Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders
Daniel J Weiner
(1, 2, 3)
,
Emilie M Wigdor
(1, 2, 3)
,
Stephan Ripke
(1, 2, 3, 4)
,
Raymond K Walters
(1, 2, 3)
,
Jack A Kosmicki
(1, 2, 3)
,
Jakob Grove
(5, 6)
,
Kaitlin E Samocha
(2, 1, 3)
,
Jacqueline I Goldstein
(2, 1, 3)
,
Aysu Okbay
(7)
,
Jonas Bybjerg-Grauholm
(6, 8)
,
Thomas Werge
(6, 9)
,
David Hougaard
(8)
,
Jacob Taylor
(2, 1, 3)
,
Marie Bækvad-Hansen
,
Ashley Dumont
,
Christine Hansen
,
Thomas Hansen
,
Daniel H Howrigan
,
Manuel Mattheisen
,
Jennifer Moran
,
Ole Mors
,
Merete Nordentoft
,
Bent Pedersen
,
Timothy Poterba
,
Jesper Poulsen
,
Christine S Stevens
,
Verneri Anttila
,
Peter Holmans
,
Hailiang Huang
,
Lambertus Klei
,
Phil H Lee
,
Sarah E Medland
,
Benjamin Neale
,
Lauren A Weiss
,
Lonnie Zwaigenbaum
,
Timothy W Yu
,
Kerstin Wittemeyer
,
a Jeremy Willsey
,
Ellen M Wijsman
,
Thomas Wassink
,
Regina Waltes
,
Christopher A Walsh
,
Simon Wallace
,
Jacob a S Vorstman
,
Veronica J Vieland
,
Astrid M Vicente
,
Herman van Engeland
,
Kathryn Tsang
,
Ann P Thompson
,
Peter Szatmari
,
Oscar Svantesson
,
Stacy Steinberg
,
Kari Stefansson
,
Hreinn Stefansson
,
Matthew W State
,
Latha Soorya
,
Teimuraz Silagadze
,
Stephen W Scherer
,
Gerard D Schellenberg
,
Sven Sandin
,
Evald Saemundsen
,
Guy A Rouleau
,
Bernadette Rogé
,
Kathryn Roeder
,
Robert Roberts
,
Jennifer Reichert
,
Abraham Reichenberg
,
Karola Rehnström
,
Regina Regan
,
Fritz Poustka
,
Christopher Poultney
,
Joseph Piven
,
Dalila Pinto
,
Margaret A Pericak-Vance
,
Milica Pejovic-Milovancevic
,
Marianne G Pedersen
,
Carsten B Pedersen
,
Andrew Paterson
,
Jeremy R Parr
,
Alistair T Pagnamenta
,
Guiomar Oliveira
,
John I Nurnberger
,
Michael T Murtha
,
Susan Mouga
,
Eric M Morrow
,
Daniel Moreno de Luca
,
Anthony P Monaco
,
Nancy Minshew
,
Alison Merikangas
,
William M Mcmahon
,
Susan G Mcgrew
,
Igor Martsenkovsky
,
Donna M Martin
,
Shrikant M Mane
,
Pall Magnusson
,
Tiago Magalhaes
,
Elena Maestrini
,
Jennifer K Lowe
,
Catherine Lord
,
Pat Levitt
,
Christa Lese Martin
,
David H Ledbetter
,
Marion Leboyer
,
Ann S Le Couteur
,
Christine Ladd-Acosta
,
Alexander Kolevzon
,
Sabine M Klauck
,
Suma Jacob
,
Bozenna Iliadou
,
Christina M Hultman
,
Irva Hertz-Picciotto
,
Robert Hendren
,
Christine S Hansen
,
Jonathan L Haines
,
Stephen J Guter
,
Dorothy E Grice
,
Jonathan M Green
,
Andrew Green
,
Arthur P Goldberg
,
Christopher Gillberg
,
John Gilbert
,
Louise Gallagher
,
Christine M Freitag
,
Eric Fombonne
,
Susan E Folstein
,
Bridget Fernandez
,
M Daniele Fallin
,
a Gulhan Ercan-Sencicek
,
Sean Ennis
,
Frederico Duque
,
Eftichia Duketis
,
Richard Delorme
,
Silvia de Rubeis
,
Maretha V de Jonge
,
Geraldine Dawson
,
Michael L Cuccaro
,
Catarina T Correia
,
Judith Conroy
,
Inês C Conceição
,
Andreas G Chiocchetti
,
Patrícia B S Celestino-Soper
,
Jillian Casey
,
Rita M Cantor
,
Cátia Café
,
Sean Brennan
,
Thomas Bourgeron
,
Patrick F Bolton
,
Sven Bölte
,
Nadia Bolshakova
,
Catalina Betancur
(10)
,
Bernie Bernier
,
Arthur L Beaudet
,
Agatino Battaglia
,
Vanessa H Bal
,
Gillian Baird
,
Anthony J Bailey
,
