Autism spectrum disorder and attention deficit hyperactivity disorder have a similar burden of rare protein-truncating variants
Open accessAbstract
The exome sequences of approximately 8,000 children with autism spectrum disorder (ASD) and/or attention deficit hyperactivity disorder (ADHD) and 5,000 controls were analyzed, finding that individuals with ASD and individuals with ADHD had a similar burden of rare protein-truncating variants in evolutionarily constrained genes, both significantly higher than controls. This motivated a combined analysis across ASD and ADHD, identifying microtubule-associated protein 1A (MAP1A) as a new exome-wide significant gene conferring risk for childhood psychiatric disorders. Using samples from the Danish Neonatal Screening Biobank, children with ASD and children with ADHD were found to have similar, significantly increased rates of rare protein-truncating variants in evolutionarily constrained genes.
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Children with autism or ADHD show more rare genetic mutations than controls.
“those with ASD and those with ADHD had an increased rate of rare genetic mutations compared with controls”
From The World Federation of ADHD International Consensus Statement: 208 Evidence-based conclusions about the disorder (2021) · cites this paper as Satterstrom et al., 2019
The Abstract and Results (‘Rates of constrained rare variation’; page not provided) report that children with ASD and children with ADHD had higher burdens than controls of rare protein-truncating variants in constrained genes. The claim omits that restriction and implies an increased rate of rare genetic mutations generally, which the paper does not establish. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe de novo mutation rate in autistic individuals from the SPARK and SSC cohorts may be generalizable.
“implying that the de novo mutation rate in autistic individuals from the SPARK and SSC cohorts may be generalizable.”
From Genetic correlates of phenotypic heterogeneity in autism (2022) · cites this paper as [100]
A previous study demonstrated that the mutation rate for rare protein-truncating variants is similar between autistic individuals and siblings from the SSC and autistic individuals and population controls from the iPSYCH sample in Denmark, which does not have a participation bias.
“However, a previous study has demonstrated that the mutation rate for rare protein-truncating variants is similar between autistic individuals and siblings from the SSC and autistic individuals and population controls from the iPSYCH sample in Denmark, which does not have a participation bias100”
From Genetic correlates of phenotypic heterogeneity in autism (2022) · cites this paper as [100]
Many types of ASD-associated de novo variants are observed more frequently in female cases.
“Many types of ASD-associated de novo variants are observed more frequently in female cases.4, 5, 6, 7, 8, 9, 10, 11, 12, 13”
From The female protective effect against autism spectrum disorder (2022) · cites this paper as [9]
Genetic studies of de novo variants have consistently supported a female protective effect against ASD.
“The possibility of a “female protective effect” (FPE) against ASD has been described extensively and has received consistent support from the results of genetic studies of de novo variants.4, 5, 6, 7, 8, 9, 10, 11, 12, 13”
From The female protective effect against autism spectrum disorder (2022) · cites this paper as [9]
The burden of rare protein-truncating variants in evolutionarily constrained genes is similar among individuals with ASD and those with ADHD.
“Recently, the burden of rare protein-truncating variants in evolutionarily constrained genes was shown to be similar among individuals with ASD and those with ADHD.17”
From Insufficient Evidence for “Autism-Specific” Genes (2020) · cites this paper as [17]
Even in an ASD-derived gene set of 212 constrained genes, the rates of constrained rare protein-truncating variants among those with ASD and those with ADHD were not significantly different.
“Even in this ASD-derived gene set, the rates of constrained rare protein-truncating variants among those with ASD and those with ADHD were not significantly different.17”
From Insufficient Evidence for “Autism-Specific” Genes (2020) · cites this paper as [17]
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Self-citation
- Authors
- iPSYCH-Broad Consortium, Satterstrom, F. K., Walters, R. K., Singh, T., Wigdor, E. M., Lescai, F., Demontis, D., Kosmicki, J. A., Grove, J., Stevens, C., Bybjerg-Grauholm, J., Bækvad-Hansen, M., Palmer, D. S., Maller, J. B., Nordentoft, M., Mors, O., Robinson, E. B., Hougaard, D. M., Werge, T. M., Bo Mortensen, P., Neale, B. M., Børglum, A. D., & Daly, M. J.
- Affiliations
- Broad Institute (US)
- Aarhus University (DK)
- University of Copenhagen (DK)
- Aarhus University Hospital (DK)
- Statens Serum Institut (DK)
- Corresponding author
- Satterstrom, F. Kyle
- Børglum, Anders D.
- Daly, Mark J.
- ORCID
- Satterstrom, F. Kyle
- Walters, Raymond K.
- Singh, Tarjinder
- Wigdor, Emilie M.
- Lescai, Francesco
- Demontis, Ditte
- Kosmicki, Jack A.
- Grove, Jakob
- Stevens, Christine
- Bybjerg-Grauholm, Jonas
- Palmer, Duncan S.
- Maller, Julian B.
- Nordentoft, Merete
- Mors, Ole
- Robinson, Elise B.
- Hougaard, David M.
- Werge, Thomas M.
- Neale, Benjamin M.
- Børglum, Anders D.
- Daly, Mark J.
- Venue
- Nature Neuroscience
- Published
- 2019-11-25
- Volume
- 22
- Issue
- 12
- Pages
- 1961-1965
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC6884695
- OpenAlex
- W2989783162
- Cited by
- 209
- References
- 31
- Citations by year
- 2026: 14 · 2025: 24 · 2024: 26 · 2023: 36 · 2022: 39 · 2021: 33 · 2020: 32 · 2019: 3 · 2018: 2
- FWCI
- 15.44
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Neuroscience (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Lundbeckfonden (R155-2014-1724, R248‐2017‐2003)
- Novo Nordisk Fonden (NNF 16OC0022018)
- National Institutes of Health (5u01mh094432-04)
- National Institute of Mental Health (U01MH109539, U01 MH094432, U01MH100229, U01MH109536, U01MH111660)
- National Human Genome Research Institute (T32HG002295)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- autism spectrum disorder, attention deficit hyperactivity disorder, genetic burden, MAP1A, child psychopathology, risk genes, exome sequencing
- MeSH terms
- Autism Spectrum Disorder, Attention Deficit Disorder with Hyperactivity, Female, Humans, Male, Microtubule-Associated Proteins, Genetic Variation, Case-Control Studies, Genetic Predisposition to Disease, Exome
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