A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder.
Jillian P Casey
,
Tiago Magalhaes
,
Judith Conroy
,
Regina Regan
,
Naisha Shah
,
Ann Anney
,
Denis C Shields
,
Brett S Abrahams
,
Joana Almeida
,
Elena Bacchelli
(1)
,
Anthony J Bailey
,
Gillian Gill
(2)
,
Agatino Battaglia
(3)
,
Tom Berney
,
Nadia Bolshakova
,
Patrick F Bolton
,
Thomas Bourgeron
(4, 5)
,
Sean Brennan
,
Phil Cali
,
Catarina Correia
,
Christina Corsello
,
Marc Coutanche
,
Geraldine Dawson
,
Maretha de Jonge
,
Richard Delorme
(6)
,
Eftichia Duketis
(7)
,
Fred Duque
,
Ann Estes
,
Penny Farrar
,
Bridget A Fernandez
(8)
,
Susan E Folstein
,
Suzanne Foley
,
Eric Fombonne
(9)
,
Christine M Freitag
(7)
,
John Gilbert
,
Christopher Gill
,
Joseph Glessner
,
Jonathan Green
(10)
,
Stephen J Guter
,
Hakon Hakonarson
,
Richard Holt
(11)
,
Vanessa Hus
,
Roberta Igliozzi
,
Cecilia Kim
,
Sabine M Klauck
(12)
,
Alexander Kolevzon
,
Janine A Lamb
,
Marion Leboyer
(13)
,
Ann Le Couteur
,
Bennett L Leventhal
,
Catherine Lord
,
Sabata C Lund
,
Elena Maestrini
(1)
,
Carine Mantoulan
,
Christian R Marshall
(14, 15)
,
Helen Mcconachie
,
Christopher J Mcdougle
,
Jane Mcgrath
,
William M Mcmahon
,
Alison Merikangas
,
Judith Miller
(16)
,
Fiorella Minopoli
,
Ghazala K Mirza
,
Jeff Munson
,
Stanley F Nelson
,
Gudrun Nygren
,
Guiomar Oliveira
(17)
,
Alistair T Pagnamenta
,
Katerina Papanikolaou
,
Jeremy R Parr
,
Barbara Parrini
,
Andrew Pickles
,
Dalila Pinto
(14)
,
Joseph Piven
,
David J Posey
,
Annemarie Poustka
,
Fritz Poustka
(7)
,
Jiannis Ragoussis
,
Bernadette Roge
,
Michael Rutter
,
Ana F Sequeira
,
Latha Soorya
,
Inês Sousa
,
Nuala Sykes
,
Vera Stoppioni
,
Raffaella Tancredi
,
Maïté Tauber
(18)
,
Ann P Thompson
(19)
,
Susanne Thomson
,
John Tsiantis
,
Herman van Engeland
,
John B Vincent
(20)
,
Fred Volkmar
,
Jacob a S Vorstman
,
Simon Wallace
,
Kai Wang
,
Thomas H Wassink
,
Kathy White
(21)
,
Kirsty Wing
,
Kerstin Wittemeyer
,
Brian L Yaspan
,
Lonnie Zwaigenbaum
(22)
,
Catalina Betancur
(23)
,
Joseph D Buxbaum
(24)
,
Rita M Cantor
,
Edwin H Cook
,
Hilary Coon
,
Michael Cuccaro
,
Daniel H. Geschwind
,
Jonathan L Haines
(25)
,
Joachim Hallmayer
,
Anthony P Monaco
,
John I Nurnberger
,
Margaret A Pericak-Vance
,
Gerard D Schellenberg
,
Stephen W Scherer
(26)
,
James S Sutcliffe
,
Peter Szatmari
(27)
,
Veronica J Vieland
,
Ellen M Wijsman
,
Andrew Green
,
Michael Gill
,
Louise Gallagher
,
Astrid Vicente
,
Sean Ennis
1
UNIBO -
Alma Mater Studiorum Università di Bologna = University of Bologna
2 Open University of Israël
3 IRCCS Fondazione Stella Maris [Pisa]
4 GHFC (UMR_3571 / U-Pasteur_1) - Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions
5 IP - Institut Pasteur [Paris]
6 AP-HP Hôpital universitaire Robert-Debré [Paris]
7 Goethe University Frankfurt
8 MUN - Memorial University of Newfoundland = Université Memorial de Terre-Neuve [St. John's, Canada]
9 McGill University = Université McGill [Montréal, Canada]
10 JHU - Johns Hopkins University
11 Autism Research Centre and Section of Developmental Psychiatry
12 DKFZ - German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg]
13 Psychiatrie génétique
14 SickKids - The Hospital for sick children [Toronto]
15 University of Toronto
16 Australian Resources Research Centre, Kensington,
17 SQPOV - Sécurité et Qualité des Produits d'Origine Végétale
18 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse
19 School of Chemistry
20 DLR Institut für Planetenforschung
21 Department of Human Genetics
22 University of Alberta
23 NPS-01 - Génétique de l'autisme = Genetics of Autism
24 Seaver Autism Center for Research and Treatment
25 ICGM ICMMM - Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier
26 University of Koblenz-Landau
27 McMaster University [Hamilton, Ontario]
2 Open University of Israël
3 IRCCS Fondazione Stella Maris [Pisa]
4 GHFC (UMR_3571 / U-Pasteur_1) - Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions
5 IP - Institut Pasteur [Paris]
6 AP-HP Hôpital universitaire Robert-Debré [Paris]
7 Goethe University Frankfurt
8 MUN - Memorial University of Newfoundland = Université Memorial de Terre-Neuve [St. John's, Canada]
9 McGill University = Université McGill [Montréal, Canada]
10 JHU - Johns Hopkins University
11 Autism Research Centre and Section of Developmental Psychiatry
12 DKFZ - German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg]
13 Psychiatrie génétique
14 SickKids - The Hospital for sick children [Toronto]
15 University of Toronto
16 Australian Resources Research Centre, Kensington,
17 SQPOV - Sécurité et Qualité des Produits d'Origine Végétale
18 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse
19 School of Chemistry
