Polygenic and developmental profiles of autism differ by age at diagnosis

作者：Xinhe Zhang, Jakob Grove, Yuanjun Gu, Cornelia K. Buus, Lea K. Nielsen, Sharon Neufeld, Mahmoud Koko, Daniel Malawsky, Emma E. Wade, Ellen Verhoef, Anna Gui, Laura Hegemann, Carrie Allison, Alex Tsompanidis, Deep Adhya, Rosemary Holt, Omar Al-Rubaie, Ramin Ali Marandi Ghoddousi, Alexander Heazell, Jonathan Mill, Alice Franklin, Rosie Bamford, Matthew E. Hurles, Mahmoud Mousa, David H. Rowitch, Kathy K. Niakan, Graham J. Burton, Tereza Cindrová‐Davies, Deepak P. Srivastava, Lucia Dutan-Polit, Adam Pavlinek, Laura Sichlinger, Roland Nagy, Madeline A. Lancaster, José M. González, Tal Biron-Shental, Lidia V. Gabis, Dorothea L. Floris, Richard A. I. Bethlehem, Michael Lombardo, Marcin A. Radecki, Meng‐Chuan Lai, Yeshaya David M. Greenberg, Elizabeth Weir, Florina Uzefovsky, Yumnah T. Khan, Juan Pablo Del Río, Jonas Bybjerg‐Grauholm, David M. Hougaard, Ole Mors, Preben Bo Mortensen, Merete Nordentoft, Thomas Werge, Caroline M. Nievergelt, Adam X. Maihofer, Elizabeth G. Atkinson, Chia-Yen Chen, Karmel W. Choi, Jonathan R. I. Coleman, Nikolaos P. Daskalakis, Laramie E. Duncan, Renato Polimanti, Cindy Aaronson, Ananda B. Amstadter, Søren Bo Andersen, Ole A. Andreassen, Paul A. Arbisi, Allison E. Ashley‐Koch, S. Bryn Austin, Esmina Avdibegović, Dragan Babić, Silviu‐Alin Bacanu, Dewleen G. Baker, Anthony Batzler, Jean C. Beckham, Síntia Belangero, Corina Benjet, Carisa Bergner, Linda M. Bierer, Joanna M. Biernacka, Laura J. Bierut, Jonathan I. Bisson, Marco P. Boks, Elizabeth Bolger, Amber Brandolino, Gerome Breen, Rodrigo A. Bressan, Richard A. Bryant, Angela C. Bustamante, Jonas Bybjerg‐Grauholm, Marie Bækvad-Hansen, Sigrid Børte, Leah Cahn, Joseph R. Calabrese, José Miguel Caldas‐de‐Almeida, Chris Chatzinakos, Sheraz Cheema, Sean Clouston, Lucía Colodro‐Conde, Brandon J. Coombes, Carlos Cruz-Fuentes, Anders M. Dale, Shareefa Dalvie, Lea K. Davis, Jürgen Deckert, Douglas L. Delahanty, Michelle F. Dennis, Frank Désarnaud, Christopher P. DiPietro, Seth G. Disner, Anna R. Docherty, Katharina Domschke, Grete Dyb, Alma Džubur Kulenović, Howard J. Edenberg, Alexandra Evans, Chiara Fabbri, Negar Fani, Lindsay A. Farrer, Adriana Feder, Norah C. Feeny, Janine D. Flory, David Forbes, Carol E. Franz, Sandro Galea, Melanie E. Garrett, Bizu Gelaye, Joel Gelernter, Elbert Geuze, Charles F. Gillespie, Slavina B. Goleva, Scott D. Gordon, Afërdita Goçi, Lana Ruvolo Grasser, Camila Guindalini, Magali Haas, Saskia P. Hagenaars, Michael A. Hauser, Andrew C. Heath, Sian Hemmings, Victor Hesselbrock, Ian B. Hickie, Kelleigh Hogan, David M. Hougaard, Hailiang Huang, Laura M. Huckins, Kristian Hveem, Miro Jakovljević, Arash Javanbakht, Gregory D. Jenkins, Jessica Johnson, Ian D. Jones, Tanja Jovanović, Karen‐Inge Karstoft, Milissa L. Kaufman, James L. Kennedy, Ronald C. Kessler, Alaptagin Khan, Nathan A. Kimbrel, Anthony P. King, Nastassja Koen, Roman Kotov, Henry R. Kranzler, Kristi Krebs, William S. Kremen, Pei Fen Kuan, Bruce R. Lawford, Lauren A. M. Lebois, Kelli Lehto, Daniel F. Levey, Catrin Lewis, Israel Liberzon, Sarah D. Linnstaedt, Mark W. Logue, Adriana Lori, Yi Lu, Benjamin J. Luft, Michelle K. Lupton, Jurjen J. Luykx, Iouri Makotkine, Jessica L. Maples‐Keller, Shelby Marchese, Charles R. Marmar, Nicholas G. Martin, Gabriela Ariadna Martínez-Levy, Kerrie McAloney, Alexander C. McFarlane, Katie A. McLaughlin, Samuel A. McLean, Sarah E. Medland, Divya Mehta, Jacquelyn L. Meyers, Vasiliki