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

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

doi:10.1038/s41593-019-0527-8

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

Nat Neurosci. 2019 Dec;22(12):1961-1965. doi: 10.1038/s41593-019-0527-8. Epub 2019 Nov 25.

Authors

F Kyle Satterstrom^{1

2

3}, Raymond K Walters^{4

5

6}, Tarjinder Singh^{4

5

6}, Emilie M Wigdor^{4

5

6}, Francesco Lescai^{7

8

9}, Ditte Demontis^{7

8

9}, Jack A Kosmicki^{4

5

6}, Jakob Grove^{7

8

9

10}, Christine Stevens⁴, Jonas Bybjerg-Grauholm^{7

11}, Marie Bækvad-Hansen^{7

11}, Duncan S Palmer^{4

5

6}, Julian B Maller^{4

5

6}; iPSYCH-Broad Consortium; Merete Nordentoft^{7

12}, Ole Mors^{7

13}, Elise B Robinson^{4

5

6

14}, David M Hougaard^{7

11}, Thomas M Werge^{7

15

16}, Preben Bo Mortensen^{7

8

17

18}, Benjamin M Neale^{4

5

6

19}, Anders D Børglum^{20

21

22}, Mark J Daly^{23

24

25

26

27}

Affiliations

¹ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. satterst@broadinstitute.org.
² Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. satterst@broadinstitute.org.
³ Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. satterst@broadinstitute.org.
⁴ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁵ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁶ Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁷ The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark.
⁸ iSEQ, Centre for Integrative Sequencing, Aarhus University, Aarhus, Denmark.
⁹ Department of Biomedicine-Human Genetics, Aarhus University, Aarhus, Denmark.
¹⁰ Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark.
¹¹ Centre for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
¹² Mental Health Services in the Capital Region of Denmark, Mental Health Centre Copenhagen, University of Copenhagen, Copenhagen, Denmark.
¹³ Psychosis Research Unit, Aarhus University Hospital, Risskov, Denmark.
¹⁴ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹⁵ Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark.
¹⁶ Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
¹⁷ National Centre for Register-based Research, Aarhus University, Aarhus, Denmark.
¹⁸ Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark.
¹⁹ Department of Medicine, Harvard Medical School, Boston, MA, USA.
²⁰ The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark. anders@biomed.au.dk.
²¹ iSEQ, Centre for Integrative Sequencing, Aarhus University, Aarhus, Denmark. anders@biomed.au.dk.
²² Department of Biomedicine-Human Genetics, Aarhus University, Aarhus, Denmark. anders@biomed.au.dk.
²³ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. mjdaly@atgu.mgh.harvard.edu.
²⁴ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. mjdaly@atgu.mgh.harvard.edu.
²⁵ Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. mjdaly@atgu.mgh.harvard.edu.
²⁶ Department of Medicine, Harvard Medical School, Boston, MA, USA. mjdaly@atgu.mgh.harvard.edu.
²⁷ Institute for Molecular Medicine Finland, HiLIFE, University of Helsinki, Helsinki, Finland. mjdaly@atgu.mgh.harvard.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Attention Deficit Disorder with Hyperactivity / complications
Attention Deficit Disorder with Hyperactivity / genetics*
Autism Spectrum Disorder / complications
Autism Spectrum Disorder / genetics*
Case-Control Studies
Exome / genetics
Female
Genetic Predisposition to Disease / genetics*
Genetic Variation / genetics*
Humans
Male
Microtubule-Associated Proteins / genetics*

Substances

MAP1A protein, human
Microtubule-Associated Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding