Convergence of genes and cellular pathways dysregulated in autism spectrum disorders

Dalila Pinto, Elsa Delaby, Daniele Merico, Mafalda Barbosa, Alison Merikangas, Lambertus Klei, Bhooma Thiruvahindrapuram, Xiao Xu, Robert Ziman, Zhuozhi Wang, Jacob A S Vorstman, Ann Thompson, Regina Regan, Marion Pilorge, Giovanna Pellecchia, Alistair T. Pagnamenta, Bárbara Oliveira, Christian R. Marshall, Tiago R. Magalhaes, Jennifer K. Lowe & 92 others Jennifer L. Howe, Anthony J. Griswold, John Gilbert, Eftichia Duketis, Beth A. Dombroski, Maretha V. De Jonge, Michael Cuccaro, Emily L. Crawford, Catarina T. Correia, Judith Conroy, Inês C. Conceição, Andreas G. Chiocchetti, Jillian P. Casey, Guiqing Cai, Christelle Cabrol, Nadia Bolshakova, Elena Bacchelli, Richard Anney, Steven Gallinger, Michelle Cotterchio, Graham Casey, Lonnie Zwaigenbaum, Kerstin Wittemeyer, Kirsty Wing, Simon Wallace, Herman Van Engeland, Ana Tryfon, Susanne Thomson, Latha Soorya, Bernadette Rogé, Wendy Roberts, Fritz Poustka, Susana Mouga, Nancy Minshew, L. Alison McInnes, Susan G. McGrew, Catherine Lord, Marion Leboyer, Ann S. Le Couteur, Alexander Kolevzon, Patricia Jiménez González, Suma Jacob, Richard Holt, Stephen Guter, Jonathan Green, Andrew Green, Christopher Gillberg, Bridget A. Fernandez, Frederico Duque, Richard Delorme, Geraldine Dawson, Pauline Chaste, Cátia Café, Sean Brennan, Thomas Bourgeron, Patrick F. Bolton, Sven Bölte, Raphael Bernier, Gillian Baird, Anthony J. Bailey, Evdokia Anagnostou, Joana Almeida, Ellen M. Wijsman, Veronica J. Vieland, Astrid M. Vicente, Gerard D. Schellenberg, Margaret Pericak-Vance, Andrew D. Paterson, Jeremy R. Parr, Guiomar Oliveira, John Nurnberger, Anthony P. Monaco, Elena Maestrini, Sabine M. Klauck, Hakon Hakonarson, Jonathan L. Haines, Daniel H. Geschwind, Christine M. Freitag, Susan E. Folstein, Sean Ennis, Hilary Coon, Agatino Battaglia, Peter Szatmari, James S. Sutcliffe, Joachim Hallmayer, Michael Gill, Edwin H. Cook, Joseph D. Buxbaum, Bernie Devlin, Louise Gallagher, Catalina Betancur, Stephen W. Scherer

Research output: Contribution to journalArticle

377 Citations (Scopus)

Abstract

Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10-5) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10-15, ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.

Original languageEnglish
Pages (from-to)677-694
Number of pages18
JournalAmerican Journal of Human Genetics
Volume94
Issue number5
DOIs
StatePublished - May 1 2014

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Genes
Fragile X Syndrome
Intellectual Disability
Synapses
Chromatin
Autism Spectrum Disorder
Nucleotides
Odds Ratio
Control Groups
Proteins
Neurodevelopmental Disorders

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Pinto, D., Delaby, E., Merico, D., Barbosa, M., Merikangas, A., Klei, L., ... Scherer, S. W. (2014). Convergence of genes and cellular pathways dysregulated in autism spectrum disorders. American Journal of Human Genetics, 94(5), 677-694. https://doi.org/10.1016/j.ajhg.2014.03.018

