, J., Won, S., Lutz, S. M., Hecker, J. & Lange, C. Effect of population stratification on SNP-by-environment interaction. Genet. Epidemiol. 43, 1046\u20131055 (2019).","journal-title":"Genet. Epidemiol."},{"key":"2601_CR57","doi-asserted-by":"crossref","first-page":"1332","DOI":"10.1038\/s41562-019-0757-5","volume":"3","author":"A Abdellaoui","year":"2019","unstructured":"Abdellaoui, A. et al. Genetic correlates of social stratification in Great Britain. Nat. Hum. Behav. 3, 1332\u20131342 (2019).","journal-title":"Nat. Hum. Behav."},{"key":"2601_CR58","doi-asserted-by":"crossref","first-page":"e3002511","DOI":"10.1371\/journal.pbio.3002511","volume":"22","author":"C Veller","year":"2024","unstructured":"Veller, C. & Coop, G. M. Interpreting population- and family-based genome-wide association studies in the presence of confounding. PLoS Biol. 22, e3002511 (2024).","journal-title":"PLoS Biol."},{"key":"2601_CR59","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1038\/s41588-022-01036-9","volume":"54","author":"O Weissbrod","year":"2022","unstructured":"Weissbrod, O. et al. Leveraging fine-mapping and multipopulation training data to improve cross-population polygenic risk scores. Nat. Genet. 54, 450\u2013458 (2022).","journal-title":"Nat. Genet."},{"key":"2601_CR60","doi-asserted-by":"crossref","first-page":"1369767","DOI":"10.3389\/fpsyt.2024.1369767","volume":"15","author":"Z Schmilovich","year":"2024","unstructured":"Schmilovich, Z. et al. Copy-number variants and polygenic risk for intelligence confer risk for autism spectrum disorder irrespective of their effects on cognitive ability. Front. Psychiatry 15, 1369767 (2024).","journal-title":"Front. Psychiatry"},{"key":"2601_CR61","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1177\/13623613241258546","volume":"29","author":"X Dai","year":"2025","unstructured":"Dai, X. et al. The role of circadian rhythms and sleep in the aetiology of autism spectrum disorder and attention-deficit\/hyperactivity disorder: new evidence from bidirectional two-sample Mendelian randomization analysis. Autism 29, 76\u201386 (2025).","journal-title":"Autism"},{"key":"2601_CR62","doi-asserted-by":"crossref","first-page":"114679","DOI":"10.1016\/j.psychres.2022.114679","volume":"314","author":"A Baranova","year":"2022","unstructured":"Baranova, A. et al. Shared genetics between autism spectrum disorder and attention-deficit\/hyperactivity disorder and their association with extraversion. Psychiatry Res. 314, 114679 (2022).","journal-title":"Psychiatry Res."},{"key":"2601_CR63","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.ajhg.2021.11.008","volume":"109","author":"F Prive","year":"2022","unstructured":"Prive, F. et al. Portability of 245 polygenic scores when derived from the UK Biobank and applied to 9 ancestry groups from the same cohort. Am. J. Hum. Genet. 109, 12\u201323 (2022).","journal-title":"Am. J. Hum. Genet."},{"key":"2601_CR64","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1176\/appi.ajp.2019.18091085","volume":"176","author":"AB Zheutlin","year":"2019","unstructured":"Zheutlin, A. B. et al. Penetrance and pleiotropy of polygenic risk scores for schizophrenia in 106,160 patients across four health care systems. Am. J. Psychiatry 176, 846\u2013855 (2019).","journal-title":"Am. J. Psychiatry"},{"key":"2601_CR65","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1038\/s41588-020-0594-5","volume":"52","author":"N Cai","year":"2020","unstructured":"Cai, N. et al. Minimal phenotyping yields genome-wide association signals of low specificity for major depression. Nat. Genet. 52, 437\u2013447 (2020).","journal-title":"Nat. Genet."},{"key":"2601_CR66","doi-asserted-by":"publisher","unstructured":"Gui, Y. et al. Sex-specific genetic association between psychiatric disorders and cognition, behavior and brain imaging in children and adults. Transl. Psychiatry https:\/\/doi.org\/10.1038\/s41398-022-02041-6 (2022).","DOI":"10.1038\/s41398-022-02041-6"},{"key":"2601_CR67","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/j.jpsychires.2022.06.019","volume":"152","author":"BB Lahey","year":"2022","unstructured":"Lahey, B. B. et al. Associations of polygenic risk for attention-deficit\/hyperactivity disorder with general and specific dimensions of childhood psychological problems and facets of impulsivity. J. Psychiatr. Res. 152, 187\u2013193 (2022).","journal-title":"J. Psychiatr. Res."},{"key":"2601_CR68","doi-asserted-by":"crossref","unstructured":"Chen, T. et al. Genomic insights for personalised care in lung cancer and smoking cessation: motivating at-risk individuals toward evidence-based health practices. eBioMedicine 110, 105441 (2024).","DOI":"10.1016\/j.ebiom.2024.105441"},{"key":"2601_CR69","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1038\/nature15393","volume":"526","author":"A Auton","year":"2015","unstructured":"Auton, A. et al. A global reference for human genetic variation. Nature 526, 68\u201374 (2015).","journal-title":"Nature"},{"key":"2601_CR70","first-page":"469","volume":"35","author":"TH Beaty","year":"2011","unstructured":"Beaty, T. H. et al. Evidence for gene-environment interaction in a genome wide study of nonsyndromic cleft palate. Genet. Epidemiol. 35, 469\u2013478 (2011).","journal-title":"Genet. Epidemiol."},{"key":"2601_CR71","doi-asserted-by":"publisher","unstructured":"Wang, Z. PGS-TRI. Zenodo https:\/\/doi.org\/10.5281\/zenodo.19189683 (2026).","DOI":"10.5281\/zenodo.19189683"},{"key":"2601_CR72","doi-asserted-by":"publisher","unstructured":"Wang, Z. PGS-TRI-Analysis. Zenodo https:\/\/doi.org\/10.5281\/zenodo.19353771 (2026).","DOI":"10.5281\/zenodo.19353771"},{"key":"2601_CR73","doi-asserted-by":"crossref","unstructured":"Pebesma, E. & Bivand, R. Spatial Data Science: With Applications in R (Chapman and Hall\/CRC, 2023).","DOI":"10.1201\/9780429459016"},{"key":"2601_CR74","doi-asserted-by":"crossref","first-page":"439","DOI":"10.32614\/RJ-2018-009","volume":"10","author":"E Pebesma","year":"2018","unstructured":"Pebesma, E. Simple features for R: standardized support for spatial vector data. The R J. 10, 439\u2013446 (2018).","journal-title":"The R J."}],"container-title":["Nature Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41588-026-02601-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41588-026-02601-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41588-026-02601-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T13:40:44Z","timestamp":1781271644000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41588-026-02601-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6]]},"references-count":74,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2026,6]]}},"alternative-id":["2601"],"URL":"https:\/\/doi.org\/10.1038\/s41588-026-02601-2","relation":{},"ISSN":["1061-4036","1546-1718"],"issn-type":[{"value":"1061-4036","type":"print"},{"value":"1546-1718","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6]]},"assertion":[{"value":"25 October 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 April 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 June 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}