The impact of the metabotropic glutamate receptor and other gene family interaction networks on autism

Dexter Hadley; Zhi Liang Wu; Charlly Kao; Akshata Kini; Alisha Mohamed-Hadley; Kelly Thomas; Lyam Vazquez; Haijun Qiu; Frank Mentch; Renata Pellegrino; Cecilia Kim; John Connolly; Joseph Glessner; Hakon Hakonarson; Dalila Pinto; Alison Merikangas; Lambertus Klei; Jacob A.S. Vorstman; Ann Thompson; Regina Regan; Alistair T. Pagnamenta; Bárbara Oliveira; Tiago R. Magalhaes; John Gilbert; Eftichia Duketis; Maretha V. De Jonge; Michael Cuccaro; Catarina T. Correia; Judith Conroy; Inês C. Conceiça; Andreas G. Chiocchetti; Jillian P. Casey; Nadia Bolshakova; Elena Bacchelli; Richard Anney; Lonnie Zwaigenbaum; Kerstin Wittemeyer; Simon Wallace; Herman Van Engeland; Latha Soorya; Bernadette Rogé; Wendy Roberts; Fritz Poustka; Susana Mouga; Nancy Minshew; Susan G. McGrew; Catherine Lord; Marion Leboyer; Ann S. Le Couteur; Alexander Kolevzon; Suma Jacob; Stephen Guter; Jonathan Green; Andrew Green; Christopher Gillberg; Bridget A. Fernandez; Frederico Duque; Richard Delorme; Geraldine Dawson; Sean Brennan; Thomas Bourgeron; Patrick F. Bolton; Sven Bölte; Raphael Bernier; Gillian Baird; Anthony J. Bailey; Evdokia Anagnostou; Ellen M. Wijsman; Veronica J. Vieland; Astrid M. Vicente; Erard D. Schellenberg; Margaret Pericak-Vance; Andrew D. Paterson; Jeremy R. Parr; Guiomar Oliveira; Joana Almeida; Cátia Café; John I. Nurnberger; Anthony P. Monaco; Elena Maestrini; Sabine M. Klauck; 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:10.1038/ncomms5074

The impact of the metabotropic glutamate receptor and other gene family interaction networks on autism

Dexter Hadley, Zhi Liang Wu, Charlly Kao, Akshata Kini, Alisha Mohamed-Hadley, Kelly Thomas, Lyam Vazquez, Haijun Qiu, Frank Mentch, Renata Pellegrino, Cecilia Kim, John Connolly, Joseph Glessner, Hakon Hakonarson, Dalila Pinto, Alison Merikangas, Lambertus Klei, Jacob A.S. Vorstman, Ann Thompson, Regina ReganAlistair T. Pagnamenta, Bárbara Oliveira, Tiago R. Magalhaes, John Gilbert, Eftichia Duketis, Maretha V. De Jonge, Michael Cuccaro, Catarina T. Correia, Judith Conroy, Inês C. Conceiça, Andreas G. Chiocchetti, Jillian P. Casey, Nadia Bolshakova, Elena Bacchelli, Richard Anney, Lonnie Zwaigenbaum, Kerstin Wittemeyer, Simon Wallace, Herman Van Engeland, Latha Soorya, Bernadette Rogé, Wendy Roberts, Fritz Poustka, Susana Mouga, Nancy Minshew, Susan G. McGrew, Catherine Lord, Marion Leboyer, Ann S. Le Couteur, Alexander Kolevzon, Suma Jacob, Stephen Guter, Jonathan Green, Andrew Green, Christopher Gillberg, Bridget A. Fernandez, Frederico Duque, Richard Delorme, Geraldine Dawson, Sean Brennan, Thomas Bourgeron, Patrick F. Bolton, Sven Bölte, Raphael Bernier, Gillian Baird, Anthony J. Bailey, Evdokia Anagnostou, Ellen M. Wijsman, Veronica J. Vieland, Astrid M. Vicente, Erard D. Schellenberg, Margaret Pericak-Vance, Andrew D. Paterson, Jeremy R. Parr, Guiomar Oliveira, Joana Almeida, Cátia Café, John I. Nurnberger, Anthony P. Monaco, Elena Maestrini, Sabine M. Klauck, 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

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Abstract

Although multiple reports show that defective genetic networks underlie the aetiology of autism, few have translated into pharmacotherapeutic opportunities. Since drugs compete with endogenous small molecules for protein binding, many successful drugs target large gene families with multiple drug binding sites. Here we search for defective gene family interaction networks (GFINs) in 6,742 patients with the ASDs relative to 12,544 neurologically normal controls, to find potentially druggable genetic targets. We find significant enrichment of structural defects (P 2.40E 09, 1.8-fold enrichment) in the metabotropic glutamate receptor (GRM) GFIN, previously observed to impact attention deficit hyperactivity disorder (ADHD) and schizophrenia. Also, the MXD-MYC-MAX network of genes, previously implicated in cancer, is significantly enriched (P 3.83E 23, 2.5-fold enrichment), as is the calmodulin 1 (CALM1) gene interaction network (P 4.16 04, 14.4-fold enrichment), which regulates voltage-independent calcium-activated action potentials at the neuronal synapse. We find that multiple defective gene family interactions underlie autism, presenting new translational opportunities to explore for therapeutic interventions.

