Individual common variants exert weak effects on the risk for autism spectrum disorders

Richard Anney, Lambertus Klei, Dalila Pinto, Joana Almeida, Elena Bacchelli, Gillian Baird, Nadia Bolshakova, Sven Bölte, Patrick F. Bolton, Thomas Bourgeron, Sean Brennan, Jessica Brian, Jillian Casey, Judith Conroy, Catarina Correia, Christina Corsello, Emily L. Crawford, Maretha De jonge, Richard Delorme, Eftichia DuketisFrederico Duque, Annette Estes, Penny Farrar, Bridget A. Fernandez, Susan E. Folstein, Eric Fombonne, John Gilbert, Christopher Gillberg, Joseph T. Glessner, Andrew Green, Jonathan Green, Stephen J. Guter, Elizabeth A. Heron, Richard Holt, Jennifer L. Howe, Gillian Hughes, Vanessa Hus, Roberta Igliozzi, Suma Jacob, Graham P. Kenny, Cecilia Kim, Alexander Kolevzon, Vlad Kustanovich, Clara M. Lajonchere, Janine A. Lamb, Miriam Law-Smith, Marion Leboyer, Ann Le couteur, Bennett L. Leventhal, Xiao Qing Liu, Frances Lombard, Catherine Lord, Linda Lotspeich, Sabata C. Lund, Tiago R. Magalhaes, Carine Mantoulan, Christopher J. McDougle, Nadine M. Melhem, Alison Merikangas, Nancy J. Minshew, Ghazala K. Mirza, Jeff Munson, Carolyn Noakes, Gudrun Nygren, Katerina Papanikolaou, Alistair T. Pagnamenta, Barbara Parrini, Tara Paton, Andrew Pickles, David J. Posey, Fritz Poustka, Jiannis Ragoussis, Regina Regan, Wendy Roberts, Kathryn Roeder, Bernadette Roge, Michael L. Rutter, Sabine Schlitt, Naisha Shah, Val C. Sheffield, Latha Soorya, Inês Sousa, Vera Stoppioni, Nuala Sykes, Raffaella Tancredi, Ann P. Thompson, Susanne Thomson, Ana Tryfon, John Tsiantis, Herman Van Engeland, John B. Vincent, Fred Volkmar, J. A S Vorstman, Simon Wallace, Kirsty Wing, Kerstin Wittemeyer, Shawn Wood, Danielle Zurawiecki, Lonnie Zwaigenbaum, Anthony J. Bailey, Agatino Battaglia, Rita M. Cantor, Hilary Coon, Michael L. Cuccaro, Geraldine Dawson, Sean Ennis, Christine M. Freitag, Daniel H. Geschwind, Jonathan L. Haines, Sabine M. Klauck, William M. Mcmahon, Elena Maestrini, Judith Miller, Anthony P. Monaco, Stanley F. Nelson, John Nurnberger, Guiomar Oliveira, Jeremy R. Parr, Margaret A. Pericak-Vance, Joseph Piven, Gerard D. Schellenberg, Stephen W. Scherer, Astrid M. Vicente, Thomas H. Wassink, Ellen M. Wijsman, Catalina Betancur, Joseph D. Buxbaum, Edwin H. Cook, Louise Gallagher, Michael Gill, Joachim Hallmayer, Andrew D. Paterson, James S. Sutcliffe, Peter Szatmari, Veronica J. Vieland, Hakon Hakonarson, Bernie Devlin

Research output: Contribution to journalArticle

221 Citations (Scopus)

Abstract

While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.

