Analysis of exonic deletions in a large population study provides novel insights into NRXN1 pathology
The NRXN1 locus is a hotspot for non-recurrent copy number variants and exon-disrupting NRXN1 deletions have been associated with increased risk of neurodevelopmental disorders in case-control studies. However, corresponding population-based estimates of prevalence and disease-associated risk are currently lacking. Also, most studies have not differentiated between deletions affecting exons of different NRXN1 splice variants nor considered intronic deletions. We used the iPSYCH2015 case-cohort sample to obtain unbiased estimates of the prevalence of NRXN1 deletions and their associated risk of autism, schizophrenia, depression, and ADHD. Most exon-disrupting deletions affected exons specific to the alpha isoform, and almost half of the non-exonic deletions represented a previously reported segregating founder deletion. Carriage of exon-disrupting NRXN1 deletions was associated with a threefold and twofold increased risk of autism and ADHD, respectively, whereas no significantly increased risk of depression or schizophrenia was observed. Our results highlight the importance of using population-based samples in genetic association studies.
Authors
- Simone Montalbano (ORCID: https://orcid.org/0000-0002-9846-0560)
- Ole Mors (ORCID: https://orcid.org/0000-0002-5660-0393)
- Preben Bo Mortensen (ORCID: https://orcid.org/0000-0002-5230-9865)
- Wesley K. Thompson (ORCID: https://orcid.org/0000-0002-1148-1976)
- Daniel H. Geschwind (ORCID: https://orcid.org/0000-0003-2896-3450)
- Marie Bækvad‐Hansen (ORCID: https://orcid.org/0000-0002-5881-1776)
- Carsten Bøcker Pedersen (ORCID: https://orcid.org/0000-0003-2077-8533)
- Andrew J. Schork (ORCID: https://orcid.org/0000-0003-4164-9335)
- Jakob Christensen (ORCID: https://orcid.org/0000-0002-9385-6435)
- Anders D. Børglum (ORCID: https://orcid.org/0000-0001-8627-7219)
- Merete Nordentoft (ORCID: https://orcid.org/0000-0003-4895-7023)
- Kajsa-Lotta Georgii Hellberg (ORCID: https://orcid.org/0000-0003-4779-7494)
- Joeri Meijsen (ORCID: https://orcid.org/0000-0002-4161-2199)
- Alfonso Buil (ORCID: https://orcid.org/0000-0002-3097-1014)
- Jakob Grove (ORCID: https://orcid.org/0000-0003-2284-5744)
- Thomas D. Als (ORCID: https://orcid.org/0000-0002-2963-1928)
- Esben Agerbo (ORCID: https://orcid.org/0000-0002-2849-524X)
- Jonas Bybjerg‐Grauholm (ORCID: https://orcid.org/0000-0003-1705-4008)
- Jesper R. Gådin (ORCID: https://orcid.org/0000-0002-9210-9534)
- Armin Raznahan (ORCID: https://orcid.org/0000-0002-5622-1190)
- Anders Rosengren (ORCID: https://orcid.org/0000-0002-6682-1288)
- Morten Dybdahl Krebs (ORCID: https://orcid.org/0000-0002-4452-0732)
- Morteza Vaez (ORCID: https://orcid.org/0000-0002-6256-5045)
- Bjarni Jóhann Vilhjálmsson (ORCID: https://orcid.org/0000-0003-2277-9249)
- Dorte Helenius
- Vivek Appadurai (ORCID: https://orcid.org/0000-0002-2148-6201)
- Liselotte Vogdrup Petersen (ORCID: https://orcid.org/0000-0002-0479-5379)
- Andrés Ingason
- Richard Zetterberg (ORCID: https://orcid.org/0000-0002-4284-4063)
- Marianne Giørtz Pedersen
- Thomas Werge
- David M. Hougaard
Institutions
- Statens Serum Institut (DK)
- University of Copenhagen (DK)
- University of California, Los Angeles (US)
- Aarhus University (DK)
- Mental Health Services (DK)
- Aarhus University Hospital (DK)
- Copenhagen University Hospital (DK)
- Lundbeck Foundation (DK)
- Capital Region of Denmark (DK)
- National Institute of Mental Health (US)
- Laureate Institute for Brain Research (US)
- Center for Autism and Related Disorders (US)
Publication Details
- Journal
- npj Genomic Medicine
- Published
- 2024-12-19
- DOI
- https://doi.org/10.1038/s41525-024-00450-8
- Citations
- 3
- Primary Topic
- Genomic variations and chromosomal abnormalities
- Type
- article
- Field-Weighted Citation Impact
- 1.65
Funders
- Lundbeckfonden
- H. Lundbeck A/S
- National Institutes of Health