A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder

Jillian P. Casey, Tiago Magalhaes, Judith M. Conroy, Regina Regan, Naisha Shah, Richard Anney, Denis C. Shields, Brett S. Abrahams, Joana Almeida, Elena Bacchelli, Anthony J. Bailey, Gillian Baird, Agatino Battaglia, Tom Berney, Nadia Bolshakova, Patrick F. Bolton, Thomas Bourgeron, Sean Brennan, Phil Cali, Catarina Correia & 106 others Christina Corsello, Marc Coutanche, Geraldine Dawson, Maretha De Jonge, Richard Delorme, Eftichia Duketis, Frederico Duque, Annette Estes, Penny Farrar, Bridget A. Fernandez, Susan E. Folstein, Suzanne Foley, Eric Fombonne, Christine M. Freitag, John Gilbert, Christopher Gillberg, Joseph T. Glessner, Jonathan Green, Stephen J. Guter, Hakon Hakonarson, Richard Holt, Gillian Hughes, Vanessa Hus, Roberta Igliozzi, Cecilia Kim, Sabine M. Klauck, Alexander Kolevzon, Janine A. Lamb, Marion Leboyer, Ann Le Couteur, Bennett L. Leventhal, Catherine Lord, Sabata C. Lund, Elena Maestrini, Carine Mantoulan, Christian R. Marshall, Helen McConachie, Christopher J. McDougle, Jane McGrath, William M. McMahon, Alison Merikangas, Judith Miller, Fiorella Minopoli, Ghazala K. Mirza, Jeff Munson, Stanley F. Nelson, Gudrun Nygren, Guiomar Oliveira, Alistair T. Pagnamenta, Katerina Papanikolaou, Jeremy R. Parr, Barbara Parrini, Andrew Pickles, Dalila Pinto, Joseph Piven, David J. Posey, Annemarie Poustka, Fritz Poustka, Jiannis Ragoussis, Bernadette Roge, Michael L. Rutter, Ana F. Sequeira, Latha Soorya, Inês Sousa, Nuala Sykes, Vera Stoppioni, Raffaella Tancredi, Maïté Tauber, Ann P. Thompson, Susanne Thomson, John Tsiantis, Herman Van Engeland, John B. Vincent, Fred Volkmar, Jacob A S Vorstman, Simon Wallace, Kai Wang, Thomas H. Wassink, Kathy White, Kirsty Wing, Kerstin Wittemeyer, Brian L. Yaspan, Lonnie Zwaigenbaum, Catalina Betancur, Joseph D. Buxbaum, Rita M. Cantor, Edwin H. Cook, Hilary Coon, Michael L. Cuccaro, Daniel H. Geschwind, Jonathan L. Haines, Joachim Hallmayer, Anthony P. Monaco, John I. Nurnberger, Margaret A. Pericak-Vance, Gerard D. Schellenberg, Stephen W. Scherer, James S. Sutcliffe, Peter Szatmari, Veronica J. Vieland, Ellen M. Wijsman, Andrew Green, Michael Gill, Louise Gallagher, Astrid Vicente, Sean Ennis

Research output: Contribution to journalArticle

117 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)565-579
Number of pages15
JournalHuman Genetics
Volume131
Issue number4
DOIs
StatePublished - Apr 2012
Externally publishedYes

Fingerprint

Haplotypes
Genes
Autism Spectrum Disorder
Aptitude
Genetic Heterogeneity
Genome-Wide Association Study
Genetic Association Studies
Autistic Disorder
Single Nucleotide Polymorphism
Language
Odds Ratio
Communication
Genome

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Casey, J. P., Magalhaes, T., Conroy, J. M., Regan, R., Shah, N., Anney, R., ... Ennis, S. (2012). A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder. Human Genetics, 131(4), 565-579. https://doi.org/10.1007/s00439-011-1094-6