Convergence of genes and cellular pathways dysregulated in autism spectrum disorders. / Pinto, Dalila; Delaby, Elsa; Merico, Daniele; Barbosa, Mafalda; Merikangas, Alison; Klei, Lambertus; Thiruvahindrapuram, Bhooma; Xu, Xiao; Ziman, Robert; Wang, Zhuozhi; Vorstman, Jacob A S; Thompson, Ann; Regan, Regina; Pilorge, Marion; Pellecchia, Giovanna; Pagnamenta, Alistair T.; Oliveira, Bárbara; Marshall, Christian R.; Magalhaes, Tiago R.; Lowe, Jennifer K.; Howe, Jennifer L.; Griswold, Anthony J.; Gilbert, John; Duketis, Eftichia; Dombroski, Beth A.; De Jonge, Maretha V.; Cuccaro, Michael; Crawford, Emily L.; Correia, Catarina T.; Conroy, Judith; Conceição, Inês C.; Chiocchetti, Andreas G.; Casey, Jillian P.; Cai, Guiqing; Cabrol, Christelle; Bolshakova, Nadia; Bacchelli, Elena; Anney, Richard; Gallinger, Steven; Cotterchio, Michelle; Casey, Graham; Zwaigenbaum, Lonnie; Wittemeyer, Kerstin; Wing, Kirsty; Wallace, Simon; Van Engeland, Herman; Tryfon, Ana; Thomson, Susanne; Soorya, Latha; Rogé, Bernadette; Roberts, Wendy; Poustka, Fritz; Mouga, Susana; Minshew, Nancy; McInnes, L. Alison; McGrew, Susan G.; Lord, Catherine; Leboyer, Marion; Le Couteur, Ann S.; Kolevzon, Alexander; Jiménez González, Patricia; Jacob, Suma; Holt, Richard; Guter, Stephen; Green, Jonathan; Green, Andrew; Gillberg, Christopher; Fernandez, Bridget A.; Duque, Frederico; Delorme, Richard; Dawson, Geraldine; Chaste, Pauline; Café, Cátia; Brennan, Sean; Bourgeron, Thomas; Bolton, Patrick F.; Bölte, Sven; Bernier, Raphael; Baird, Gillian; Bailey, Anthony J.; Anagnostou, Evdokia; Almeida, Joana; Wijsman, Ellen M.; Vieland, Veronica J.; Vicente, Astrid M.; Schellenberg, Gerard D.; Pericak-Vance, Margaret; Paterson, Andrew D.; Parr, Jeremy R.; Oliveira, Guiomar; Nurnberger, John; Monaco, Anthony P.; Maestrini, Elena; Klauck, Sabine M.; Hakonarson, Hakon; Haines, Jonathan L.; Geschwind, Daniel H.; Freitag, Christine M.; Folstein, Susan E.; Ennis, Sean; Coon, Hilary; Battaglia, Agatino; Szatmari, Peter; Sutcliffe, James S.; Hallmayer, Joachim; Gill, Michael; Cook, Edwin H.; Buxbaum, Joseph D.; Devlin, Bernie; Gallagher, Louise; Betancur, Catalina; Scherer, Stephen W.

In: American Journal of Human Genetics, Vol. 94, No. 5, 01.05.2014, p. 677-694.

