Genetic correlates of phenotypic heterogeneity in autism
Varun Warrier, Xinhe Zhang, Patrick Reed, Alexandra Havdahl, Tyler M. Moore, Freddy Cliquet, Claire S. Leblond, Thomas Rolland, Anders Rosengren, EU-AIMS LEAP, Antonia San José Cáceres, Hannah Hayward, Daisy Crawley, Jessica Faulkner, Jessica Sabet, Claire L. Ellis, Bethany Oakley, Eva Loth, Tony Charman, Declan Murphy, Rosemary Holt, Jack Waldman, Jessica Upadhyay, Nicola Gunby, Meng‐Chuan Lai, Gwilym Renouf, Amber Ruigrok, Emily Taylor, Hisham Ziauddeen, Julia Deakin, Sara Ambrosino di Bruttopilo, Sarai van Dijk, Yvonne Rijks, Tabitha Koops, Miriam Douma, Alyssia Spaan, Iris Selten, Maarten Steffers, Anna Ver Loren van Themaat, Nico Bast, Sarah Baumeister, Larry O’Dwyer, Carsten Bours, Annika Rausch, Daniel von Rhein, Ineke Cornelissen, Yvette de Bruin, Maartje J. Graauwmans, Elżbieta Kostrzewa, Élodie Cauvet, Kristiina Tammimies, Rouslan Sitnikow, Guillaume Dumas, Yang-Min Kim, Thomas Bourgeron, iPSYCH-Autism Working Group, David M. Hougaard, Jonas Bybjerg‐Grauholm, Thomas Werge, Preben Bo Mortensen, Ole Mors, Merete Nordentoft, Spectrum 10K and APEX Consortia, Dwaipayan Adhya, Armandina Alamanza, Carrie Allison, Isabelle Garvey, Tracey Parsons, Paula Smith, Alex Tsompanidis, Graham J. Burton, Alexander Heazell, Lidia V. Gabis, Tal Biron-Shental, Madeline A. Lancaster, Deepak P. Srivastava, Jonathan Mill, David H. Rowitch, Matthew E. Hurles, Daniel H. Geschwind, Anders D. Børglum, Elise Robinson, Jakob Grove, Hilary C. Martin, Thomas Bourgeron, Simon Baron‐Cohen
Abstract
Abstract The substantial phenotypic heterogeneity in autism limits our understanding of its genetic etiology. To address this gap, here we investigated genetic differences between autistic individuals ( n max = 12,893) based on core and associated features of autism, co-occurring developmental disabilities and sex. We conducted a comprehensive factor analysis of core autism features in autistic individuals and identified six factors. Common genetic variants were associated with the core factors, but de novo variants were not. We found that higher autism polygenic scores (PGS) were associated with lower likelihood of co-occurring developmental disabilities in autistic individuals. Furthermore, in autistic individuals without co-occurring intellectual disability (ID), autism PGS are overinherited by autistic females compared to males. Finally, we observed higher SNP heritability for autistic males and for autistic individuals without ID. Deeper phenotypic characterization will be critical in determining how the complex underlying genetics shape cognition, behavior and co-occurring conditions in autism.