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Elevated polygenic burden for autism is associated with differential DNA methylation at birth

Eilis Hannon, Diana Schendel, Christine Ladd-Acosta, Jakob Grove, iPSYCH-Broad ASD Group, Christine Søholm Hansen, Shan V. Andrews, David Michael Hougaard, Michaeline Bresnahan, Ole Mors, Mads Vilhelm Hollegaard, Marie Bækvad-Hansen, Mady Hornig, Preben Bo Mortensen, Anders D. Børglum, Thomas Werge, Marianne Giørtz Pedersen, Merete Nordentoft, Joseph Buxbaum, M Daniele Fallin, Jonas Bybjerg-Grauholm, Abraham Reichenberg, Jonathan Mill
doi: https://doi.org/10.1101/225193
Eilis Hannon
1University of Exeter Medical School, University of Exeter, UK
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Diana Schendel
2Department of Public Health, Aarhus University, Aarhus, Denmark
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Christine Ladd-Acosta
3Department of Epidemiology and Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
4Wendy Klag Center for Autism and Developmental Disabilities, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
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Jakob Grove
5Department of Biomedicine, Aarhus University, Aarhus, Denmark
6iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Denmark
7Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark
8Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark
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Christine Søholm Hansen
6iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Denmark
9Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark
10Institute of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark
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Shan V. Andrews
3Department of Epidemiology and Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
4Wendy Klag Center for Autism and Developmental Disabilities, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
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David Michael Hougaard
6iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Denmark
9Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark
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Michaeline Bresnahan
11Center for Infection and Immunity, Columbia University Mailman School of Public Health, New York, USA
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Ole Mors
6iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Denmark
13Psychosis Research Unit, Aarhus University Hospital, Risskov, Denmark
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Mads Vilhelm Hollegaard
6iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Denmark
9Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark
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Marie Bækvad-Hansen
6iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Denmark
9Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark
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Mady Hornig
11Center for Infection and Immunity, Columbia University Mailman School of Public Health, New York, USA
12Department of Epidemiology, Columbia University Mailman School of Public Health, New York, USA
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Preben Bo Mortensen
6iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Denmark
14Department of Clinical Medicine, Aarhus University; Aarhus University Hospital, Risskov
15National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark
16Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark
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Anders D. Børglum
5Department of Biomedicine, Aarhus University, Aarhus, Denmark
6iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Denmark
7Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark
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Thomas Werge
6iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Denmark
10Institute of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark
17Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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Marianne Giørtz Pedersen
6iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Denmark
13Psychosis Research Unit, Aarhus University Hospital, Risskov, Denmark
16Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark
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Merete Nordentoft
6iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Denmark
18Mental Health Services in the Capital Region of Denmark, Mental Health Center Copenhagen, University of Copenhagen, Copenhagen, Denmark
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Joseph Buxbaum
19Department of Psychiatry, Mount Sinai School of Medicine, USA
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M Daniele Fallin
4Wendy Klag Center for Autism and Developmental Disabilities, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
11Center for Infection and Immunity, Columbia University Mailman School of Public Health, New York, USA
20Department of Psychiatry, Columbia University, New York, USA
21Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD USA
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Jonas Bybjerg-Grauholm
6iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Denmark
9Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark
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Abraham Reichenberg
19Department of Psychiatry, Mount Sinai School of Medicine, USA
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Jonathan Mill
1University of Exeter Medical School, University of Exeter, UK
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  • For correspondence: J.Mill@exeter.ac.uk
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ABSTRACT

Background Autism spectrum disorder (ASD) is a severe neurodevelopmental disorder characterized by deficits in social communication and restricted, repetitive behaviors, interests, or activities. The etiology of ASD involves both inherited and environmental risk factors, with epigenetic processes hypothesized as one mechanism by which both genetic and non-genetic variation influence gene regulation and pathogenesis.