Original languageEnglish
Article numberdds301
Pages (from-to)4781-4792
Number of pages12
JournalHuman Molecular Genetics
Volume21
Issue number21
DOIs
StatePublished - Nov 1 2012

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Single Nucleotide Polymorphism
Alleles
Genome
Language Development
Genome-Wide Association Study
Autistic Disorder
Autism Spectrum Disorder
Phenotype
Genes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Anney, R., Klei, L., Pinto, D., Almeida, J., Bacchelli, E., Baird, G., ... Devlin, B. (2012). Individual common variants exert weak effects on the risk for autism spectrum disorders. Human Molecular Genetics, 21(21), 4781-4792. [dds301]. https://doi.org/10.1093/hmg/dds301

Individual common variants exert weak effects on the risk for autism spectrum disorders. / Anney, Richard; Klei, Lambertus; Pinto, Dalila; Almeida, Joana; Bacchelli, Elena; Baird, Gillian; Bolshakova, Nadia; Bölte, Sven; Bolton, Patrick F.; Bourgeron, Thomas; Brennan, Sean; Brian, Jessica; Casey, Jillian; Conroy, Judith; Correia, Catarina; Corsello, Christina; Crawford, Emily L.; De jonge, Maretha; Delorme, Richard; Duketis, Eftichia; Duque, Frederico; Estes, Annette; Farrar, Penny; Fernandez, Bridget A.; Folstein, Susan E.; Fombonne, Eric; Gilbert, John; Gillberg, Christopher; Glessner, Joseph T.; Green, Andrew; Green, Jonathan; Guter, Stephen J.; Heron, Elizabeth A.; Holt, Richard; Howe, Jennifer L.; Hughes, Gillian; Hus, Vanessa; Igliozzi, Roberta; Jacob, Suma; Kenny, Graham P.; Kim, Cecilia; Kolevzon, Alexander; Kustanovich, Vlad; Lajonchere, Clara M.; Lamb, Janine A.; Law-Smith, Miriam; Leboyer, Marion; Le couteur, Ann; Leventhal, Bennett L.; Liu, Xiao Qing; Lombard, Frances; Lord, Catherine; Lotspeich, Linda; Lund, Sabata C.; Magalhaes, Tiago R.; Mantoulan, Carine; McDougle, Christopher J.; Melhem, Nadine M.; Merikangas, Alison; Minshew, Nancy J.; Mirza, Ghazala K.; Munson, Jeff; Noakes, Carolyn; Nygren, Gudrun; Papanikolaou, Katerina; Pagnamenta, Alistair T.; Parrini, Barbara; Paton, Tara; Pickles, Andrew; Posey, David J.; Poustka, Fritz; Ragoussis, Jiannis; Regan, Regina; Roberts, Wendy; Roeder, Kathryn; Roge, Bernadette; Rutter, Michael L.; Schlitt, Sabine; Shah, Naisha; Sheffield, Val C.; Soorya, Latha; Sousa, Inês; Stoppioni, Vera; Sykes, Nuala; Tancredi, Raffaella; Thompson, Ann P.; Thomson, Susanne; Tryfon, Ana; Tsiantis, John; Van Engeland, Herman; Vincent, John B.; Volkmar, Fred; Vorstman, J. A S; Wallace, Simon; Wing, Kirsty; Wittemeyer, Kerstin; Wood, Shawn; Zurawiecki, Danielle; Zwaigenbaum, Lonnie; Bailey, Anthony J.; Battaglia, Agatino; Cantor, Rita M.; Coon, Hilary; Cuccaro, Michael L.; Dawson, Geraldine; Ennis, Sean; Freitag, Christine M.; Geschwind, Daniel H.; Haines, Jonathan L.; Klauck, Sabine M.; Mcmahon, William M.; Maestrini, Elena; Miller, Judith; Monaco, Anthony P.; Nelson, Stanley F.; Nurnberger, John; Oliveira, Guiomar; Parr, Jeremy R.; Pericak-Vance, Margaret A.; Piven, Joseph; Schellenberg, Gerard D.; Scherer, Stephen W.; Vicente, Astrid M.; Wassink, Thomas H.; Wijsman, Ellen M.; Betancur, Catalina; Buxbaum, Joseph D.; Cook, Edwin H.; Gallagher, Louise; Gill, Michael; Hallmayer, Joachim; Paterson, Andrew D.; Sutcliffe, James S.; Szatmari, Peter; Vieland, Veronica J.; Hakonarson, Hakon; Devlin, Bernie.