Original language	English
Article number	4074
Journal	Nature Communications
Volume	5
DOIs	https://doi.org/10.1038/ncomms5074
State	Published - 13 Jun 2014

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Hadley, D., Wu, Z. L., Kao, C., Kini, A., Mohamed-Hadley, A., Thomas, K., Vazquez, L., Qiu, H., Mentch, F., Pellegrino, R., Kim, C., Connolly, J., Glessner, J., Hakonarson, H., Pinto, D., Merikangas, A., Klei, L., Vorstman, J. A. S., Thompson, A., ... Scherer, S. W. (2014). The impact of the metabotropic glutamate receptor and other gene family interaction networks on autism. Nature Communications, 5, Article 4074. https://doi.org/10.1038/ncomms5074

@article{8344a2e9965146709fc35415107b4b6a,

title = "The impact of the metabotropic glutamate receptor and other gene family interaction networks on autism",

abstract = "Although multiple reports show that defective genetic networks underlie the aetiology of autism, few have translated into pharmacotherapeutic opportunities. Since drugs compete with endogenous small molecules for protein binding, many successful drugs target large gene families with multiple drug binding sites. Here we search for defective gene family interaction networks (GFINs) in 6,742 patients with the ASDs relative to 12,544 neurologically normal controls, to find potentially druggable genetic targets. We find significant enrichment of structural defects (P 2.40E 09, 1.8-fold enrichment) in the metabotropic glutamate receptor (GRM) GFIN, previously observed to impact attention deficit hyperactivity disorder (ADHD) and schizophrenia. Also, the MXD-MYC-MAX network of genes, previously implicated in cancer, is significantly enriched (P 3.83E 23, 2.5-fold enrichment), as is the calmodulin 1 (CALM1) gene interaction network (P 4.16 04, 14.4-fold enrichment), which regulates voltage-independent calcium-activated action potentials at the neuronal synapse. We find that multiple defective gene family interactions underlie autism, presenting new translational opportunities to explore for therapeutic interventions.",

author = "Dexter Hadley and Wu, {Zhi Liang} and Charlly Kao and Akshata Kini and Alisha Mohamed-Hadley and Kelly Thomas and Lyam Vazquez and Haijun Qiu and Frank Mentch and Renata Pellegrino and Cecilia Kim and John Connolly and Joseph Glessner and Hakon Hakonarson and Dalila Pinto and Alison Merikangas and Lambertus Klei and Vorstman, {Jacob A.S.} and Ann Thompson and Regina Regan and Pagnamenta, {Alistair T.} and B{\'a}rbara Oliveira and Magalhaes, {Tiago R.} and John Gilbert and Eftichia Duketis and {De Jonge}, {Maretha V.} and Michael Cuccaro and Correia, {Catarina T.} and Judith Conroy and Concei{\c c}a, {In{\^e}s C.} and Chiocchetti, {Andreas G.} and Casey, {Jillian P.} and Nadia Bolshakova and Elena Bacchelli and Richard Anney and Lonnie Zwaigenbaum and Kerstin Wittemeyer and Simon Wallace and {Van Engeland}, Herman and Latha Soorya and Bernadette Rog{\'e} and Wendy Roberts and Fritz Poustka and Susana Mouga and Nancy Minshew and McGrew, {Susan G.} and Catherine Lord and Marion Leboyer and {Le Couteur}, {Ann S.} and Alexander Kolevzon and Suma Jacob 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 Sean Brennan and Thomas Bourgeron and Bolton, {Patrick F.} and Sven B{\"o}lte and Raphael Bernier and Gillian Baird and Bailey, {Anthony J.} and Evdokia Anagnostou and Wijsman, {Ellen M.} and Vieland, {Veronica J.} and Vicente, {Astrid M.} and Schellenberg, {Erard D.} and Margaret Pericak-Vance and Paterson, {Andrew D.} and Parr, {Jeremy R.} and Guiomar Oliveira and Joana Almeida and C{\'a}tia Caf{\'e} and Nurnberger, {John I.} and Monaco, {Anthony P.} and Elena Maestrini and Klauck, {Sabine M.} 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.}",

