Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) have a similar burden of rare protein-truncating variants

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Abstract

We analyze the exome sequences of approximately 8,000 children with autism spectrum disorder (ASD) and/or attention-deficit/hyperactivity disorder (ADHD) and 5,000 controls, and we find that ASD and ADHD have a similar burden of rare protein-truncating variants in evolutionarily constrained genes, both significantly higher than controls. This motivates a combined analysis across ASD and ADHD, which identifies microtubule-associated protein 1A ( MAP1A) as a novel exome-wide significant gene conferring risk for childhood psychiatric disorders.

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Most cited references 11

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Testing for an Unusual Distribution of Rare Variants

Benjamin M. Neale, Manuel A. Rivas, Benjamin Voight … (2011)

Introduction High throughput sequencing of the human genome is now a reality: recent advances in sequencing technology now permit near complete ascertainment of genetic variation, including rare variants ( p0), some neutral, and some protective (pi

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Mutations in RAI1 associated with Smith-Magenis syndrome.

Sarah H Elsea, Brenda Finucane, Allen T. Newton … (2003)

Smith-Magenis syndrome (SMS) is a mental retardation syndrome associated with deletions involving chromosome 17p11.2. Persons with SMS have characteristic behavioral abnormalities, including self-injurious behaviors and sleep disturbance, and distinct craniofacial and skeletal anomalies. We identified dominant frameshift mutations leading to protein truncation in RAI1 in three individuals who have phenotypic features consistent with SMS but do not have 17p11.2 deletions detectable by standard fluorescence in situ hybridization techniques.

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Biological Overlap of Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder: Evidence From Copy Number Variants

Joanna Martin, Miriam Cooper, Marian Hamshere … (2014)

Objective Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) often co-occur and share genetic risks. The aim of this analysis was to determine more broadly whether ADHD and ASD share biological underpinnings. Method We compared copy number variant (CNV) data from 727 children with ADHD and 5,081 population controls to data from 996 individuals with ASD and an independent set of 1,287 controls. Using pathway analyses, we investigated whether CNVs observed in individuals with ADHD have an impact on genes in the same biological pathways as on those observed in individuals with ASD. Results The results suggest that the biological pathways affected by CNVs in ADHD overlap with those affected by CNVs in ASD more than would be expected by chance. Moreover, this was true even when specific CNV regions common to both disorders were excluded from the analysis. After correction for multiple testing, genes involved in 3 biological processes (nicotinic acetylcholine receptor signalling pathway, cell division, and response to drug) showed significant enrichment for case CNV hits in the combined ADHD and ASD sample. Conclusion The results of this study indicate the presence of significant overlap of shared biological processes disrupted by large rare CNVs in children with these 2 neurodevelopmental conditions.

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Author and article information

Journal

Journal ID (nlm-journal-id): 9809671

Journal ID (pubmed-jr-id): 21092

Journal ID (nlm-ta): Nat Neurosci

Journal ID (iso-abbrev): Nat. Neurosci.

Title: Nature neuroscience

ISSN (Print): 1097-6256

ISSN (Electronic): 1546-1726

Publication date Nihms-submitted: 29 October 2019

Publication date (Electronic): 25 November 2019

Publication date (Print): December 2019

Publication date PMC-release: 25 May 2020

Volume: 22

Issue: 12

Pages: 1961-1965

Affiliations

[1) ]Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA

[2) ]Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA

[3) ]Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA

[4) ]The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark

[5) ]iSEQ, Centre for Integrative Sequencing, Aarhus University, Aarhus, Denmark

[6) ]Department of Biomedicine—Human Genetics, Aarhus University, Aarhus, Denmark

[7) ]Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark

[8) ]Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark

[9) ]A full list of authors can be found in the Supplementary Note

[10) ]Mental Health Services in the Capital Region of Denmark, Mental Health Center Copenhagen, University of Copenhagen, Copenhagen, Denmark

[11) ]Psychosis Research Unit, Aarhus University Hospital, Risskov, Denmark

[12) ]Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA

[13) ]Institute of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark

[14) ]Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

[15) ]National Centre for Register-based Research, Aarhus University, Aarhus, Denmark

[16) ]Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark

[17) ]Department of Medicine, Harvard Medical School, Boston, MA, USA

[18) ]Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland

Author notes

Author contributions

F.K.S. performed the analysis, and R.K.W., T.S., E.M.W., F.L., D.D., J.A.K., J.G., D.S.P., and J.B.M. contributed to the analysis. F.K.S., R.K.W., C.S., J.B.-G., M.B.-H., M.N., O.M., D.M.H., T.M.W., P.B.M., A.D.B., and the iPSYCH-Broad Consortium were involved in sample selection, handling, processing, and quality control. M.N., O.M., E.B.R., D.M.H., T.M.W., P.B.M., B.M.N., A.D.B., and M.J.D. were the project core PI group. M.J.D. directed the project, and B.M.N. and A.D.B. contributed to project direction. F.K.S. and M.J.D. wrote the manuscript.

[* ]: Corresponding authors, satterst@ 123456broadinstitute.org (F.K.S.), anders@ 123456biomed.au.dk (A.D.B.), and mjdaly@ 123456atgu.mgh.harvard.edu (M.J.D.).

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Manuscript ID: NIHMS1540803

DOI: 10.1038/s41593-019-0527-8

PMC ID: 6884695

PubMed ID: 31768057

SO-VID: 5027bd25-dd12-4e06-8113-0e4b11f963bf

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Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) have a similar burden of rare protein-truncating variants

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Most cited references 11

Testing for an Unusual Distribution of Rare Variants

Mutations in RAI1 associated with Smith-Magenis syndrome.

Biological Overlap of Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder: Evidence From Copy Number Variants

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