In: Human Molecular Genetics, Vol. 21, No. 21, dds301, 01.11.2012, p. 4781-4792.

Research output: Contribution to journalArticle

Anney, R, Klei, L, Pinto, D, Almeida, J, Bacchelli, E, Baird, G, Bolshakova, N, Bölte, S, Bolton, PF, Bourgeron, T, Brennan, S, Brian, J, Casey, J, Conroy, J, Correia, C, Corsello, C, Crawford, EL, De jonge, M, Delorme, R, Duketis, E, Duque, F, Estes, A, Farrar, P, Fernandez, BA, Folstein, SE, Fombonne, E, Gilbert, J, Gillberg, C, Glessner, JT, Green, A, Green, J, Guter, SJ, Heron, EA, Holt, R, Howe, JL, Hughes, G, Hus, V, Igliozzi, R, Jacob, S, Kenny, GP, Kim, C, Kolevzon, A, Kustanovich, V, Lajonchere, CM, Lamb, JA, Law-Smith, M, Leboyer, M, Le couteur, A, Leventhal, BL, Liu, XQ, Lombard, F, Lord, C, Lotspeich, L, Lund, SC, Magalhaes, TR, Mantoulan, C, McDougle, CJ, Melhem, NM, Merikangas, A, Minshew, NJ, Mirza, GK, Munson, J, Noakes, C, Nygren, G, Papanikolaou, K, Pagnamenta, AT, Parrini, B, Paton, T, Pickles, A, Posey, DJ, Poustka, F, Ragoussis, J, Regan, R, Roberts, W, Roeder, K, Roge, B, Rutter, ML, Schlitt, S, Shah, N, Sheffield, VC, Soorya, L, Sousa, I, Stoppioni, V, Sykes, N, Tancredi, R, Thompson, AP, Thomson, S, Tryfon, A, Tsiantis, J, Van Engeland, H, Vincent, JB, Volkmar, F, Vorstman, JAS, Wallace, S, Wing, K, Wittemeyer, K, Wood, S, Zurawiecki, D, Zwaigenbaum, L, Bailey, AJ, Battaglia, A, Cantor, RM, Coon, H, Cuccaro, ML, Dawson, G, Ennis, S, Freitag, CM, Geschwind, DH, Haines, JL, Klauck, SM, Mcmahon, WM, Maestrini, E, Miller, J, Monaco, AP, Nelson, SF, Nurnberger, J, Oliveira, G, Parr, JR, Pericak-Vance, MA, Piven, J, Schellenberg, GD, Scherer, SW, Vicente, AM, Wassink, TH, Wijsman, EM, Betancur, C, Buxbaum, JD, Cook, EH, Gallagher, L, Gill, M, Hallmayer, J, Paterson, AD, Sutcliffe, JS, Szatmari, P, Vieland, VJ, Hakonarson, H & Devlin, B 2012, 'Individual common variants exert weak effects on the risk for autism spectrum disorders', Human Molecular Genetics, vol. 21, no. 21, dds301, pp. 4781-4792. https://doi.org/10.1093/hmg/dds301
Anney R, Klei L, Pinto D, Almeida J, Bacchelli E, Baird G et al. Individual common variants exert weak effects on the risk for autism spectrum disorders. Human Molecular Genetics. 2012 Nov 1;21(21):4781-4792. dds301. https://doi.org/10.1093/hmg/dds301
Anney, Richard ; Klei, Lambertus ; Pinto, Dalila ; Almeida, Joana ; Bacchelli, Elena ; Baird, Gillian ; Bolshakova, Nadia ; Bölte, Sven ; Bolton, Patrick F. ; Bourgeron, Thomas ; Brennan, Sean ; Brian, Jessica ; Casey, Jillian ; Conroy, Judith ; Correia, Catarina ; Corsello, Christina ; Crawford, Emily L. ; De jonge, Maretha ; Delorme, Richard ; Duketis, Eftichia ; Duque, Frederico ; Estes, Annette ; Farrar, Penny ; Fernandez, Bridget A. ; Folstein, Susan E. ; Fombonne, Eric ; Gilbert, John ; Gillberg, Christopher ; Glessner, Joseph T. ; Green, Andrew ; Green, Jonathan ; Guter, Stephen J. ; Heron, Elizabeth A. ; Holt, Richard ; Howe, Jennifer L. ; Hughes, Gillian ; Hus, Vanessa ; Igliozzi, Roberta ; Jacob, Suma ; Kenny, Graham P. ; Kim, Cecilia ; Kolevzon, Alexander ; Kustanovich, Vlad ; Lajonchere, Clara M. ; Lamb, Janine A. ; Law-Smith, Miriam ; Leboyer, Marion ; Le couteur, Ann ; Leventhal, Bennett L. ; Liu, Xiao Qing ; Lombard, Frances ; Lord, Catherine ; Lotspeich, Linda ; Lund, Sabata C. ; Magalhaes, Tiago R. ; Mantoulan, Carine ; McDougle, Christopher J. ; Melhem, Nadine M. ; Merikangas, Alison ; Minshew, Nancy J. ; Mirza, Ghazala K. ; Munson, Jeff ; Noakes, Carolyn ; Nygren, Gudrun ; Papanikolaou, Katerina ; Pagnamenta, Alistair T. ; Parrini, Barbara ; Paton, Tara ; Pickles, Andrew ; Posey, David J. ; Poustka, Fritz ; Ragoussis, Jiannis ; Regan, Regina ; Roberts, Wendy ; Roeder, Kathryn ; Roge, Bernadette ; Rutter, Michael L. ; Schlitt, Sabine ; Shah, Naisha ; Sheffield, Val C. ; Soorya, Latha ; Sousa, Inês ; Stoppioni, Vera ; Sykes, Nuala ; Tancredi, Raffaella ; Thompson, Ann P. ; Thomson, Susanne ; Tryfon, Ana ; Tsiantis, John ; Van Engeland, Herman ; Vincent, John B. ; Volkmar, Fred ; Vorstman, J. A S ; Wallace, Simon ; Wing, Kirsty ; Wittemeyer, Kerstin ; Wood, Shawn ; Zurawiecki, Danielle ; Zwaigenbaum, Lonnie ; Bailey, Anthony J. ; Battaglia, Agatino ; Cantor, Rita M. ; Coon, Hilary ; Cuccaro, Michael L. ; Dawson, Geraldine ; Ennis, Sean ; Freitag, Christine M. ; Geschwind, Daniel H. ; Haines, Jonathan L. ; Klauck, Sabine M. ; Mcmahon, William M. ; Maestrini, Elena ; Miller, Judith ; Monaco, Anthony P. ; Nelson, Stanley F. ; Nurnberger, John ; Oliveira, Guiomar ; Parr, Jeremy R. ; Pericak-Vance, Margaret A. ; Piven, Joseph ; Schellenberg, Gerard D. ; Scherer, Stephen W. ; Vicente, Astrid M. ; Wassink, Thomas H. ; Wijsman, Ellen M. ; Betancur, Catalina ; Buxbaum, Joseph D. ; Cook, Edwin H. ; Gallagher, Louise ; Gill, Michael ; Hallmayer, Joachim ; Paterson, Andrew D. ; Sutcliffe, James S. ; Szatmari, Peter ; Vieland, Veronica J. ; Hakonarson, Hakon ; Devlin, Bernie. / Individual common variants exert weak effects on the risk for autism spectrum disorders. In: Human Molecular Genetics. 2012 ; Vol. 21, No. 21. pp. 4781-4792.
@article{c789b1557c4347f7832639c716afe9fb,
title = "Individual common variants exert weak effects on the risk for autism spectrum disorders",
abstract = "While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1{\%}). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.",