Research output: Contribution to journalArticle

Pinto, D, Delaby, E, Merico, D, Barbosa, M, Merikangas, A, Klei, L, Thiruvahindrapuram, B, Xu, X, Ziman, R, Wang, Z, Vorstman, JAS, Thompson, A, Regan, R, Pilorge, M, Pellecchia, G, Pagnamenta, AT, Oliveira, B, Marshall, CR, Magalhaes, TR, Lowe, JK, Howe, JL, Griswold, AJ, Gilbert, J, Duketis, E, Dombroski, BA, De Jonge, MV, Cuccaro, M, Crawford, EL, Correia, CT, Conroy, J, Conceição, IC, Chiocchetti, AG, Casey, JP, Cai, G, Cabrol, C, Bolshakova, N, Bacchelli, E, Anney, R, Gallinger, S, Cotterchio, M, Casey, G, Zwaigenbaum, L, Wittemeyer, K, Wing, K, Wallace, S, Van Engeland, H, Tryfon, A, Thomson, S, Soorya, L, Rogé, B, Roberts, W, Poustka, F, Mouga, S, Minshew, N, McInnes, LA, McGrew, SG, Lord, C, Leboyer, M, Le Couteur, AS, Kolevzon, A, Jiménez González, P, Jacob, S, Holt, R, Guter, S, Green, J, Green, A, Gillberg, C, Fernandez, BA, Duque, F, Delorme, R, Dawson, G, Chaste, P, Café, C, Brennan, S, Bourgeron, T, Bolton, PF, Bölte, S, Bernier, R, Baird, G, Bailey, AJ, Anagnostou, E, Almeida, J, Wijsman, EM, Vieland, VJ, Vicente, AM, Schellenberg, GD, Pericak-Vance, M, Paterson, AD, Parr, JR, Oliveira, G, Nurnberger, J, Monaco, AP, Maestrini, E, Klauck, SM, Hakonarson, H, Haines, JL, Geschwind, DH, Freitag, CM, Folstein, SE, Ennis, S, Coon, H, Battaglia, A, Szatmari, P, Sutcliffe, JS, Hallmayer, J, Gill, M, Cook, EH, Buxbaum, JD, Devlin, B, Gallagher, L, Betancur, C & Scherer, SW 2014, 'Convergence of genes and cellular pathways dysregulated in autism spectrum disorders', American Journal of Human Genetics, vol. 94, no. 5, pp. 677-694. https://doi.org/10.1016/j.ajhg.2014.03.018
Pinto, Dalila ; Delaby, Elsa ; Merico, Daniele ; Barbosa, Mafalda ; Merikangas, Alison ; Klei, Lambertus ; Thiruvahindrapuram, Bhooma ; Xu, Xiao ; Ziman, Robert ; Wang, Zhuozhi ; Vorstman, Jacob A S ; Thompson, Ann ; Regan, Regina ; Pilorge, Marion ; Pellecchia, Giovanna ; Pagnamenta, Alistair T. ; Oliveira, Bárbara ; Marshall, Christian R. ; Magalhaes, Tiago R. ; Lowe, Jennifer K. ; Howe, Jennifer L. ; Griswold, Anthony J. ; Gilbert, John ; Duketis, Eftichia ; Dombroski, Beth A. ; De Jonge, Maretha V. ; Cuccaro, Michael ; Crawford, Emily L. ; Correia, Catarina T. ; Conroy, Judith ; Conceição, Inês C. ; Chiocchetti, Andreas G. ; Casey, Jillian P. ; Cai, Guiqing ; Cabrol, Christelle ; Bolshakova, Nadia ; Bacchelli, Elena ; Anney, Richard ; Gallinger, Steven ; Cotterchio, Michelle ; Casey, Graham ; Zwaigenbaum, Lonnie ; Wittemeyer, Kerstin ; Wing, Kirsty ; Wallace, Simon ; Van Engeland, Herman ; Tryfon, Ana ; Thomson, Susanne ; Soorya, Latha ; Rogé, Bernadette ; Roberts, Wendy ; Poustka, Fritz ; Mouga, Susana ; Minshew, Nancy ; McInnes, L. Alison ; McGrew, Susan G. ; Lord, Catherine ; Leboyer, Marion ; Le Couteur, Ann S. ; Kolevzon, Alexander ; Jiménez González, Patricia ; Jacob, Suma ; Holt, Richard ; Guter, Stephen ; Green, Jonathan ; Green, Andrew ; Gillberg, Christopher ; Fernandez, Bridget A. ; Duque, Frederico ; Delorme, Richard ; Dawson, Geraldine ; Chaste, Pauline ; Café, Cátia ; Brennan, Sean ; Bourgeron, Thomas ; Bolton, Patrick F. ; Bölte, Sven ; Bernier, Raphael ; Baird, Gillian ; Bailey, Anthony J. ; Anagnostou, Evdokia ; Almeida, Joana ; Wijsman, Ellen M. ; Vieland, Veronica J. ; Vicente, Astrid M. ; Schellenberg, Gerard D. ; Pericak-Vance, Margaret ; Paterson, Andrew D. ; Parr, Jeremy R. ; Oliveira, Guiomar ; Nurnberger, John ; Monaco, Anthony P. ; Maestrini, Elena ; Klauck, Sabine M. ; Hakonarson, Hakon ; Haines, Jonathan L. ; Geschwind, Daniel H. ; Freitag, Christine M. ; Folstein, Susan E. ; Ennis, Sean ; Coon, Hilary ; Battaglia, Agatino ; Szatmari, Peter ; Sutcliffe, James S. ; Hallmayer, Joachim ; Gill, Michael ; Cook, Edwin H. ; Buxbaum, Joseph D. ; Devlin, Bernie ; Gallagher, Louise ; Betancur, Catalina ; Scherer, Stephen W. / Convergence of genes and cellular pathways dysregulated in autism spectrum disorders. In: American Journal of Human Genetics. 2014 ; Vol. 94, No. 5. pp. 677-694.
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T1 - Convergence of genes and cellular pathways dysregulated in autism spectrum disorders

