Autismespectrumstoornis en aandachtstekortstoornis met hyperactiviteit hebben een vergelijkbare last van zeldzame eiwitafkappingsvarianten

Autismespectrumstoornis en aandachtstekortstoornis met hyperactiviteit hebben een vergelijkbare last van zeldzame eiwitafkappingsvarianten

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Abstract

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.

Fig. 1: Rates of constrained rare PVTs.

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: http://ipsych.au.dk/downloads. For inquiries about more detailed data, contact iPSYCH lead investigator A.D.B. (anders@biomed.au.dk).

Code availability

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

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Acknowledgements

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

Author notes

  1. A list of members and affiliations appears in the Supplementary Note.

Affiliations

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

    • F. Kyle Satterstrom
    • , Raymond K. Walters
    • , Tarjinder Singh
    • , Emilie M. Wigdor
    • , Jack A. Kosmicki
    • , Christine Stevens
    • , Duncan S. Palmer
    • , Julian B. Maller
    • , Elise B. Robinson
    • , Benjamin M. Neale
    •  & Mark J. Daly
  2. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    • F. Kyle Satterstrom
    • , Raymond K. Walters
    • , Tarjinder Singh
    • , Emilie M. Wigdor
    • , Jack A. Kosmicki
    • , Duncan S. Palmer
    • , Julian B. Maller
    • , Elise B. Robinson
    • , Benjamin M. Neale
    •  & Mark J. Daly
  3. Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA

    • F. Kyle Satterstrom
    • , Raymond K. Walters
    • , Tarjinder Singh
    • , Emilie M. Wigdor
    • , Jack A. Kosmicki
    • , Duncan S. Palmer
    • , Julian B. Maller
    • , Elise B. Robinson
    • , Benjamin M. Neale
    •  & Mark J. Daly
  4. The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark

    • Francesco Lescai
    • , Ditte Demontis
    • , Jakob Grove
    • , Jonas Bybjerg-Grauholm
    • , Marie Bækvad-Hansen
    • , Merete Nordentoft
    • , Ole Mors
    • , David M. Hougaard
    • , Thomas M. Werge
    • , Preben Bo Mortensen
    •  & Anders D. Børglum
  5. iSEQ, Centre for Integrative Sequencing, Aarhus University, Aarhus, Denmark

    • Francesco Lescai
    • , Ditte Demontis
    • , Jakob Grove
    • , Preben Bo Mortensen
    •  & Anders D. Børglum
  6. Department of Biomedicine—Human Genetics, Aarhus University, Aarhus, Denmark

    • Francesco Lescai
    • , Ditte Demontis
    • , Jakob Grove
    •  & Anders D. Børglum
  7. Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark

    • Jakob Grove
  8. Centre for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark

    • Jonas Bybjerg-Grauholm
    • , Marie Bækvad-Hansen
    •  & David M. Hougaard
  9. Mental Health Services in the Capital Region of Denmark, Mental Health Centre Copenhagen, University of Copenhagen, Copenhagen, Denmark

    • Merete Nordentoft
  10. Psychosis Research Unit, Aarhus University Hospital, Risskov, Denmark

    • Ole Mors
  11. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    • Elise B. Robinson
  12. Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark

    • Thomas M. Werge
  13. Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

    • Thomas M. Werge
  14. National Centre for Register-based Research, Aarhus University, Aarhus, Denmark

    • Preben Bo Mortensen
  15. Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark

    • Preben Bo Mortensen
  16. Department of Medicine, Harvard Medical School, Boston, MA, USA

    • Benjamin M. Neale
    •  & Mark J. Daly
  17. Institute for Molecular Medicine Finland, HiLIFE, University of Helsinki, Helsinki, Finland

    • Mark J. Daly

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Consortia

iPSYCH-Broad Consortium

Contributions

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 or Anders D. Børglum or Mark J. Daly.

Ethics declarations

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.

Additional information

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 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) 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 c) Mean rare synonymous variants/person, all genes. ‘Rare’ as described in the main text. * denotes p (compared to controls) 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 value s zijn voor vergelijking met controles (n = 5.002) door logistieke regressie. OF = odds ratio. Bereik = OF /- standaardfout. ‘Zeldzaam’ zoals beschreven in de hoofdtekst.

Aanvullende figuur 6 Kwantiel-kwantiel plots voor genassociatie-analyse waarbij Deense gegevens worden gecombineerd met gnomAD.

a) Proteïne- verkorte varianten, b) synonieme varianten en c) missense varianten met MPC ≥ 2. Analyses waren beperkt tot genen met een case-control odds ratio groter dan 1 (gebaseerd op een tweezijdige Fisher’s exacte test van zeldzame varianten telt, met ‘zeldzaam’ zoals beschreven in de hoofdtekst). Om bias te voorkomen, werden genen uitgesloten van de PTV- en missense-analyses als ze een case-control synonieme odds-ratio van meer dan 1 hadden (exclusief 1.615 / 17.903 of 9,0% van de genen). Voorbeeldnummers zijn 8.340 cases (een combinatie van de casecategorieën die worden weergegeven in tabel 1 ) en 49.781 controles (combinatie van 5.002 Deense controles met 44.779 niet-Finse Europeanen uit de niet-psychiatrische exome subset van gnomAD). Het aantal geplotte genen is a) 3.182, b) 1.615 en c) 957.

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Satterstrom, FK, Walters, RK, Singh, T. et al. Autismespectrumstoornis en aandachtstekortstoornis met hyperactiviteit hebben een vergelijkbare last van zeldzame eiwitafkappingsvarianten.                      Nat Neurosci (2019) doi: 10.1038 / s41593-019-0527-8

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