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


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.

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Fig. 1: Rates of constrained rare PVTs.

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Data availability

Supplementary data are available as supplementary files to this manuscript (see Supplementary Tables 1, 3 and 5) or at the iPSYCH download page: For inquiries about more detailed data, contact iPSYCH lead investigator A.D.B. (

Code availability

Hail (0.1) and R scripts used to handle and analyze these data are available upon reasonable request from F.K.S. (


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The iPSYCH project is funded by the Lundbeck Foundation (grant nos. R102-A9118 and R155-2014-1724) and the universities and university hospitals of Aarhus and Copenhagen. The DNSB resource at the Statens Serum Institut was supported by the Novo Nordisk Foundation. Sequencing of iPSYCH samples was supported by grants from the Simons Foundation (grant no. SFARI 311789 to M.J.D.) and the Stanley Foundation. Other support for this study was received from the National Institute of Mental Health (grant nos. 5U01MH094432-02, 5U01MH111660-02 and U01MH100229 to M.J.D.). Computational resources for handling and statistical analysis of iPSYCH data on the GenomeDK and Computerome HPC facilities were provided by, respectively, the Centre for Integrative Sequencing, iSEQ, Aarhus University, Denmark (grant to A.D.B.) and iPSYCH.

Author information

Authors and Affiliations




F.K.S. performed the analysis. 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 principal investigator group. M.J.D. directed the project. B.M.N. and A.D.B. contributed to project direction. F.K.S. and M.J.D. wrote the manuscript.

Corresponding authors

Correspondence to F. Kyle Satterstrom, Anders D. Børglum or Mark J. Daly.

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Competing interests

T.M.W. has acted as advisor and lecturer to the pharmaceutical company H. Lundbeck A/S. B.M.N. is a member of the scientific advisory board at Deep Genomics and is a consultant for Camp4 Therapeutics, Takeda Pharmaceuticals and Biogen Inc.

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Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Integrated supplementary information

Supplementary Figure 1 Variant groups for constrained rare PTV rate comparison.

a) Mean rare PTVs/person in constrained genes only (pLI ≥ 0.9). b) Mean rare PTVs/person in unconstrained genes only (pLI < 0.9). c) Mean rare synonymous variants/person in constrained genes only (pLI ≥ 0.9). ‘Rare’ as described in the main text. *** denotes p (compared to controls) < 0.001; all p values by logistic regression (Methods). For exact p values, see Supplementary Table 1. Sample numbers are as follows: ASD, no ID: 3,091; ASD+ADHD, no ID: 684; ADHD, no ID: 3,206; ASD, ID: 871; ASD+ADHD, ID: 217; ADHD, ID: 271; Control: 5,002. ID = intellectual disability. Error bars are Poisson standard error.

Supplementary Figure 2 Proportion of individuals within each phenotype category with 0, 1, 2, 3, or 4 crPTVs.

Simulated p value is chi-square test against Poisson expectation using observed mean, based on 10,000 replicates. Note that only one crPTV is counted per person per gene (removes approx. 0.2% of variants). crPTV = constrained (pLI ≥ 0.9) rare protein-truncating variant; ‘rare’ as described in the main text. ID = intellectual disability.

Supplementary Figure 3 Per-person rates of rare missense variants across phenotypes, considering only variants with MPC ≥ 2.

MPC score is a measure of the deleteriousness of a missense variant based on a regional model of constraint15, with higher values indicating a greater degree of deleteriousness. P values are for comparison to controls by logistic regression. ‘Rare’ as described in the main text. ID = intellectual disability.

Supplementary Figure 4 Variant groups for rare missense variant rate comparison.

a) Mean rare missense variants/person, MPC ≥ 2 only. b) Mean rare missense variants/person, MPC < 2 only. c) Mean rare synonymous variants/person, all genes. ‘Rare’ as described in the main text. * denotes p (compared to controls) < 0.05; ** denotes p < 0.01; *** denotes p < 0.001; all p values by logistic regression. For exact p values, see Supplementary Table 1. Sample numbers are as follows: ASD, no ID: 3,091; ASD+ADHD, no ID: 684; ADHD, no ID: 3,206; ASD, ID: 871; ASD+ADHD, ID: 217; ADHD, ID: 271; Control: 5,002. ID = intellectual disability. Error bars are Poisson standard error.

Supplementary Figure 5 Rates of constrained rare synonymous variants, considering ASD cases (n = 2,430) and ADHD cases (n = 2,360) with only a single diagnosis.

a) Rates in all constrained (pLI ≥ 0.9) genes; b) rates in the 212 constrained genes with a published rare de novo PTV in ASD (‘ASD de novo genes’)14. ‘Single’ diagnosis refers to ASD and ADHD cases without comorbid ASD+ADHD or intellectual disability, and without diagnoses of schizophrenia, bipolar disorder, affective disorder, or anorexia. Error bars are Poisson standard error. In the accompanying box, OR and p values are for comparison to controls (n = 5,002) by logistic regression. OR = odds ratio. Range = OR +/- standard error. ‘Rare’ as described in the main text.

Supplementary Figure 6 Quantile-quantile plots for gene association analysis combining Danish data with gnomAD.

a) Protein-truncating variants, b) synonymous variants, and c) missense variants with MPC ≥ 2. Analyses were limited to genes with a case-control odds ratio greater than 1 (based on a two-tailed Fisher’s exact test of rare variant counts, with ‘rare’ as described in the main text). To avoid bias, genes were excluded from the PTV and missense analyses if they had a case-control synonymous odds ratio greater than 1 (excluded 1,615/17,903, or 9.0% of genes). Sample numbers are 8,340 cases (combining the case categories shown in Table 1) and 49,781 controls (combining the 5,002 Danish controls with 44,779 non-Finnish Europeans from the non-psychiatric exome subset of gnomAD). The numbers of genes plotted are a) 3,182, b) 1,615, and c) 957.

Supplementary information

Supplementary Information

Supplementary Figs. 1–6, Supplementary Tables 2, 4 and 6 and Supplementary Note.

Reporting Summary

Supplementary Table 1

Rates, odds ratios and P values displayed in manuscript.

Supplementary Table 3

Lists of genes used in c-alpha tests, as well as test P values.

Supplementary Table 5

Full results of gene discovery analysis.

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Satterstrom, F.K., Walters, R.K., Singh, T. et al. Autism spectrum disorder and attention deficit hyperactivity disorder have a similar burden of rare protein-truncating variants. Nat Neurosci 22, 1961–1965 (2019).

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