Autism spectrum disorder and attention deficit hyperactivity disorder have a similar burden of rare protein-truncating variants

Satterstrom, F. Kyle; Walters, Raymond; Singh, Tarjinder; Wigdor, Emilie M.; Lescai, Francesco; Demontis, Ditte; Kosmicki, Jack A.; Grove, Jakob; Stevens, Christine; Bybjerg‐Grauholm, Jonas; Bækvad‐Hansen, Marie; Palmer, Duncan S.; Maller, Julian; Nordentoft, Merete; Mors, Ole; Robinson, Elise; Hougaard, David M.; Werge, Thomas; Mortensen, Preben Bo; Neale, Benjamin M.; Børglum, Anders D.; Daly, Mark J.

doi:10.1038/s41593-019-0527-8

Cited by 158 publications

(172 citation statements)

References 35 publications

Supporting

Mentioning

156

Contrasting

Order By: Relevance

“…Next we compared the list of de novo loci with rare CNV loci implicated in other neurodevelopmental disorders, using previously published studies of ASD 8 , DD/ID 20 , schizophrenia 21,22 , and Tourette disorder 14 . We also annotated each de novo CNV locus with genes and examined if any of these genes have been implicated in ASD, ADHD or DD/ID, based on studies of loss-offunction exonic mutations and deleterious missense variation 3,9,23 . A number of regions and genes overlapped across disorders.…”

Section: Genotyping Cnv Calling and Quality Control (Qc)mentioning

confidence: 99%

“…Attention deficit hyperactivity disorder (ADHD) is a highly heritable (~70%), common and impairing neurodevelopmental disorder with a complex genetic architecture 1 . Recent case-control genome-wide studies point to the involvement of thousands of relatively common single-nucleotide polymorphisms 2 , very rare proteintruncating sequence variants and likely pathogenic missense mutations 3 , as well as large, rare copy number variants (CNVs) [4][5][6] . Although all of these classes of variant are associated with ADHD risk, robustly implicating specific risk alleles is an ongoing process.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A brief report: de novo copy number variants in children with attention deficit hyperactivity disorder

et al. 2020

View full text Add to dashboard Cite

Recent case-control genetic studies of attention deficit hyperactivity disorder (ADHD) have implicated common and rare genetic risk alleles, highlighting the polygenic and complex aetiology of this neurodevelopmental disorder. Studies of other neurodevelopmental disorders, such as autism spectrum disorder (ASD), Tourette disorder, developmental delay/intellectual disability and schizophrenia indicate that identification of specific risk alleles and additional insights into disorder biology can be gained by studying non-inherited de novo variation. In this study, we aimed to identify large de novo copy number variants (CNVs) in children with ADHD. Children with a confirmed diagnosis of ADHD and their parents were genotyped and included in this sample. We used PennCNV to call large (>200 kb) CNVs and identified those calls that were present in the proband and absent in both biological parents. In 305 parent-offspring trios, we detected 14 de novo CNVs in 13 probands, giving a mutation rate of 4.6% and a per individual rate of 4.3%. This rate is higher than published reports in controls and similar to those observed for ASD, schizophrenia and Tourette disorder. We also identified de novo mutations at four genomic loci (15q13.1-13.2 duplication, 16p13.11 duplication, 16p12.2 deletion and 22q11.21 duplication) that have previously been implicated in other neurodevelopmental disorders, two of which (16p13.11 and 22q11.21) have also been implicated in case-control ADHD studies. Our study complements ADHD case-control genomic analyses and demonstrates the need for larger parent-offspring trio genetic studies to gain further insights into the complex aetiology of ADHD.

show abstract

Section: Genotyping Cnv Calling and Quality Control (Qc)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A brief report: de novo copy number variants in children with attention deficit hyperactivity disorder

et al. 2020

View full text Add to dashboard Cite

show abstract

“…7,8 Furthermore, the two disorders share several genetic variants. 9 Despite these clear genetic involvements, heritability has not been able to satisfyingly predict the disorders, and instead, they are believed to be the result of a complex interaction between genetic and environmental factors. 7,8, For both ASD and ADHD, gastrointestinal (GI) symptoms are common, with constipation, diarrhea, and GI pain affecting up to 70% of ASD patients, 10,11 and the intensity of GI symptoms are positively correlated with ASD severity.…”

Section: Introductionmentioning

confidence: 99%

Gut microbiota profiles of autism spectrum disorder and attention deficit/hyperactivity disorder: A systematic literature review.

