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; Barbara Oliveira; Christian R. Marshall; Tiago R. Magalhaes; Jennifer K. Lowe; 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; Ines C. Conceicao; 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 Roge; 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 Jimenez Gonzalez; Suma Jacob; Richard Holt; Stephen Guter; Jonathan Green; Andrew Green; Christopher Gillberg; Bridget A. Fernandez; Frederico Duque; Richard Delorme; Geraldine Dawson; Pauline Chaste; Catia Cafe; Sean Brennan; Thomas Bourgeron; Patrick F. Bolton; Sven Boelte; 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 I. 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

doi:10.1016/j.ajhg.2014.03.018

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, Barbara Oliveira, Christian R. Marshall, Tiago R. Magalhaes, Jennifer K. LoweJennifer 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, Ines C. Conceicao, 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 Roge, 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 Jimenez Gonzalez, Suma Jacob, Richard Holt, Stephen Guter, Jonathan Green, Andrew Green, Christopher Gillberg, Bridget A. Fernandez, Frederico Duque, Richard Delorme, Geraldine Dawson, Pauline Chaste, Catia Cafe, Sean Brennan, Thomas Bourgeron, Patrick F. Bolton, Sven Boelte, 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 I. 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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

726 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 x 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 x 10(-15), similar to 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 language	English
Pages (from-to)	677-694
Number of pages	18
Journal	American Journal of Human Genetics
Volume	94
Issue number	5
DOIs	https://doi.org/10.1016/j.ajhg.2014.03.018
Publication status	Published - 1 May 2014

Keywords

DE-NOVO MUTATIONS
COPY NUMBER VARIANTS
GENOME-WIDE ASSOCIATION
FRAGILE-X-SYNDROME
INTELLECTUAL DISABILITY
STRUCTURAL VARIATION
PHENOTYPE ONTOLOGY
DELETIONS
DUPLICATIONS
RISK

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10.1016/j.ajhg.2014.03.018

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Pinto, D., Delaby, E., Merico, D., Barbosa, M., Merikangas, A., Klei, L., Thiruvahindrapuram, B., Xu, X., Ziman, R., Wang, Z., Vorstman, J. A. S., Thompson, A., Regan, R., Pilorge, M., Pellecchia, G., Pagnamenta, A. T., Oliveira, B., Marshall, C. R., Magalhaes, T. R., ... 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

@article{635750d8d28d4f6c898e58ebca3d64fe,

title = "Convergence of Genes and Cellular Pathways Dysregulated in Autism Spectrum Disorders",

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 x 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 x 10(-15), similar to 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.",

keywords = "DE-NOVO MUTATIONS, COPY NUMBER VARIANTS, GENOME-WIDE ASSOCIATION, FRAGILE-X-SYNDROME, INTELLECTUAL DISABILITY, STRUCTURAL VARIATION, PHENOTYPE ONTOLOGY, DELETIONS, DUPLICATIONS, RISK",

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

year = "2014",

month = may,

day = "1",

doi = "10.1016/j.ajhg.2014.03.018",

language = "English",

volume = "94",

pages = "677--694",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Elsevier",

number = "5",

}

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, Conceicao, 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, Roge, B, Roberts, W, Poustka, F, Mouga, S, Minshew, N, McInnes, LA, McGrew, SG, Lord, C, Leboyer, M, Le Couteur, AS, Kolevzon, A, Gonzalez, PJ, Jacob, S, Holt, R, Guter, S, Green, J, Green, A, Gillberg, C, Fernandez, BA, Duque, F, Delorme, R, Dawson, G, Chaste, P, Cafe, C, Brennan, S, Bourgeron, T, Bolton, PF, Boelte, 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, JI, 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

TY - JOUR

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, Barbara

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 - Conceicao, Ines 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 - Roge, 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 - Gonzalez, Patricia Jimenez

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 - Cafe, Catia

AU - Brennan, Sean

AU - Bourgeron, Thomas

AU - Bolton, Patrick F.

AU - Boelte, 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 I.

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 x 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 x 10(-15), similar to 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 x 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 x 10(-15), similar to 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.

KW - DE-NOVO MUTATIONS

KW - COPY NUMBER VARIANTS

KW - GENOME-WIDE ASSOCIATION

KW - FRAGILE-X-SYNDROME

KW - INTELLECTUAL DISABILITY

KW - STRUCTURAL VARIATION

KW - PHENOTYPE ONTOLOGY

KW - DELETIONS

KW - DUPLICATIONS

KW - RISK

U2 - 10.1016/j.ajhg.2014.03.018

DO - 10.1016/j.ajhg.2014.03.018

M3 - Article

SN - 0002-9297

VL - 94

SP - 677

EP - 694

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 5

ER -

Convergence of Genes and Cellular Pathways Dysregulated in Autism Spectrum Disorders

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