note = "Funding Information: We thank all study participants and their families. We thank all the staff at the Center for Applied Genomics at CHOP for their invaluable contributions to recruitment of study subjects and genotyping of samples. We also gratefully acknowledge the resources provided by the AGRE Consortium and their participating families, and by the Autism Genome Project (AGP) Consortium and their participating families. The study was funded by an Institutional Development Fund from The Children{\textquoteright}s Hospital of Philadelphia; The Margaret Q Landenberger Foundation; The Lurie Family Foundation; The Kubert Estate Fund and by U01HG005830. AGRE is a program of Autism Speaks and is at present supported, in part, by grant 1U24MH081810 from the National Institute of Mental Health to C.M. Lajonchere (PI) and formerly by grant MH64547 to D.H. Geschwind (PI). AGRE-approved academic researchers can acquire the data sets from AGRE at http://www.agre.org. There were 1,693 cases of the full AGP data sets that were genotyped by the AGP consortium. The full AGP data sets are made available from dbGaP at http://www.ncbi.nlm.nih.gov/gap. The remaining 5,049 cases and all 12,544 controls were all genotyped by the Center for Applied Genomics at the Children{\textquoteright}s Hospital of Philadelphia.",

year = "2014",

month = jun,

day = "13",

doi = "10.1038/ncomms5074",

language = "English",

volume = "5",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

}

Hadley, D, Wu, ZL, Kao, C, Kini, A, Mohamed-Hadley, A, Thomas, K, Vazquez, L, Qiu, H, Mentch, F, Pellegrino, R, Kim, C, Connolly, J, Glessner, J, Hakonarson, H, Pinto, D, Merikangas, A, Klei, L, Vorstman, JAS, Thompson, A, Regan, R, Pagnamenta, AT, Oliveira, B, Magalhaes, TR, Gilbert, J, Duketis, E, De Jonge, MV, Cuccaro, M, Correia, CT, Conroy, J, Conceiça, IC, Chiocchetti, AG, Casey, JP, Bolshakova, N, Bacchelli, E, Anney, R, Zwaigenbaum, L, Wittemeyer, K, Wallace, S, Van Engeland, H, Soorya, L, Rogé, B, Roberts, W, Poustka, F, Mouga, S, Minshew, N, McGrew, SG, Lord, C, Leboyer, M, Le Couteur, AS, Kolevzon, A, Jacob, S, Guter, S, Green, J, Green, A, Gillberg, C, Fernandez, BA, Duque, F, Delorme, R, Dawson, G, Brennan, S, Bourgeron, T, Bolton, PF, Bölte, S, Bernier, R, Baird, G, Bailey, AJ, Anagnostou, E, Wijsman, EM, Vieland, VJ, Vicente, AM, Schellenberg, ED, Pericak-Vance, M, Paterson, AD, Parr, JR, Oliveira, G, Almeida, J, Café, C, Nurnberger, JI, Monaco, AP, Maestrini, E, Klauck, SM, 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, 'The impact of the metabotropic glutamate receptor and other gene family interaction networks on autism', Nature Communications, vol. 5, 4074. https://doi.org/10.1038/ncomms5074

TY - JOUR

T1 - The impact of the metabotropic glutamate receptor and other gene family interaction networks on autism

AU - Hadley, Dexter

AU - Wu, Zhi Liang

AU - Kao, Charlly

AU - Kini, Akshata

AU - Mohamed-Hadley, Alisha

AU - Thomas, Kelly

AU - Vazquez, Lyam

AU - Qiu, Haijun

AU - Mentch, Frank

AU - Pellegrino, Renata

AU - Kim, Cecilia

AU - Connolly, John

AU - Glessner, Joseph

AU - Hakonarson, Hakon

AU - Pinto, Dalila

AU - Merikangas, Alison

AU - Klei, Lambertus

AU - Vorstman, Jacob A.S.

AU - Thompson, Ann

AU - Regan, Regina

AU - Pagnamenta, Alistair T.

AU - Oliveira, Bárbara

AU - Magalhaes, Tiago R.

AU - Gilbert, John

AU - Duketis, Eftichia

AU - De Jonge, Maretha V.

AU - Cuccaro, Michael

AU - Correia, Catarina T.

AU - Conroy, Judith

AU - Conceiça, Inês C.

AU - Chiocchetti, Andreas G.

AU - Casey, Jillian P.

AU - Bolshakova, Nadia

AU - Bacchelli, Elena

AU - Anney, Richard

AU - Zwaigenbaum, Lonnie

AU - Wittemeyer, Kerstin

AU - Wallace, Simon

AU - Van Engeland, Herman

AU - Soorya, Latha

AU - Rogé, Bernadette

AU - Roberts, Wendy

AU - Poustka, Fritz

AU - Mouga, Susana

AU - Minshew, Nancy

AU - McGrew, Susan G.