author = "Richard Anney and Lambertus Klei and Dalila Pinto and Joana Almeida and Elena Bacchelli and Gillian Baird and Nadia Bolshakova and Sven B{\"o}lte and Bolton, {Patrick F.} and Thomas Bourgeron and Sean Brennan and Jessica Brian and Jillian Casey and Judith Conroy and Catarina Correia and Christina Corsello and Crawford, {Emily L.} 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 Eric Fombonne and John Gilbert and Christopher Gillberg and Glessner, {Joseph T.} and Andrew Green and Jonathan Green and Guter, {Stephen J.} and Heron, {Elizabeth A.} and Richard Holt and Howe, {Jennifer L.} and Gillian Hughes and Vanessa Hus and Roberta Igliozzi and Suma Jacob and Kenny, {Graham P.} and Cecilia Kim and Alexander Kolevzon and Vlad Kustanovich and Lajonchere, {Clara M.} and Lamb, {Janine A.} and Miriam Law-Smith and Marion Leboyer and {Le couteur}, Ann and Leventhal, {Bennett L.} and Liu, {Xiao Qing} and Frances Lombard and Catherine Lord and Linda Lotspeich and Lund, {Sabata C.} and Magalhaes, {Tiago R.} and Carine Mantoulan and McDougle, {Christopher J.} and Melhem, {Nadine M.} and Alison Merikangas and Minshew, {Nancy J.} and Mirza, {Ghazala K.} and Jeff Munson and Carolyn Noakes and Gudrun Nygren and Katerina Papanikolaou and Pagnamenta, {Alistair T.} and Barbara Parrini and Tara Paton and Andrew Pickles and Posey, {David J.} and Fritz Poustka and Jiannis Ragoussis and Regina Regan and Wendy Roberts and Kathryn Roeder and Bernadette Roge and Rutter, {Michael L.} and Sabine Schlitt and Naisha Shah and Sheffield, {Val C.} and Latha Soorya and In{\^e}s Sousa and Vera Stoppioni and Nuala Sykes and Raffaella Tancredi and Thompson, {Ann P.} and Susanne Thomson and Ana Tryfon and John Tsiantis and {Van Engeland}, Herman and Vincent, {John B.} and Fred Volkmar and Vorstman, {J. A S} and Simon Wallace and Kirsty Wing and Kerstin Wittemeyer and Shawn Wood and Danielle Zurawiecki and Lonnie Zwaigenbaum and Bailey, {Anthony J.} and Agatino Battaglia and Cantor, {Rita M.} and Hilary Coon and Cuccaro, {Michael L.} and Geraldine Dawson and Sean Ennis and Freitag, {Christine M.} and Geschwind, {Daniel H.} and Haines, {Jonathan L.} and Klauck, {Sabine M.} and Mcmahon, {William M.} and Elena Maestrini and Judith Miller and Monaco, {Anthony P.} and Nelson, {Stanley F.} and John Nurnberger and Guiomar Oliveira and Parr, {Jeremy R.} and Pericak-Vance, {Margaret A.} and Joseph Piven and Schellenberg, {Gerard D.} and Scherer, {Stephen W.} and Vicente, {Astrid M.} and Wassink, {Thomas H.} and Wijsman, {Ellen M.} and Catalina Betancur and Buxbaum, {Joseph D.} and Cook, {Edwin H.} and Louise Gallagher and Michael Gill and Joachim Hallmayer and Paterson, {Andrew D.} and Sutcliffe, {James S.} and Peter Szatmari and Vieland, {Veronica J.} and Hakon Hakonarson and Bernie Devlin",
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month = "11",
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T1 - Individual common variants exert weak effects on the risk for autism spectrum disorders

