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; Armin Raznahan; Wesley K. Thompson; Dorte Helenius; Thomas Werge; Andrés Ingason; iPSYCH Investigators

doi:10.1038/s41525-024-00450-8

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, Armin Raznahan, Wesley K. Thompson, Dorte Helenius, Thomas Werge, Andrés Ingason^*, iPSYCH Investigators

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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.

Original language	English
Article number	67
Journal	npj Genomic Medicine
Volume	9
Issue	1
ISSN	2056-7944
DOIs	https://doi.org/10.1038/s41525-024-00450-8
Publication status	Published - Dec 2024

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Montalbano, S., Krebs, M. D., Rosengren, A., Vaez, M., Hellberg, K. L. G., Mortensen, P. B., Børglum, A. D., Geschwind, D. H., Raznahan, A., Thompson, W. K., Helenius, D., Werge, T., Ingason, A., & iPSYCH Investigators (2024). Analysis of exonic deletions in a large population study provides novel insights into NRXN1 pathology. npj Genomic Medicine, 9(1), Article 67. https://doi.org/10.1038/s41525-024-00450-8

@article{9d8323dd1bb94d1c98adf650675c6d09,

title = "Analysis of exonic deletions in a large population study provides novel insights into NRXN1 pathology",

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.",

author = "Simone Montalbano and Krebs, {Morten Dybdahl} and Anders Rosengren and Morteza Vaez and Hellberg, {Kajsa Lotta Georgii} and Mortensen, {Preben B.} and B{\o}rglum, {Anders D.} and Geschwind, {Daniel H.} and Marie B{\ae}kvad-Hansen and Jonas Bybjerg-Grauholm and Pedersen, {Marianne Gi{\o}rtz} and Petersen, {Liselotte V.} and Jakob Christensen and Esben Agerbo and Pedersen, {Carsten B.} and Vilhj{\'a}lmsson, {Bjarni J.} and Joeri Meijsen and Vivek Appadurai and Richard Zetterberg and Jesper G{\aa}din and Schork, {Andrew J.} and Alfonso Buil and Als, {Thomas D.} and Jakob Grove and Ole Mors and Merete Nordentoft and Hougaard, {David M.} and Armin Raznahan and Thompson, {Wesley K.} and Dorte Helenius and Thomas Werge and Andr{\'e}s Ingason and {iPSYCH Investigators}",

year = "2024",

month = dec,

doi = "10.1038/s41525-024-00450-8",

language = "English",

volume = "9",

journal = "npj Genomic Medicine",

issn = "2056-7944",

publisher = "Nature Publishing Group",

number = "1",

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Montalbano, S, Krebs, MD, Rosengren, A, Vaez, M, Hellberg, KLG, Mortensen, PB , Børglum, AD, Geschwind, DH, Raznahan, A, Thompson, WK, Helenius, D, Werge, T, Ingason, A & iPSYCH Investigators 2024, 'Analysis of exonic deletions in a large population study provides novel insights into NRXN1 pathology', npj Genomic Medicine, vol. 9, no. 1, 67. https://doi.org/10.1038/s41525-024-00450-8

Analysis of exonic deletions in a large population study provides novel insights into NRXN1 pathology. / Montalbano, Simone; Krebs, Morten Dybdahl; Rosengren, Anders et al.
In: npj Genomic Medicine, Vol. 9, No. 1, 67, 12.2024.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Analysis of exonic deletions in a large population study provides novel insights into NRXN1 pathology

AU - Montalbano, Simone

AU - Krebs, Morten Dybdahl

AU - Rosengren, Anders

AU - Vaez, Morteza

AU - Hellberg, Kajsa Lotta Georgii

AU - Mortensen, Preben B.

AU - Børglum, Anders D.

AU - Geschwind, Daniel H.

AU - Bækvad-Hansen, Marie

AU - Bybjerg-Grauholm, Jonas

AU - Pedersen, Marianne Giørtz

AU - Petersen, Liselotte V.

AU - Christensen, Jakob

AU - Agerbo, Esben

AU - Pedersen, Carsten B.

AU - Vilhjálmsson, Bjarni J.

AU - Meijsen, Joeri

AU - Appadurai, Vivek

AU - Zetterberg, Richard

AU - Gådin, Jesper

AU - Schork, Andrew J.

AU - Buil, Alfonso

AU - Als, Thomas D.

AU - Grove, Jakob

AU - Mors, Ole

AU - Nordentoft, Merete

AU - Hougaard, David M.

AU - Raznahan, Armin

AU - Thompson, Wesley K.

AU - Helenius, Dorte

AU - Werge, Thomas

AU - Ingason, Andrés

AU - iPSYCH Investigators

PY - 2024/12

Y1 - 2024/12

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85212680913&partnerID=8YFLogxK

U2 - 10.1038/s41525-024-00450-8

DO - 10.1038/s41525-024-00450-8

M3 - Journal article

C2 - 39695155

SN - 2056-7944

VL - 9

JO - npj Genomic Medicine

JF - npj Genomic Medicine

IS - 1

M1 - 67

ER -

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

Abstract

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