20 DLR Institut für Planetenforschung
21 Department of Human Genetics
22 University of Alberta
23 NPS-01 - Génétique de l'autisme = Genetics of Autism
24 Seaver Autism Center for Research and Treatment
25 ICGM ICMMM - Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier
26 University of Koblenz-Landau
27 McMaster University [Hamilton, Ontario]
Jillian P Casey
- Function : Author
Tiago Magalhaes
- Function : Author
Judith Conroy
- Function : Author
Regina Regan
- Function : Author
Naisha Shah
- Function : Author
Ann Anney
- Function : Author
Denis C Shields
- Function : Author
Brett S Abrahams
- Function : Author
Joana Almeida
- Function : Author
Anthony J Bailey
- Function : Author
Tom Berney
- Function : Author
Nadia Bolshakova
- Function : Author
Patrick F Bolton
- Function : Author
Thomas Bourgeron
- Function : Author
- PersonId : 747963
- IdHAL : thomas-bourgeron
- ORCID : 0000-0001-8164-9220
- IdRef : 119761955
Sean Brennan
- Function : Author
Phil Cali
- Function : Author
Catarina Correia
- Function : Author
Christina Corsello
- Function : Author
Marc Coutanche
- Function : Author
Geraldine Dawson
- Function : Author
Maretha de Jonge
- Function : Author
Fred Duque
- Function : Author
Ann Estes
- Function : Author
Penny Farrar
- Function : Author
Susan E Folstein
- Function : Author
Suzanne Foley
- Function : Author
John Gilbert
- Function : Author
Christopher Gill
- Function : Author
Joseph Glessner
- Function : Author
Jonathan Green
- Function : Author
- PersonId : 763155
- ORCID : 0000-0002-5003-0203
Stephen J Guter
- Function : Author
Hakon Hakonarson
- Function : Author
- PersonId : 763145
- ORCID : 0000-0003-2814-7461
Vanessa Hus
- Function : Author
Roberta Igliozzi
- Function : Author
Cecilia Kim
- Function : Author
Alexander Kolevzon
- Function : Author
Janine A Lamb
- Function : Author
Marion Leboyer
- Function : Author
- PersonId : 756830
- ORCID : 0000-0001-5473-3697
- IdRef : 089352475
Ann Le Couteur
- Function : Author
Bennett L Leventhal
- Function : Author
Catherine Lord
- Function : Author
Sabata C Lund
- Function : Author
Carine Mantoulan
- Function : Author
Helen Mcconachie
- Function : Author
Christopher J Mcdougle
- Function : Author
Jane Mcgrath
- Function : Author
William M Mcmahon
- Function : Author
Alison Merikangas
- Function : Author
Fiorella Minopoli
- Function : Author
Ghazala K Mirza
- Function : Author
Jeff Munson
- Function : Author
Stanley F Nelson
- Function : Author
Gudrun Nygren
- Function : Author
Alistair T Pagnamenta
- Function : Author
Katerina Papanikolaou
- Function : Author
Jeremy R Parr
- Function : Author
Barbara Parrini
- Function : Author
Andrew Pickles
- Function : Author
Joseph Piven
- Function : Author
David J Posey
- Function : Author
Annemarie Poustka
- Function : Author
Jiannis Ragoussis
- Function : Author
- PersonId : 763156
- ORCID : 0000-0002-8515-0934
Bernadette Roge
- Function : Author
Michael Rutter
- Function : Author
Ana F Sequeira
- Function : Author
Latha Soorya
- Function : Author
Inês Sousa
- Function : Author
Nuala Sykes
- Function : Author
Vera Stoppioni
- Function : Author
Raffaella Tancredi
- Function : Author
Maïté Tauber
- Function : Author
- PersonId : 1097566
- ORCID : 0000-0002-0363-7862
- IdRef : 085677167
Susanne Thomson
- Function : Author
John Tsiantis
- Function : Author
Herman van Engeland
- Function : Author
Fred Volkmar
- Function : Author
Jacob a S Vorstman
- Function : Author
Simon Wallace
- Function : Author
Kai Wang
- Function : Author
- PersonId : 763158
- ORCID : 0000-0001-6269-3517
Thomas H Wassink
- Function : Author
Kirsty Wing
- Function : Author
Kerstin Wittemeyer
- Function : Author
Brian L Yaspan
- Function : Author
Catalina Betancur
- Function : Author
- PersonId : 13320
- IdHAL : catalina-betancur
- ORCID : 0000-0002-3327-4804
- IdRef : 180835750
Rita M Cantor
- Function : Author
Edwin H Cook
- Function : Author
Hilary Coon
- Function : Author
Michael Cuccaro
- Function : Author
Daniel H. Geschwind
- Function : Author
Joachim Hallmayer
- Function : Author
Anthony P Monaco
- Function : Author
John I Nurnberger
- Function : Author
Margaret A Pericak-Vance
- Function : Author
Gerard D Schellenberg
- Function : Author
James S Sutcliffe
- Function : Author
Veronica J Vieland
- Function : Author
Ellen M Wijsman
- Function : Author
Andrew Green
- Function : Author
Michael Gill
- Function : Author
Louise Gallagher
- Function : Author
Astrid Vicente
- Function : Author
Sean Ennis
- Function : Author
Abstract
Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data.
Domains
Neurons and Cognition [q-bio.NC]Origin | Publication funded by an institution |
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