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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 565-579 |
| Number of pages | 15 |
| Journal | Human genetics |
| Volume | 131 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 2012 |
ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
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A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder. / Casey, Jillian P.; Magalhaes, Tiago; Conroy, Judith M.; Regan, Regina; Shah, Naisha; Anney, Richard; Shields, Denis C.; Abrahams, Brett S.; Almeida, Joana; Bacchelli, Elena; Bailey, Anthony J.; Baird, Gillian; Battaglia, Agatino; Berney, Tom; Bolshakova, Nadia; Bolton, Patrick F.; Bourgeron, Thomas; Brennan, Sean; Cali, Phil; Correia, Catarina; Corsello, Christina; Coutanche, Marc; Dawson, Geraldine; De Jonge, Maretha; Delorme, Richard; Duketis, Eftichia; Duque, Frederico; Estes, Annette; Farrar, Penny; Fernandez, Bridget A.; Folstein, Susan E.; Foley, Suzanne; Fombonne, Eric; Freitag, Christine M.; Gilbert, John; Gillberg, Christopher; Glessner, Joseph T.; Green, Jonathan; Guter, Stephen J.; Hakonarson, Hakon; Holt, Richard; Hughes, Gillian; Hus, Vanessa; Igliozzi, Roberta; Kim, Cecilia; Klauck, Sabine M.; Kolevzon, Alexander; Lamb, Janine A.; Leboyer, Marion; Couteur, Ann Le; Leventhal, Bennett L.; Lord, Catherine; Lund, Sabata C.; Maestrini, Elena; Mantoulan, Carine; Marshall, Christian R.; McConachie, Helen; McDougle, Christopher J.; McGrath, Jane; McMahon, William M.; Merikangas, Alison; Miller, Judith; Minopoli, Fiorella; Mirza, Ghazala K.; Munson, Jeff; Nelson, Stanley F.; Nygren, Gudrun; Oliveira, Guiomar; Pagnamenta, Alistair T.; Papanikolaou, Katerina; Parr, Jeremy R.; Parrini, Barbara; Pickles, Andrew; Pinto, Dalila; Piven, Joseph; Posey, David J.; Poustka, Annemarie; Poustka, Fritz; Ragoussis, Jiannis; Roge, Bernadette; Rutter, Michael L.; Sequeira, Ana F.; Soorya, Latha; Sousa, Inês; Sykes, Nuala; Stoppioni, Vera; Tancredi, Raffaella; Tauber, Maïté; Thompson, Ann P.; Thomson, Susanne; Tsiantis, John; Van Engeland, Herman; Vincent, John B.; Volkmar, Fred; Vorstman, Jacob A.S.; Wallace, Simon; Wang, Kai; Wassink, Thomas H.; White, Kathy; Wing, Kirsty; Wittemeyer, Kerstin; Yaspan, Brian L.; Zwaigenbaum, Lonnie; Betancur, Catalina; Buxbaum, Joseph D.; Cantor, Rita M.; Cook, Edwin H.; Coon, Hilary; Cuccaro, Michael L.; Geschwind, Daniel H.; Haines, Jonathan L.; Hallmayer, Joachim; Monaco, Anthony P.; Nurnberger, John I.; Pericak-Vance, Margaret A.; Schellenberg, Gerard D.; Scherer, Stephen W.; Sutcliffe, James S.; Szatmari, Peter; Vieland, Veronica J.; Wijsman, Ellen M.; Green, Andrew; Gill, Michael; Gallagher, Louise; Vicente, Astrid; Ennis, Sean.
In: Human genetics, Vol. 131, No. 4, 04.2012, p. 565-579.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder
AU - Casey, Jillian P.
AU - Magalhaes, Tiago
AU - Conroy, Judith M.
AU - Regan, Regina
AU - Shah, Naisha
AU - Anney, Richard
AU - Shields, Denis C.
AU - Abrahams, Brett S.
AU - Almeida, Joana
AU - Bacchelli, Elena
AU - Bailey, Anthony J.
AU - Baird, Gillian
AU - Battaglia, Agatino
AU - Berney, Tom
AU - Bolshakova, Nadia
AU - Bolton, Patrick F.
AU - Bourgeron, Thomas
AU - Brennan, Sean
AU - Cali, Phil
AU - Correia, Catarina
AU - Corsello, Christina
AU - Coutanche, Marc
AU - Dawson, Geraldine
AU - De Jonge, Maretha
AU - Delorme, Richard
AU - Duketis, Eftichia
AU - Duque, Frederico
AU - Estes, Annette
AU - Farrar, Penny
AU - Fernandez, Bridget A.
AU - Folstein, Susan E.
AU - Foley, Suzanne
AU - Fombonne, Eric
AU - Freitag, Christine M.
AU - Gilbert, John
AU - Gillberg, Christopher
AU - Glessner, Joseph T.
AU - Green, Jonathan
AU - Guter, Stephen J.
AU - Hakonarson, Hakon
AU - Holt, Richard
AU - Hughes, Gillian
AU - Hus, Vanessa
AU - Igliozzi, Roberta
AU - Kim, Cecilia
AU - Klauck, Sabine M.
AU - Kolevzon, Alexander
AU - Lamb, Janine A.
AU - Leboyer, Marion
AU - Couteur, Ann Le
AU - Leventhal, Bennett L.
AU - Lord, Catherine
AU - Lund, Sabata C.