Joel S Bader
,
Elena Bacchelli
,
Evdokia Anagnostou
,
David Amaral
,
Joana Almeida
,
Joseph D Buxbaum
,
Aravinda Chakravarti
,
Edwin H Cook
,
Hilary Coon
,
Daniel H. Geschwind
,
Michael Gill
,
Hakon Hakonarson
,
Joachim Hallmayer
,
Aarno Palotie
,
Susan Santangelo
,
James S Sutcliffe
,
Dan E Arking
,
David Skuse
(11)
,
Bernie Devlin
(12)
,
Richard Anney
(13)
,
Stephan J Sanders
(14)
,
Somer Bishop
(14)
,
Preben Bo Mortensen
(5, 6)
,
Anders D Børglum
(5, 6)
,
George Davey Smith
(15)
,
Mark J Daly
(2, 1, 3)
,
Elise B Robinson
(2, 1, 3)
1
HMS -
Harvard Medical School [Boston]
2 Massachusetts General Hospital [Boston]
3 BROAD INSTITUTE - Broad Institute of MIT and Harvard
4 Charité - UniversitätsMedizin = Berlin University Medicine
5 Aarhus University [Aarhus]
6 iPSYCH - The Lundbeck Foundation Initiative for Integrative Psychiatric Research
7 VU - Vrije Universiteit Amsterdam [Amsterdam]
8 Statens Serum Institut [Copenhagen]
9 UCPH - University of Copenhagen = Københavns Universitet
10 NPS - Neuroscience Paris Seine
11 UCL - University College of London [London]
12 University of Pittsburgh School of Medicine
13 Cardiff University
14 UC - University of California
15 University of Bristol [Bristol]
2 Massachusetts General Hospital [Boston]
3 BROAD INSTITUTE - Broad Institute of MIT and Harvard
4 Charité - UniversitätsMedizin = Berlin University Medicine
5 Aarhus University [Aarhus]
6 iPSYCH - The Lundbeck Foundation Initiative for Integrative Psychiatric Research
7 VU - Vrije Universiteit Amsterdam [Amsterdam]
8 Statens Serum Institut [Copenhagen]
9 UCPH - University of Copenhagen = Københavns Universitet
10 NPS - Neuroscience Paris Seine
11 UCL - University College of London [London]
12 University of Pittsburgh School of Medicine
13 Cardiff University
14 UC - University of California
15 University of Bristol [Bristol]
Marie Bækvad-Hansen
- Function : Author
Ashley Dumont
- Function : Author
- PersonId : 782849
- ORCID : 0000-0002-0280-1624
Christine Hansen
- Function : Author
Thomas Hansen
- Function : Author
Daniel H Howrigan
- Function : Author
Manuel Mattheisen
- Function : Author
Jennifer Moran
- Function : Author
Ole Mors
- Function : Author
Merete Nordentoft
- Function : Author
Bent Pedersen
- Function : Author
Timothy Poterba
- Function : Author
Jesper Poulsen
- Function : Author
Christine S Stevens
- Function : Author
Verneri Anttila
- Function : Author
Peter Holmans
- Function : Author
Hailiang Huang
- Function : Author
Lambertus Klei
- Function : Author
Phil H Lee
- Function : Author
Sarah E Medland
- Function : Author
Benjamin Neale
- Function : Author
Lauren A Weiss
- Function : Author
Lonnie Zwaigenbaum
- Function : Author
Timothy W Yu
- Function : Author
Kerstin Wittemeyer
- Function : Author
a Jeremy Willsey
- Function : Author
Ellen M Wijsman
- Function : Author
Thomas Wassink
- Function : Author
Regina Waltes
- Function : Author
Christopher A Walsh
- Function : Author
Simon Wallace
- Function : Author
Jacob a S Vorstman
- Function : Author
Veronica J Vieland
- Function : Author
Astrid M Vicente
- Function : Author
