Analysis of exonic deletions in a large population study provides novel insights into NRXN1 pathology

Simone Montalbano; Morten Dybdahl Krebs; Anders Rosengren; Morteza Vaez; Kajsa-Lotta Georgii Hellberg; Preben B Mortensen; Anders D Børglum; Daniel H Geschwind; iPSYCH Investigators; Armin Raznahan; Wesley K Thompson; Dorte Helenius; Thomas Werge; Andrés Ingason

doi:10.1038/s41525-024-00450-8

Analysis of exonic deletions in a large population study provides novel insights into NRXN1 pathology

NPJ Genom Med. 2024 Dec 19;9(1):67. doi: 10.1038/s41525-024-00450-8.

Authors

Simone Montalbano^{1

2}, Morten Dybdahl Krebs^{1

2}, Anders Rosengren^{1

2}, Morteza Vaez^{1

2}, Kajsa-Lotta Georgii Hellberg^{1

2}, Preben B Mortensen^{2

3}, Anders D Børglum^{2

4

5}, Daniel H Geschwind^{6

7

8

9}; iPSYCH Investigators; Armin Raznahan¹⁰, Wesley K Thompson^{2

11}, Dorte Helenius^{1

2}, Thomas Werge^{1

2

12}, Andrés Ingason^{13

14}

Collaborators

iPSYCH Investigators:
David M Hougaard, Merete Nordentoft, Ole Mors, Jakob Grove, Thomas D Als, Alfonso Buil, Andrew J Schork, Jesper Gådin, Richard Zetterberg, Vivek Appadurai, Joeri Meijsen, Bjarni J Vilhjálmsson, Carsten B Pedersen, Esben Agerbo, Jakob Christensen, Liselotte V Petersen, Marianne Giørtz Pedersen, Jonas Bybjerg-Grauholm, Marie Bækvad-Hansen

Affiliations

¹ Institute of Biological Psychiatry, Mental Health Services, Copenhagen University Hospital, Roskilde, Denmark.
² The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Copenhagen and Aarhus, Denmark.
³ National Centre for Register-based Research, Aarhus University, Aarhus, Denmark.
⁴ Department of Biomedicine - Human Genetics and the iSEQ Center, Aarhus University, Aarhus, Denmark.
⁵ Center for Genomics and Personalized Medicine, Aarhus, Denmark.
⁶ Department of Neurology, University of California, Los Angeles, CA, USA.
⁷ Department of Human Genetics, University of California, Los Angeles, CA, USA.
⁸ Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
⁹ Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
¹⁰ Section on Developmental Neurogenomics, Human Genetics Branch, National Institute of Mental Health Intramural Research Program, Bethesda, MD, USA.
¹¹ Laureate Institute for Brain Research, Tulsa, OK, USA.
¹² Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
¹³ Institute of Biological Psychiatry, Mental Health Services, Copenhagen University Hospital, Roskilde, Denmark. [email protected].
¹⁴ The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Copenhagen and Aarhus, Denmark. [email protected].

Abstract

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.

Abstract

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