Michopoulos, Elizabeth A. Mikita, Lili Milani, William Milberg, Mark W. Miller, Rajendra A. Morey, C. Phillip Morris, Ole Mors, Mary S. Mufford, Elliot C. Nelson, Sonya B. Norman, Nicole R Nugent, Meaghan O’Donnell, Holly K. Orcutt, Pedro Mário Pan, Matthew S. Panizzon, Gita A. Pathak, Edward Peters, Alan L. Peterson, Matthew Peverill, Robert H. Pietrzak, Melissa A. Polusny, Bernice Porjesz, Abigail Powers, Xuejun Qin, Andrew Ratanatharathorn, Victoria B. Risbrough, Andrea L. Roberts, Alex O. Rothbaum, Barbara O. Rothbaum, Peter Roy‐Byrne, Kenneth J. Ruggiero, Ariane L. Rung, Heiko Runz, Bart P. F. Rutten, Stacey Saenz de Viteri, Giovanni Abrahão Salum, Laura Sampson, Sixto E. Sánchez, Marcos Santoro, Carina Seah, Soraya Seedat, Julia S. Seng, Andrey A. Shabalin, Christina M. Sheerin, Derrick Silove, Alicia K. Smith, Jordan W. Smoller, Scott R. Sponheim, Dan J. Stein, Synne Øien Stensland, Jennifer S. Stevens, Jennifer A. Sumner, Martin H. Teicher, Wesley K. Thompson, Arun Tiwari, Edward Trapido, Monica Uddin, Robert J. Ursano, Unnur Valdimarsdóttir, Miranda Van Hooff, Eric Vermetten, Christiaan H. Vinkers, Joanne Voisey, Yunpeng Wang, Zhewu Wang, Monika A. Waszczuk, Heike Weber, Frank R. Wendt, Michelle A. Williams, Douglas E. Williamson, Bendik S Winsvold, Sherry Winternitz, Christiane Wolf, Erika J. Wolf, Yan Xia, Xiong Ying, Rachel Yehuda, Keith A. Young, Ross McD. Young, Clement C. Zai, Gwyneth Zai, Mark Zervas, Hongyu Zhao, Lori A. Zoellner, John‐Anker Zwart, Terri A. deRoon‐Cassini, Sanne J.H. van Rooij, Leigh L. van den Heuvel, Murray B. Stein, Kerry J. Ressler, Karestan C. Koenen, Daniel H. Geschwind, Naomi R. Wray, Alexandra Havdahl, Angelica Ronald, Beaté St Pourcain, Elise Robinson, Thomas Bourgeron, Simon Baron‐Cohen, Anders D. Børglum, Hilary C. Martin, Varun Warrier · 发表于：Nature · 年份：2025 · DOI：10.1038/s41586-025-09542-6 · 被引用次数：35 · 研究领域：Autism Spectrum Disorder Research、Genetics and Neurodevelopmental Disorders、Child Nutrition and Feeding Issues

Abstract Although autism has historically been conceptualized as a condition that emerges in early childhood 1,2 , many autistic people are diagnosed later in life 3–5 . It is unknown whether earlier- and later-diagnosed autism have different developmental trajectories and genetic profiles. Using longitudinal data from four independent birth cohorts, we demonstrate that two different socioemotional and behavioural trajectories are associated with age at diagnosis. In independent cohorts of autistic individuals, common genetic variants account for approximately 11% of the variance in age at autism diagnosis, similar to the contribution of individual sociodemographic and clinical factors, which typically explain less than 15% of this variance. We further demonstrate that the polygenic architecture of autism can be broken down into two modestly genetically correlated ( r g = 0.38, s.e. = 0.07) autism polygenic factors. One of these factors is associated with earlier autism diagnosis and lower social and communication abilities in early childhood, but is only moderately genetically correlated with attention deficit–hyperactivity disorder (ADHD) and mental-health conditions. Conversely, the second factor is associated with later autism diagnosis and increased socioemotional and behavioural difficulties in adolescence, and has moderate to high positive genetic correlations with ADHD and mental-health conditions. These findings indicate that earlier- and later-diagnosed autism have ...