et al. 2020

View full text Add to dashboard Cite

Accumulating evidence has implicated an involvement of the gut-brain axis in autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD), however with highly diverse results. This systematic review aims to describe and evaluate studies investigating the gut microbiota composition in individuals with ASD or ADHD and to evaluate if variations in gut microbiota are associated with these disorders.Twenty-four articles were identified in a systematic literature search of PubMed and Embase up to July 22, 2019. They consisted of 20 studies investigating ASD and four studies investigating ADHD. For ASD, several studies agreed on an overall difference in β-diversity, although no consistent bacterial variation between all studies was reported. For ADHD, the results were more diverse, with no clear differences observed.Several common characteristics in gut microbiota function were identified for ASD compared to controls. In contrast, highly heterogeneous results were reported for ADHD, and thus the association between gut microbiota composition and ADHD remains unclear. For both disorders, methodological differences hampered the comparison of studies. ARTICLE HISTORY

show abstract

“…We interpret the borderline signi cant association between ADHD and hydrocephalus (p = 0.07) mainly to be the result of a substantial common genetic variant correlation between ASD and ADHD, and the recently documented overlap in genes affected by protein-truncating variants in ASD and ADHD. (14,28) The ASD diagnosis in the Danish Psychiatric Central Register has been validated. (29) Finally, one could argue that patients with autism spectrum disorder are more likely to undergo brain imaging studies than patients with the other psychiatric disorders investigated in this study.…”

Section: Discussionmentioning

confidence: 99%

Co-occurring Hydrocephalus and Polygenic Risk in Autism Spectrum Disorder: A Danish Population-based Cohort Study

Munch

Hedley

Hagen

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Background The association between autism spectrum disorder and hydrocephalus is not well understood, despite demonstrated links between autism spectrum disorder and cerebrospinal fluid abnormalities. Based on the hypothesis that autism spectrum disorder and hydrocephalus may, at least in some cases, be two manifestations of a shared congenital brain pathology, we investigated the potential association between autism spectrum disorder and hydrocephalus in a large Danish population-based cohort, and whether the polygenic risk scores for autism spectrum disorder changed as a function of the presence of hydrocephalus. Methods Patients and controls were obtained from the Lundbeck Foundation Initiative for Integrative Psychiatric Research iPSYCH2012 case-cohort, which includes all patients with selected psychiatric disorders born in Denmark 1981–2005 along with randomly selected population controls (end of follow-up, December 31, 2016). The associations between individual psychiatric disorders and hydrocephalus were estimated using binary logistic regression with adjustment for age and sex. Polygenic risk scores for autism spectrum disorder were used to compare the genetic architecture of autism spectrum disorder as a function of the presence of hydrocephalus. Results The cohort consisted of 86,571 individuals, of which 14,654 were diagnosed with autism spectrum disorder, 28,606 were population controls, and the remaining were diagnosed with other psychiatric disorders. We identified 201 hydrocephalus cases; 68 among autism spectrum disorder patients and 40 among controls (OR 3.77, 95% CI 2.48–5.78). The autism spectrum disorder-hydrocephalus association was significant over the entire subgroup spectrum of autism spectrum disorder. The presence of hydrocephalus did not markedly influence the polygenic risk scores in patients with autism spectrum disorder, which may indicate overlapping genetic architectures or other common aetiology. Conclusions Given the very strong association, we suggest that patients with autism spectrum disorder should be evaluated for co-occurring hydrocephalus on a routine basis as timely neurosurgical intervention is important. Further clarification of the genetic aetiology of both diseases, may help in elucidating shared genetic pathways between autism spectrum disorder and hydrocephalus, and it may elucidate the role of abnormal CSF dynamics in the pathogenesis of autism spectrum disorders.

show abstract

Autism spectrum disorder and attention deficit hyperactivity disorder have a similar burden of rare protein-truncating variants

Abstract: For inquiries about more detailed data, contact iPSYCH lead investigator A.D.B.

Cited by 158 publications

References 35 publications

A brief report: de novo copy number variants in children with attention deficit hyperactivity disorder

A brief report: de novo copy number variants in children with attention deficit hyperactivity disorder

Gut microbiota profiles of autism spectrum disorder and attention deficit/hyperactivity disorder: A systematic literature review.

Co-occurring Hydrocephalus and Polygenic Risk in Autism Spectrum Disorder: A Danish Population-based Cohort Study

Contact Info

Product

Resources

About