Methods We quantified neonatal methylomic variation in 1,263 infants - of whom ~50% went on to subsequently develop ASD – using DNA isolated from a unique collection of archived blood spots taken shortly after birth. We used matched genetic data from the same individuals to examine the molecular consequences of ASD genetic risk variants, identifying methylomic variation associated with elevated polygenic burden for ASD. In addition, we performed DNA methylation quantitative trait loci (mQTL) mapping to prioritize target genes from ASD GWAS findings.

Results Although we did not identify specific loci showing consistent changes in neonatal DNA methylation associated with later ASD, we found a significant association between increased polygenic burden for autism and methylomic variation at two CpG sites located proximal to a robust GWAS signal for ASD on chromosome 8.

Conclusions This study is the largest analysis of DNA methylation in ASD yet undertaken and the first to integrate both genetic and epigenetic variation at birth in ASD. We demonstrate the utility of using a polygenic risk score to identify molecular variation associated with disease, and of using mQTL to refine the functional and regulatory variation associated with ASD risk variants.

Footnotes

  • ↵§ iPSYCH-Broad ASD Group

  • Author e-mail addresses: Eilis Hannon: e.j.hannon{at}exeter.ac.uk, Diana Schendel: diana.schendel{at}ph.au.dk, Christine Ladd-Acosta: claddac1{at}jhu.edu, Jakob Grove: grove{at}biomed.au.dk, Christine Søholm Hansen: CHSH{at}ssi.dk, Shan V. Andrews: shan.andrews{at}gmail.com, David Michael Hougaard: DH{at}ssi.dk, Michaeline Bresnahan: mab29{at}cumc.columbia.edu, Ole Mors: nielmors{at}rm.dk, Marie Bækvad-Hansen: MABH{at}ssi.dk, Mady Hornig: mh2092{at}cumc.columbia.edu, Preben Bo Mortensen: pbm{at}econ.au.dk, Anders D. Børglum: anders{at}biomed.au.dk, Thomas Werge: Thomas.Werge{at}regionh.dk, Marianne Giørtz Pedersen: mgp{at}econ.au.dk, Merete Nordentoft: merete.nordentoft{at}dadlnet.dk, Joseph Buxbaum: joseph.buxbaum{at}mssm.edu, M Daniele Fallin: dfallin{at}jhu.edu, Jonas Bybjerg-Grauholm: JOGR{at}ssi.dk, Abraham Reichenberg: avi.reichenberg{at}mssm.edu, Jonathan Mill: j.mill{at}exeter.ac.uk

Copyright 
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 4.0 International license.
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Posted November 26, 2017.
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Elevated polygenic burden for autism is associated with differential DNA methylation at birth
Eilis Hannon, Diana Schendel, Christine Ladd-Acosta, Jakob Grove, iPSYCH-Broad ASD Group, Christine Søholm Hansen, Shan V. Andrews, David Michael Hougaard, Michaeline Bresnahan, Ole Mors, Mads Vilhelm Hollegaard, Marie Bækvad-Hansen, Mady Hornig, Preben Bo Mortensen, Anders D. Børglum, Thomas Werge, Marianne Giørtz Pedersen, Merete Nordentoft, Joseph Buxbaum, M Daniele Fallin, Jonas Bybjerg-Grauholm, Abraham Reichenberg, Jonathan Mill
bioRxiv 225193; doi: https://doi.org/10.1101/225193
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Elevated polygenic burden for autism is associated with differential DNA methylation at birth
Eilis Hannon, Diana Schendel, Christine Ladd-Acosta, Jakob Grove, iPSYCH-Broad ASD Group, Christine Søholm Hansen, Shan V. Andrews, David Michael Hougaard, Michaeline Bresnahan, Ole Mors, Mads Vilhelm Hollegaard, Marie Bækvad-Hansen, Mady Hornig, Preben Bo Mortensen, Anders D. Børglum, Thomas Werge, Marianne Giørtz Pedersen, Merete Nordentoft, Joseph Buxbaum, M Daniele Fallin, Jonas Bybjerg-Grauholm, Abraham Reichenberg, Jonathan Mill
bioRxiv 225193; doi: https://doi.org/10.1101/225193

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