AU - Anney, Richard

AU - Klei, Lambertus

AU - Pinto, Dalila

AU - Almeida, Joana

AU - Bacchelli, Elena

AU - Baird, Gillian

AU - Bolshakova, Nadia

AU - Bölte, Sven

AU - Bolton, Patrick F.

AU - Bourgeron, Thomas

AU - Brennan, Sean

AU - Brian, Jessica

AU - Casey, Jillian

AU - Conroy, Judith

AU - Correia, Catarina

AU - Corsello, Christina

AU - Crawford, Emily L.

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 - Fombonne, Eric

AU - Gilbert, John

AU - Gillberg, Christopher

AU - Glessner, Joseph T.

AU - Green, Andrew

AU - Green, Jonathan

AU - Guter, Stephen J.

AU - Heron, Elizabeth A.

AU - Holt, Richard

AU - Howe, Jennifer L.

AU - Hughes, Gillian

AU - Hus, Vanessa

AU - Igliozzi, Roberta

AU - Jacob, Suma

AU - Kenny, Graham P.

AU - Kim, Cecilia

AU - Kolevzon, Alexander

AU - Kustanovich, Vlad

AU - Lajonchere, Clara M.

AU - Lamb, Janine A.

AU - Law-Smith, Miriam

AU - Leboyer, Marion

AU - Le couteur, Ann

AU - Leventhal, Bennett L.

AU - Liu, Xiao Qing

AU - Lombard, Frances

AU - Lord, Catherine

AU - Lotspeich, Linda

AU - Lund, Sabata C.

AU - Magalhaes, Tiago R.

AU - Mantoulan, Carine

AU - McDougle, Christopher J.

AU - Melhem, Nadine M.

AU - Merikangas, Alison

AU - Minshew, Nancy J.

AU - Mirza, Ghazala K.

AU - Munson, Jeff

AU - Noakes, Carolyn

AU - Nygren, Gudrun

AU - Papanikolaou, Katerina

AU - Pagnamenta, Alistair T.

AU - Parrini, Barbara

AU - Paton, Tara

AU - Pickles, Andrew

AU - Posey, David J.

AU - Poustka, Fritz

AU - Ragoussis, Jiannis

AU - Regan, Regina

AU - Roberts, Wendy

AU - Roeder, Kathryn

AU - Roge, Bernadette

AU - Rutter, Michael L.

AU - Schlitt, Sabine

AU - Shah, Naisha

AU - Sheffield, Val C.

AU - Soorya, Latha

AU - Sousa, Inês

AU - Stoppioni, Vera

AU - Sykes, Nuala

AU - Tancredi, Raffaella

AU - Thompson, Ann P.

AU - Thomson, Susanne

AU - Tryfon, Ana

AU - Tsiantis, John

AU - Van Engeland, Herman

AU - Vincent, John B.

AU - Volkmar, Fred

AU - Vorstman, J. A S

AU - Wallace, Simon

AU - Wing, Kirsty

AU - Wittemeyer, Kerstin

AU - Wood, Shawn

AU - Zurawiecki, Danielle

AU - Zwaigenbaum, Lonnie

AU - Bailey, Anthony J.

AU - Battaglia, Agatino

AU - Cantor, Rita M.

AU - Coon, Hilary

AU - Cuccaro, Michael L.

AU - Dawson, Geraldine

AU - Ennis, Sean

AU - Freitag, Christine M.

AU - Geschwind, Daniel H.

AU - Haines, Jonathan L.

AU - Klauck, Sabine M.

AU - Mcmahon, William M.

AU - Maestrini, Elena

AU - Miller, Judith

AU - Monaco, Anthony P.

AU - Nelson, Stanley F.

AU - Nurnberger, John

AU - Oliveira, Guiomar

AU - Parr, Jeremy R.

AU - Pericak-Vance, Margaret A.

AU - Piven, Joseph

AU - Schellenberg, Gerard D.

AU - Scherer, Stephen W.

AU - Vicente, Astrid M.

AU - Wassink, Thomas H.

AU - Wijsman, Ellen M.

AU - Betancur, Catalina

AU - Buxbaum, Joseph D.

AU - Cook, Edwin H.

AU - Gallagher, Louise

AU - Gill, Michael

AU - Hallmayer, Joachim

AU - Paterson, Andrew D.

AU - Sutcliffe, James S.

AU - Szatmari, Peter

AU - Vieland, Veronica J.

AU - Hakonarson, Hakon

AU - Devlin, Bernie

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N2 - While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.

AB - While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.

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