AU - Pinto, Dalila

AU - Delaby, Elsa

AU - Merico, Daniele

AU - Barbosa, Mafalda

AU - Merikangas, Alison

AU - Klei, Lambertus

AU - Thiruvahindrapuram, Bhooma

AU - Xu, Xiao

AU - Ziman, Robert

AU - Wang, Zhuozhi

AU - Vorstman, Jacob A S

AU - Thompson, Ann

AU - Regan, Regina

AU - Pilorge, Marion

AU - Pellecchia, Giovanna

AU - Pagnamenta, Alistair T.

AU - Oliveira, Bárbara

AU - Marshall, Christian R.

AU - Magalhaes, Tiago R.

AU - Lowe, Jennifer K.

AU - Howe, Jennifer L.

AU - Griswold, Anthony J.

AU - Gilbert, John

AU - Duketis, Eftichia

AU - Dombroski, Beth A.

AU - De Jonge, Maretha V.

AU - Cuccaro, Michael

AU - Crawford, Emily L.

AU - Correia, Catarina T.

AU - Conroy, Judith

AU - Conceição, Inês C.

AU - Chiocchetti, Andreas G.

AU - Casey, Jillian P.

AU - Cai, Guiqing

AU - Cabrol, Christelle

AU - Bolshakova, Nadia

AU - Bacchelli, Elena

AU - Anney, Richard

AU - Gallinger, Steven

AU - Cotterchio, Michelle

AU - Casey, Graham

AU - Zwaigenbaum, Lonnie

AU - Wittemeyer, Kerstin

AU - Wing, Kirsty

AU - Wallace, Simon

AU - Van Engeland, Herman

AU - Tryfon, Ana

AU - Thomson, Susanne

AU - Soorya, Latha

AU - Rogé, Bernadette

AU - Roberts, Wendy

AU - Poustka, Fritz

AU - Mouga, Susana

AU - Minshew, Nancy

AU - McInnes, L. Alison

AU - McGrew, Susan G.

AU - Lord, Catherine

AU - Leboyer, Marion

AU - Le Couteur, Ann S.

AU - Kolevzon, Alexander

AU - Jiménez González, Patricia

AU - Jacob, Suma

AU - Holt, Richard

AU - Guter, Stephen

AU - Green, Jonathan

AU - Green, Andrew

AU - Gillberg, Christopher

AU - Fernandez, Bridget A.

AU - Duque, Frederico

AU - Delorme, Richard

AU - Dawson, Geraldine

AU - Chaste, Pauline

AU - Café, Cátia

AU - Brennan, Sean

AU - Bourgeron, Thomas

AU - Bolton, Patrick F.

AU - Bölte, Sven

AU - Bernier, Raphael

AU - Baird, Gillian

AU - Bailey, Anthony J.

AU - Anagnostou, Evdokia

AU - Almeida, Joana

AU - Wijsman, Ellen M.

AU - Vieland, Veronica J.

AU - Vicente, Astrid M.

AU - Schellenberg, Gerard D.

AU - Pericak-Vance, Margaret

AU - Paterson, Andrew D.

AU - Parr, Jeremy R.

AU - Oliveira, Guiomar

AU - Nurnberger, John

AU - Monaco, Anthony P.

AU - Maestrini, Elena

AU - Klauck, Sabine M.

AU - Hakonarson, Hakon

AU - Haines, Jonathan L.

AU - Geschwind, Daniel H.

AU - Freitag, Christine M.

AU - Folstein, Susan E.

AU - Ennis, Sean

AU - Coon, Hilary

AU - Battaglia, Agatino

AU - Szatmari, Peter

AU - Sutcliffe, James S.

AU - Hallmayer, Joachim

AU - Gill, Michael

AU - Cook, Edwin H.

AU - Buxbaum, Joseph D.

AU - Devlin, Bernie

AU - Gallagher, Louise

AU - Betancur, Catalina

AU - Scherer, Stephen W.

PY - 2014/5/1

Y1 - 2014/5/1

N2 - Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10-5) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10-15, ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.

AB - Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10-5) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10-15, ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.

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