Herman van Engeland
- Function : Author
Kathryn Tsang
- Function : Author
Ann P Thompson
- Function : Author
Peter Szatmari
- Function : Author
Oscar Svantesson
- Function : Author
Stacy Steinberg
- Function : Author
Kari Stefansson
- Function : Author
Hreinn Stefansson
- Function : Author
Matthew W State
- Function : Author
Latha Soorya
- Function : Author
Teimuraz Silagadze
- Function : Author
Stephen W Scherer
- Function : Author
Gerard D Schellenberg
- Function : Author
Sven Sandin
- Function : Author
Evald Saemundsen
- Function : Author
Guy A Rouleau
- Function : Author
Bernadette Rogé
- Function : Author
Kathryn Roeder
- Function : Author
Robert Roberts
- Function : Author
Jennifer Reichert
- Function : Author
Abraham Reichenberg
- Function : Author
Karola Rehnström
- Function : Author
Regina Regan
- Function : Author
Fritz Poustka
- Function : Author
Christopher Poultney
- Function : Author
Joseph Piven
- Function : Author
Dalila Pinto
- Function : Author
Margaret A Pericak-Vance
- Function : Author
Milica Pejovic-Milovancevic
- Function : Author
Marianne G Pedersen
- Function : Author
Carsten B Pedersen
- Function : Author
Andrew Paterson
- Function : Author
- PersonId : 770483
- ORCID : 0000-0002-4296-9528
Jeremy R Parr
- Function : Author
Alistair T Pagnamenta
- Function : Author
Guiomar Oliveira
- Function : Author
John I Nurnberger
- Function : Author
Michael T Murtha
- Function : Author
Susan Mouga
- Function : Author
Eric M Morrow
- Function : Author
Daniel Moreno de Luca
- Function : Author
Anthony P Monaco
- Function : Author
Nancy Minshew
- Function : Author
Alison Merikangas
- Function : Author
William M Mcmahon
- Function : Author
Susan G Mcgrew
- Function : Author
Igor Martsenkovsky
- Function : Author
Donna M Martin
- Function : Author
Shrikant M Mane
- Function : Author
Pall Magnusson
- Function : Author
Tiago Magalhaes
- Function : Author
Elena Maestrini
- Function : Author
Jennifer K Lowe
- Function : Author
Catherine Lord
- Function : Author
Pat Levitt
- Function : Author
Christa Lese Martin
- Function : Author
David H Ledbetter
- Function : Author
Marion Leboyer
- Function : Author
- PersonId : 756830
- ORCID : 0000-0001-5473-3697
- IdRef : 089352475
Ann S Le Couteur
- Function : Author
Christine Ladd-Acosta
- Function : Author
Alexander Kolevzon
- Function : Author
Sabine M Klauck
- Function : Author
Suma Jacob
- Function : Author
Bozenna Iliadou
- Function : Author
Christina M Hultman
- Function : Author
Irva Hertz-Picciotto
- Function : Author
Robert Hendren
- Function : Author
Christine S Hansen
- Function : Author
Jonathan L Haines
- Function : Author
Stephen J Guter
- Function : Author
Dorothy E Grice
- Function : Author
Jonathan M Green
- Function : Author
Andrew Green
- Function : Author
Arthur P Goldberg
- Function : Author
Christopher Gillberg
- Function : Author
John Gilbert
- Function : Author
Louise Gallagher
- Function : Author
Christine M Freitag
- Function : Author
Eric Fombonne
- Function : Author
Susan E Folstein
- Function : Author
Bridget Fernandez
- Function : Author