AU - Maestrini, Elena
AU - Mantoulan, Carine
AU - Marshall, Christian R.
AU - McConachie, Helen
AU - McDougle, Christopher J.
AU - McGrath, Jane
AU - McMahon, William M.
AU - Merikangas, Alison
AU - Miller, Judith
AU - Minopoli, Fiorella
AU - Mirza, Ghazala K.
AU - Munson, Jeff
AU - Nelson, Stanley F.
AU - Nygren, Gudrun
AU - Oliveira, Guiomar
AU - Pagnamenta, Alistair T.
AU - Papanikolaou, Katerina
AU - Parr, Jeremy R.
AU - Parrini, Barbara
AU - Pickles, Andrew
AU - Pinto, Dalila
AU - Piven, Joseph
AU - Posey, David J.
AU - Poustka, Annemarie
AU - Poustka, Fritz
AU - Ragoussis, Jiannis
AU - Roge, Bernadette
AU - Rutter, Michael L.
AU - Sequeira, Ana F.
AU - Soorya, Latha
AU - Sousa, Inês
AU - Sykes, Nuala
AU - Stoppioni, Vera
AU - Tancredi, Raffaella
AU - Tauber, Maïté
AU - Thompson, Ann P.
AU - Thomson, Susanne
AU - Tsiantis, John
AU - Van Engeland, Herman
AU - Vincent, John B.
AU - Volkmar, Fred
AU - Vorstman, Jacob A.S.
AU - Wallace, Simon
AU - Wang, Kai
AU - Wassink, Thomas H.
AU - White, Kathy
AU - Wing, Kirsty
AU - Wittemeyer, Kerstin
AU - Yaspan, Brian L.
AU - Zwaigenbaum, Lonnie
AU - Betancur, Catalina
AU - Buxbaum, Joseph D.
AU - Cantor, Rita M.
AU - Cook, Edwin H.
AU - Coon, Hilary
AU - Cuccaro, Michael L.
AU - Geschwind, Daniel H.
AU - Haines, Jonathan L.
AU - Hallmayer, Joachim
AU - Monaco, Anthony P.
AU - Nurnberger, John I.
AU - Pericak-Vance, Margaret A.
AU - Schellenberg, Gerard D.
AU - Scherer, Stephen W.
AU - Sutcliffe, James S.
AU - Szatmari, Peter
AU - Vieland, Veronica J.
AU - Wijsman, Ellen M.
AU - Green, Andrew
AU - Gill, Michael
AU - Gallagher, Louise
AU - Vicente, Astrid
AU - Ennis, Sean
N1 - Funding Information: Acknowledgments The authors acknowledge the families participating in the study and the main funders of the Autism Genome Project Consortium (AGP): Autism Speaks (USA), the Health Research Board (HRB; Ireland), The Medical Research Council (MRC; UK), Genome Canada/Ontario Genomics Institute, and the Hilibrand Foundation (USA). Additional support for individual groups was provided by the US National Institutes of Health (NIH grants HD055751, HD055782, HD055784, HD35465, MH52708, MH55284, MH57881, MH061009, MH06359, MH066673, MH080647, MH081754, MH66766, NS026630, NS042165, NS049 261), the Canadian Institute for Advanced Research (CIFAR), the Canadian Institutes for Health Research (CIHR), Assistance Publiq-ue–Hôpitaux de Paris (France), Autistica, Canada Foundation for Innovation/Ontario Innovation Trust, Deutsche Forschungsgemeins-chaft (grant Po 255/17-4) (Germany), EC Sixth FP AUTISM MOL-GEN, Fundac¸ão Calouste Gulbenkian (Portugal), Fondation de France, Fondation FondaMental (France), Fondation Orange (France), Fondation pour la Recherche Médicale (France), Fundac¸ão para a Ciência e Tecnologia (Portugal), the Hospital for Sick Children Foundation and University of Toronto (Canada), INSERM (France), Institut Pasteur (France), the Italian Ministry of Health (convention 181 of 19.10.2001), the John P. Hussman Foundation (USA), McLaughlin Centre (Canada), Ontario Ministry of Research and Innovation (Canada), the Seaver Foundation (USA), the Swedish Science Council, The Centre for Applied Genomics (Canada), the Utah Autism Foundation (USA) and the Wellcome Trust core award 075491/Z/04 (UK). We acknowledge support from the Autism Genetic Resource Exchange (AGRE) and Autism Speaks. We gratefully acknowledge the resources provided by the AGRE consortium and the participating AGRE families. AGRE is a program of Autism Speaks and is supported, in part, by grant 1U24MH081810 from the National Institute of Mental Health to Clara M. Lajonchere (PI). We wish to acknowledge the National Children’s Research Centre Our Lady’s Children’s Hospital Crumlin Ireland for providing additional support and the Wellcome Trust Case–Control Consortium for providing data sets that were used as part of this study. J.P.C is supported by an EMBARK postgraduate award from the Irish Research Council for Science, Engineering and Technology (IRCSET).
PY - 2012/4
Y1 - 2012/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84860879137&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84860879137&partnerID=8YFLogxK
U2 - 10.1007/s00439-011-1094-6
DO - 10.1007/s00439-011-1094-6
M3 - Article
C2 - 21996756
AN - SCOPUS:84860879137
VL - 131
SP - 565
EP - 579
JO - Human Genetics
JF - Human Genetics
SN - 0340-6717
IS - 4
ER -