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 journalArticle

Casey, JP, Magalhaes, T, Conroy, JM, Regan, R, Shah, N, Anney, R, Shields, DC, Abrahams, BS, Almeida, J, Bacchelli, E, Bailey, AJ, Baird, G, Battaglia, A, Berney, T, Bolshakova, N, Bolton, PF, Bourgeron, T, Brennan, S, Cali, P, Correia, C, Corsello, C, Coutanche, M, Dawson, G, De Jonge, M, Delorme, R, Duketis, E, Duque, F, Estes, A, Farrar, P, Fernandez, BA, Folstein, SE, Foley, S, Fombonne, E, Freitag, CM, Gilbert, J, Gillberg, C, Glessner, JT, Green, J, Guter, SJ, Hakonarson, H, Holt, R, Hughes, G, Hus, V, Igliozzi, R, Kim, C, Klauck, SM, Kolevzon, A, Lamb, JA, Leboyer, M, Couteur, AL, Leventhal, BL, Lord, C, Lund, SC, Maestrini, E, Mantoulan, C, Marshall, CR, McConachie, H, McDougle, CJ, McGrath, J, McMahon, WM, Merikangas, A, Miller, J, Minopoli, F, Mirza, GK, Munson, J, Nelson, SF, Nygren, G, Oliveira, G, Pagnamenta, AT, Papanikolaou, K, Parr, JR, Parrini, B, Pickles, A, Pinto, D, Piven, J, Posey, DJ, Poustka, A, Poustka, F, Ragoussis, J, Roge, B, Rutter, ML, Sequeira, AF, Soorya, L, Sousa, I, Sykes, N, Stoppioni, V, Tancredi, R, Tauber, M, Thompson, AP, Thomson, S, Tsiantis, J, Van Engeland, H, Vincent, JB, Volkmar, F, Vorstman, JAS, Wallace, S, Wang, K, Wassink, TH, White, K, Wing, K, Wittemeyer, K, Yaspan, BL, Zwaigenbaum, L, Betancur, C, Buxbaum, JD, Cantor, RM, Cook, EH, Coon, H, Cuccaro, ML, Geschwind, DH, Haines, JL, Hallmayer, J, Monaco, AP, Nurnberger, JI, Pericak-Vance, MA, Schellenberg, GD, Scherer, SW, Sutcliffe, JS, Szatmari, P, Vieland, VJ, Wijsman, EM, Green, A, Gill, M, Gallagher, L, Vicente, A & Ennis, S 2012, 'A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder', Human Genetics, vol. 131, no. 4, pp. 565-579. https://doi.org/10.1007/s00439-011-1094-6
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. / A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder. In: Human Genetics. 2012 ; Vol. 131, No. 4. pp. 565-579.
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title = "A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder",
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.",
author = "Casey, {Jillian P.} and Tiago Magalhaes and Conroy, {Judith M.} and Regina Regan and Naisha Shah and Richard Anney and Shields, {Denis C.} and Abrahams, {Brett S.} and Joana Almeida and Elena Bacchelli and Bailey, {Anthony J.} and Gillian Baird and Agatino Battaglia and Tom Berney and Nadia Bolshakova and Bolton, {Patrick F.} and Thomas Bourgeron and Sean Brennan and Phil Cali and Catarina Correia and Christina Corsello and Marc Coutanche and Geraldine Dawson and {De Jonge}, Maretha and Richard Delorme and Eftichia Duketis and Frederico Duque and Annette Estes and Penny Farrar and Fernandez, {Bridget A.} and Folstein, {Susan E.} and Suzanne Foley and Eric Fombonne and Freitag, {Christine M.} and John Gilbert and Christopher Gillberg and Glessner, {Joseph T.} and Jonathan Green and Guter, {Stephen J.} and Hakon Hakonarson and Richard Holt and Gillian Hughes and Vanessa Hus and Roberta Igliozzi and Cecilia Kim and Klauck, {Sabine M.} and Alexander Kolevzon and Lamb, {Janine A.} and Marion Leboyer and Couteur, {Ann Le} and Leventhal, {Bennett L.} and Catherine Lord and Lund, {Sabata C.} and Elena Maestrini and Carine Mantoulan and Marshall, {Christian R.} and Helen McConachie and McDougle, {Christopher J.} and Jane McGrath and McMahon, {William M.} and Alison Merikangas and Judith Miller and Fiorella Minopoli and Mirza, {Ghazala K.} and Jeff Munson and Nelson, {Stanley F.} and Gudrun Nygren and Guiomar Oliveira and Pagnamenta, {Alistair T.} and Katerina Papanikolaou and Parr, {Jeremy R.} and Barbara Parrini and Andrew Pickles and Dalila Pinto and Joseph Piven and Posey, {David J.} and Annemarie Poustka and Fritz Poustka and Jiannis Ragoussis and Bernadette Roge and Rutter, {Michael L.} and Sequeira, {Ana F.} and Latha Soorya and In{\^e}s Sousa and Nuala Sykes and Vera Stoppioni and Raffaella Tancredi and Ma{\"i}t{\'e} Tauber and Thompson, {Ann P.} and Susanne Thomson and John Tsiantis and {Van Engeland}, Herman and Vincent, {John B.} and Fred Volkmar and Vorstman, {Jacob A S} and Simon Wallace and Kai Wang and Wassink, {Thomas H.} and Kathy White and Kirsty Wing and Kerstin Wittemeyer and Yaspan, {Brian L.} and Lonnie Zwaigenbaum and Catalina Betancur and Buxbaum, {Joseph D.} and Cantor, {Rita M.} and Cook, {Edwin H.} and Hilary Coon and Cuccaro, {Michael L.} and Geschwind, {Daniel H.} and Haines, {Jonathan L.} and Joachim Hallmayer and Monaco, {Anthony P.} and Nurnberger, {John I.} and Pericak-Vance, {Margaret A.} and Schellenberg, {Gerard D.} and Scherer, {Stephen W.} and Sutcliffe, {James S.} and Peter Szatmari and Vieland, {Veronica J.} and Wijsman, {Ellen M.} and Andrew Green and Michael Gill and Louise Gallagher and Astrid Vicente and Sean Ennis",
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pages = "565--579",
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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

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.

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