M Daniele Fallin
- Function : Author
a Gulhan Ercan-Sencicek
- Function : Author
Sean Ennis
- Function : Author
Frederico Duque
- Function : Author
Eftichia Duketis
- Function : Author
Richard Delorme
- Function : Author
Silvia de Rubeis
- Function : Author
Maretha V de Jonge
- Function : Author
Geraldine Dawson
- Function : Author
Michael L Cuccaro
- Function : Author
Catarina T Correia
- Function : Author
Judith Conroy
- Function : Author
Inês C Conceição
- Function : Author
Andreas G Chiocchetti
- Function : Author
Patrícia B S Celestino-Soper
- Function : Author
Jillian Casey
- Function : Author
Rita M Cantor
- Function : Author
Cátia Café
- Function : Author
Sean Brennan
- Function : Author
Thomas Bourgeron
- Function : Author
- PersonId : 747963
- IdHAL : thomas-bourgeron
- ORCID : 0000-0001-8164-9220
- IdRef : 119761955
Patrick F Bolton
- Function : Author
Sven Bölte
- Function : Author
Nadia Bolshakova
- Function : Author
Catalina Betancur
- Function : Author
- PersonId : 13320
- IdHAL : catalina-betancur
- ORCID : 0000-0002-3327-4804
- IdRef : 180835750
Bernie Bernier
- Function : Author
Arthur L Beaudet
- Function : Author
Agatino Battaglia
- Function : Author
Vanessa H Bal
- Function : Author
Gillian Baird
- Function : Author
Anthony J Bailey
- Function : Author
Joel S Bader
- Function : Author
Elena Bacchelli
- Function : Author
Evdokia Anagnostou
- Function : Author
David Amaral
- Function : Author
Joana Almeida
- Function : Author
Joseph D Buxbaum
- Function : Author
Aravinda Chakravarti
- Function : Author
Edwin H Cook
- Function : Author
Hilary Coon
- Function : Author
Daniel H. Geschwind
- Function : Author
Michael Gill
- Function : Author
Hakon Hakonarson
- Function : Author
- PersonId : 763145
- ORCID : 0000-0003-2814-7461
Joachim Hallmayer
- Function : Author
Aarno Palotie
- Function : Author
Susan Santangelo
- Function : Author
James S Sutcliffe
- Function : Author
Dan E Arking
- Function : Author
Abstract
Autism spectrum disorder (ASD) risk is influenced by common polygenic and de novo variation. We aimed to clarify the influence of polygenic risk for ASD and to identify subgroups of ASD cases, including those with strongly acting de novo variants, in which polygenic risk is relevant. Using a novel approach called the polygenic transmission disequilibrium test and data from 6,454 families with a child with ASD, we show that polygenic risk for ASD, schizophrenia, and greater educational attainment is over-transmitted to children with ASD. These findings hold independent of proband IQ. We find that polygenic variation contributes additively to risk in ASD cases who carry a strongly acting de novo variant. Lastly, we show that elements of polygenic risk are independent and differ in their relationship with phenotype. These results confirm that the genetic influences on ASD are additive and suggest that they create risk through at least partially distinct etiologic pathways.
Domains
Neurons and Cognition [q-bio.NC]Origin | Files produced by the author(s) |
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