Polygenic scores for autism are associated with reduced neurite density in adults and children from the general population
Genetic variants linked to autism are thought to change cognition and behaviour by altering the structure and function of the brain. Although a substantial body of literature has identified structural brain differences in autism, it is unknown whether autism-associated common genetic variants are linked to changes in cortical macro- and micro-structure. We investigated this using neuroimaging and genetic data from adults (UK Biobank, N = 31,748) and children (ABCD, N = 4928). Using polygenic scores and genetic correlations we observe a robust negative association between common variants for autism and a magnetic resonance imaging derived phenotype for neurite density (intracellular volume fraction) in the general population. This result is consistent across both children and adults, in both the cortex and in white matter tracts, and confirmed using polygenic scores and genetic correlations. There were no sex differences in this association. Mendelian randomisation analyses provide no evidence for a causal relationship between autism and intracellular volume fraction, although this should be revisited using better powered instruments. Overall, this study provides evidence for shared common variant genetics between autism and cortical neurite density.
Authors
- Deepak Srivastava (ORCID: https://orcid.org/0000-0002-3480-5953)
- Joanna Davis
- Adam Pavlinek (ORCID: https://orcid.org/0000-0002-0138-8321)
- Varun Warrier (ORCID: https://orcid.org/0000-0003-4532-8571)
- Richard A. I. Bethlehem (ORCID: https://orcid.org/0000-0002-0714-0685)
- Ole Mors (ORCID: https://orcid.org/0000-0002-5660-0393)
- Daniel H. Geschwind (ORCID: https://orcid.org/0000-0003-2896-3450)
- Marcin A. Radecki (ORCID: https://orcid.org/0000-0001-8702-2381)
- Rafael Romero-García (ORCID: https://orcid.org/0000-0002-5199-4573)
- Laura Sichlinger (ORCID: https://orcid.org/0000-0003-1359-9633)
- David M. Greenberg (ORCID: https://orcid.org/0000-0001-8658-2352)
- Anders D. Børglum (ORCID: https://orcid.org/0000-0001-8627-7219)
- Merete Nordentoft (ORCID: https://orcid.org/0000-0003-4895-7023)
- Alexandra Havdahl (ORCID: https://orcid.org/0000-0002-9268-0423)
- Xinhe Zhang (ORCID: https://orcid.org/0000-0001-6634-1287)
- Simon Baron‐Cohen (ORCID: https://orcid.org/0000-0001-9217-2544)
- Lucia Dutan Polit
- Meng‐Chuan Lai (ORCID: https://orcid.org/0000-0002-9593-5508)
- David H. Rowitch (ORCID: https://orcid.org/0000-0002-0079-0060)
- Mahmoud Koko (ORCID: https://orcid.org/0000-0001-9512-0184)
- Dorothea L. Floris (ORCID: https://orcid.org/0000-0001-5838-6821)
- Jonathan S. Mill (ORCID: https://orcid.org/0000-0003-1115-3224)
- Jakob Grove (ORCID: https://orcid.org/0000-0003-2284-5744)
- Thomas Werge (ORCID: https://orcid.org/0000-0003-1829-0766)
- Jonas Bybjerg‐Grauholm (ORCID: https://orcid.org/0000-0003-1705-4008)
- Saashi A. Bedford (ORCID: https://orcid.org/0000-0002-0491-5342)
- Elizabeth Weir (ORCID: https://orcid.org/0000-0001-5434-9193)
- Deep Adhya
- Carrie Allison (ORCID: https://orcid.org/0000-0003-2272-2090)
- Florina Uzefovsky (ORCID: https://orcid.org/0000-0003-4571-2514)
- Eva-Maria Stauffer (ORCID: https://orcid.org/0000-0003-2904-5555)
- Matthew E. Hurles (ORCID: https://orcid.org/0000-0002-2333-7015)
- Hilary C. Martin (ORCID: https://orcid.org/0000-0002-4454-9084)
- Alex Tsompanidis (ORCID: https://orcid.org/0000-0002-7338-6536)
- Yuanjun Gu (ORCID: https://orcid.org/0000-0001-9475-0010)
- Alexander E. P. Heazell (ORCID: https://orcid.org/0000-0002-4303-7845)
- Rosemary Holt (ORCID: https://orcid.org/0000-0002-3650-0977)
- Madeline A. Lancaster (ORCID: https://orcid.org/0000-0003-2324-8853)
- Alice Franklin (ORCID: https://orcid.org/0000-0001-9793-582X)
- Lidia V. Gabis (ORCID: https://orcid.org/0000-0002-1612-5487)
- Yumnah Khan
- Kathy K. Niakan (ORCID: https://orcid.org/0000-0003-1646-4734)
- Michael Lombardo (ORCID: https://orcid.org/0000-0001-6780-8619)
- Preben Bo Mortensen (ORCID: https://orcid.org/0000-0002-4782-1450)
- José M. González (ORCID: https://orcid.org/0000-0001-5569-0705)
- Jonathan P. Davies (ORCID: https://orcid.org/0000-0002-9954-1565)
- Tal Biron-Shental
- David M. Hougaard
- Graham J. Burton
- Rosie Bamford
- Bonnie Ayeung
Institutions
- Statens Serum Institut (DK)
- University of Copenhagen (DK)
- Ben-Gurion University of the Negev (IL)
- IMT School for Advanced Studies Lucca (IT)
- Babraham Institute (GB)
- Norwegian Institute of Public Health (NO)
- Centre for Addiction and Mental Health (CA)
- Radboud University Nijmegen (NL)
- University of California, Los Angeles (US)
- Tel Aviv University (IL)
- MRC Laboratory of Molecular Biology (GB)
- King's College London (GB)
- University of Oslo (NO)
- University of Toronto (CA)
- University of Zurich (CH)
- Aarhus University (DK)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- University of Exeter (GB)
- University of Cambridge (GB)
- Mental Health Services (DK)
- The Francis Crick Institute (GB)
- Hospital for Sick Children (CA)
- Meir Medical Center (IL)
- Aarhus University Hospital (DK)
- Wellcome Sanger Institute (GB)
- Copenhagen University Hospital (DK)
- Radboud University Medical Center (NL)
- Maccabi Healthcare Services (IL)
- University of Manchester (GB)
- Italian Institute of Technology (IT)
- Spanish National Cancer Research Centre (ES)
- Centro de Investigación Biomédica en Red de Salud Mental (ES)
- Manchester University NHS Foundation Trust (GB)
- Lovisenberg Diakonale Høgskole (NO)
- Center for Neuroscience and Cognitive Systems (IT)
- Lundbeck Foundation (DK)
- National Taiwan University Hospital (TW)
- Instituto de Biomedicina de Sevilla (ES)
- Universidad de Sevilla (ES)
- Center for Autism and Related Disorders (US)
- University of Edinburgh (GB)
Publication Details
- Journal
- Molecular Psychiatry
- Published
- 2025-02-24
- DOI
- https://doi.org/10.1038/s41380-025-02927-z
- Citations
- 5
- Primary Topic
- Autism Spectrum Disorder Research
- Type
- article
- Field-Weighted Citation Impact
- 7.16
Funders
- Autism Speaks
- Aarhus Universitet
- Wellcome Trust
- European Federation of Pharmaceutical Industries and Associations
- UK Research and Innovation
- Simons Foundation Autism Research Initiative
- National Institute for Health and Care Research
- European Commission
- Lundbeckfonden
- Novo Nordisk
- H. Lundbeck A/S
- HORIZON EUROPE Framework Programme
- Medical Research Council
- NIHR Cambridge Biomedical Research Centre
- National Institute of Mental Health