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ASD and ADHD 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: https://doi.org/10.1101/277707
F. Kyle Satterstrom
Broad Institute / Massachusetts General Hospital;
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  • For correspondence: satterst@broadinstitute.org
Raymond K. Walters
Broad Institute / Massachusetts General Hospital;
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Tarjinder Singh
Broad Institute / Massachusetts General Hospital;
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Emilie M. Wigdor
Broad Institute / Massachusetts General Hospital;
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Francesco Lescai
iPSYCH / Aarhus University;
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Ditte Demontis
iPSYCH / Aarhus University;
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Jack A. Kosmicki
Broad Institute / Massachusetts General Hospital;
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Jakob Grove
iPSYCH / Aarhus University;
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Christine Stevens
Broad Institute;
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Jonas Bybjerg-Grauholm
iPSYCH / Statens Serum Institut;
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Marie Bækvad-Hansen
iPSYCH / Statens Serum Institut;
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Duncan S. Palmer
Broad Institute / Massachusetts General Hospital;
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Julian B. Maller
Broad Institute / Massachusetts General Hospital;
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-;
Merete Nordentoft
iPSYCH / University of Copenhagen;
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Ole Mors
iPSYCH / Aarhus University Hospital;
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Elise B. Robinson
Harvard T.H. Chan School of Public Health / Broad Institute / Massachusetts General Hospital;
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David M. Hougaard
iPSYCH / Statens Serum Institut;
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Thomas M. Werge
iPSYCH / University of Copenhagen / Mental Health Services Copenhagen;
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Preben Bo Mortensen
iPSYCH / Aarhus University;
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Benjamin M. Neale
Broad Institute / Massachusetts General Hospital / Harvard Medical School
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Anders D. Børglum
iPSYCH / Aarhus University;
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Mark J. Daly
Broad Institute / Massachusetts General Hospital / Harvard Medical School
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Abstract

Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) are substantially heritable, but individuals with psychiatric diagnoses often do not have blood drawn as part of routine medical procedure, making it difficult to collect large cohorts for genetic study. To overcome this challenge, we drew upon two Danish national resources: the Danish Neonatal Screening Biobank (DNSB) and the Danish national psychiatric registry. We have previously validated the use of archived bloodspots from the DNSB for genotyping and sequencing, and we recently performed common variant analysis on dried bloodspot material in both ASD and ADHD. Here, we present exome sequences from over 13,000 DNSB samples, finding that ASD and ADHD show a strikingly similar burden of rare protein-truncating variants, both significantly higher than controls. Additionally, the distributions of genes hit by these variants are not distinguishable between the two disorders, suggesting that many risk genes may be shared between them. These results motivate a combined analysis across ASD and ADHD, which--in conjunction with incorporation of the gnomAD reference database as additional population controls--leads to the identification of genes conferring general risk for childhood psychiatric disorders, including the novel gene MAP1A.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted March 06, 2018.
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ASD and ADHD 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
bioRxiv 277707; doi: https://doi.org/10.1101/277707
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ASD and ADHD 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
bioRxiv 277707; doi: https://doi.org/10.1101/277707

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