AU - Lord, Catherine

AU - Leboyer, Marion

AU - Le Couteur, Ann S.

AU - Kolevzon, Alexander

AU - Jacob, Suma

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 - 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 - Wijsman, Ellen M.

AU - Vieland, Veronica J.

AU - Vicente, Astrid M.

AU - Schellenberg, Erard D.

AU - Pericak-Vance, Margaret

AU - Paterson, Andrew D.

AU - Parr, Jeremy R.

AU - Oliveira, Guiomar

AU - Almeida, Joana

AU - Café, Cátia

AU - Nurnberger, John I.

AU - Monaco, Anthony P.

AU - Maestrini, Elena

AU - Klauck, Sabine M.

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.

N1 - Funding Information: We thank all study participants and their families. We thank all the staff at the Center for Applied Genomics at CHOP for their invaluable contributions to recruitment of study subjects and genotyping of samples. We also gratefully acknowledge the resources provided by the AGRE Consortium and their participating families, and by the Autism Genome Project (AGP) Consortium and their participating families. The study was funded by an Institutional Development Fund from The Children’s Hospital of Philadelphia; The Margaret Q Landenberger Foundation; The Lurie Family Foundation; The Kubert Estate Fund and by U01HG005830. AGRE is a program of Autism Speaks and is at present supported, in part, by grant 1U24MH081810 from the National Institute of Mental Health to C.M. Lajonchere (PI) and formerly by grant MH64547 to D.H. Geschwind (PI). AGRE-approved academic researchers can acquire the data sets from AGRE at http://www.agre.org. There were 1,693 cases of the full AGP data sets that were genotyped by the AGP consortium. The full AGP data sets are made available from dbGaP at http://www.ncbi.nlm.nih.gov/gap. The remaining 5,049 cases and all 12,544 controls were all genotyped by the Center for Applied Genomics at the Children’s Hospital of Philadelphia.

PY - 2014/6/13

Y1 - 2014/6/13

N2 - Although multiple reports show that defective genetic networks underlie the aetiology of autism, few have translated into pharmacotherapeutic opportunities. Since drugs compete with endogenous small molecules for protein binding, many successful drugs target large gene families with multiple drug binding sites. Here we search for defective gene family interaction networks (GFINs) in 6,742 patients with the ASDs relative to 12,544 neurologically normal controls, to find potentially druggable genetic targets. We find significant enrichment of structural defects (P 2.40E 09, 1.8-fold enrichment) in the metabotropic glutamate receptor (GRM) GFIN, previously observed to impact attention deficit hyperactivity disorder (ADHD) and schizophrenia. Also, the MXD-MYC-MAX network of genes, previously implicated in cancer, is significantly enriched (P 3.83E 23, 2.5-fold enrichment), as is the calmodulin 1 (CALM1) gene interaction network (P 4.16 04, 14.4-fold enrichment), which regulates voltage-independent calcium-activated action potentials at the neuronal synapse. We find that multiple defective gene family interactions underlie autism, presenting new translational opportunities to explore for therapeutic interventions.

AB - Although multiple reports show that defective genetic networks underlie the aetiology of autism, few have translated into pharmacotherapeutic opportunities. Since drugs compete with endogenous small molecules for protein binding, many successful drugs target large gene families with multiple drug binding sites. Here we search for defective gene family interaction networks (GFINs) in 6,742 patients with the ASDs relative to 12,544 neurologically normal controls, to find potentially druggable genetic targets. We find significant enrichment of structural defects (P 2.40E 09, 1.8-fold enrichment) in the metabotropic glutamate receptor (GRM) GFIN, previously observed to impact attention deficit hyperactivity disorder (ADHD) and schizophrenia. Also, the MXD-MYC-MAX network of genes, previously implicated in cancer, is significantly enriched (P 3.83E 23, 2.5-fold enrichment), as is the calmodulin 1 (CALM1) gene interaction network (P 4.16 04, 14.4-fold enrichment), which regulates voltage-independent calcium-activated action potentials at the neuronal synapse. We find that multiple defective gene family interactions underlie autism, presenting new translational opportunities to explore for therapeutic interventions.

UR - http://www.scopus.com/inward/record.url?scp=84902504072&partnerID=8YFLogxK

U2 - 10.1038/ncomms5074

DO - 10.1038/ncomms5074

M3 - Article

C2 - 24927284

AN - SCOPUS:84902504072

SN - 2041-1723

VL - 5

JO - Nature Communications

JF - Nature Communications

M1 - 4074

ER -

The impact of the metabotropic glutamate receptor and other gene family interaction networks on autism

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