The impact of the metabotropic glutamate receptor and other gene family interaction networks on autism.
Dexter Hadley
(1)
,
Zhi Liang Wu
(1)
,
Charlly Kao
(1)
,
Akshata Kini
(1)
,
Alisha Mohamed-Hadley
(1)
,
Kelly Thomas
(1)
,
Lyam Vazquez
(1)
,
Haijun Qiu
(1)
,
Frank Mentch
(1)
,
Renata Pellegrino
(1)
,
Cecilia Kim
(1)
,
John Connolly
(1)
,
Dalila Pinto
(2, 3, 4, 5, 6, 7)
,
Alison Merikangas
(8)
,
Lambertus Klei
(9)
,
Jacob Vorstman
(10)
,
Ann Thompson
(11)
,
Regina Regan
(12, 13)
,
Alistair T. Pagnamenta
(14)
,
Barbara Oliveira
(15, 16)
,
Tiago R. Magalhaes
(12, 13)
,
John Gilbert
(17)
,
Eftichia Duketis
(18)
,
Maretha V. de Jonge
(10)
,
Michael Cuccaro
(17)
,
Catarina Correia
(15, 16)
,
Judith Conroy
(12, 19)
,
Inês C. Conceição
(15, 16)
,
Andreas G. Chiocchetti
(18)
,
Jillian Casey
(12, 13)
,
Nadia Bolshakova
(8)
,
Elena Bacchelli
(20)
,
Richard Anney
(8)
,
Lonnie Zwaigenbaum
(21)
,
Kerstin Wittemeyer
(22)
,
Simon Wallace
(23)
,
Herman van Engeland
(10)
,
Latha Soorya
(2, 3)
,
Bernadette Rogé
(24)
,
Wendy Roberts
(25)
,
Fritz Poustka
(18)
,
Susana Mouga
(26, 27)
,
Nancy Minshew
(9)
,
Susan G. Mcgrew
(28)
,
Catherine Lord
(29)
,
Marion Leboyer
(30, 31, 32)
,
Ann S. Le Couteur
(33)
,
Alexander Kolevzon
(2, 3, 7)
,
Suma Jacob
(34)
,
Stephen Guter
(34)
,
Jonathan Green
(35, 36)
,
Andrew Green
(12, 37)
,
Christopher Gillberg
(38)
,
Bridget A. Fernandez
(39)
,
Frederico Duque
(26, 27)
,
Richard Delorme
(32, 40, 41)
,
Geraldine Dawson
(42)
,
Cátia Café
(26)
,
Sean Brennan
(8)
,
Thomas Bourgeron
(32, 40, 43)
,
Patrick F. Bolton
(44, 45)
,
Sven Bölte
(18)
,
Raphael Bernier
(46)
,
Gillian Baird
(47)
,
Anthony J. Bailey
(48, 49)
,
Evdokia Anagnostou
(50)
,
Joana Almeida
(26)
,
Ellen M. Wijsman
(51, 52)
,
Veronica J. Vieland
(53)
,
Astrid M. Vicente
(15, 54)
,
Gerard D. Schellenberg
(55)
,
Margaret Pericak-Vance
(17)
,
Andrew D. Paterson
(56)
,
Jeremy R. Parr
(57)
,
Guiomar Oliveira
(26, 27)
,
John I. Nurnberger
(58)
,
Anthony P. Monaco
(14)
,
Elena Maestrini
(20)
,
Sabine M. Klauck
(59)
,
Jonathan L. Haines
(60, 61)
,
Daniel H. Geschwind
(62)
,
Christine M. Freitag
(18)
,
Susan E. Folstein
(63)
,
Sean Ennis
(12)
,
Hilary Coon
(64)
,
Agatino Battaglia
(65)
,
Peter Szatmari
(11)
,
James S. Sutcliffe
(60, 61)
,
Joachim Hallmayer
(66)
,
Michael Gill
(67)
,
Edwin H. Cook
(68)
,
Joseph D. Buxbaum
(69, 70, 71, 72, 73, 74)
,
Bernie Devlin
(9)
,
Louise Gallagher
(67)
,
Catalina Betancur
(75)
,
Stephen W. Scherer
(56, 76)
,
Joseph Glessner
(1)
,
Hakon Hakonarson
(1, 77)
1
The Center for Applied Genomics
2 Seaver Autism Center for Research and Treatment
3 Department of Psychiatry
4 Department of Genetics and Genomic Sciences
5 The Mindich Child Health and Development Institute
6 The Icahn Institute for Genomics and Multiscale Biology
7 Friedman Brain Institute
8 Discipline of Psychiatry [Dublin]
9 Department of Psychiatry [Pittsburgh]
10 Department of Psychiatry
11 Department of Psychiatry and Behavioural Neurosciences
12 ACoRD - Academic Centre on Rare Diseases
13 National Children's Research Centre
14 The Wellcome Trust Centre for Human Genetics [Oxford]
15 INSA - Instituto Nacional de Saùde Dr Ricardo Jorge [Portugal]
16 Center for Biodiversity, Functional & Integrative Genomics
17 John P. Hussman Institute for Human Genomics
18 Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy
19 Children's University Hospital
20 Department of Pharmacy and Biotechnology
21 Department of Pediatrics
22 School of Education
23 Department of Psychiatry
24 Octogone - Octogone Unité de Recherche Interdisciplinaire
25 Autism Research Unit
26 UNDA - Unidade de Neurodesenvolvimento e Autismo
27 Institute for Biomedical Imaging and Life Science
28 Department of Pediatrics
29 CADB - Center for Autism and the Developing Brain
30 IMRB - Institut Mondor de Recherche Biomédicale
31 Service de psychiatrie
32 Foundation Fondamental
33 Institute of Health and Society
34 Institute for Juvenile Research and Department of Psychiatry
35 Manchester Academic Health Sciences Centre
36 Institute of Brain, Behaviour and Mental Health
37 National Centre for Medical Genetics
38 Gillberg Neuropsychiatry Centre [Göteborg, Sueden]
39 Disciplines of Genetics and Medicine
40 Génétique Humaine et Fonctions Cognitives
41 Service de psychopathologie de l'enfant et de l'adolescent
42 Department of Psychiatry and Behavioral Sciences
43 UPD7 - Université Paris Diderot - Paris 7
44 Institute of Psychiatry
45 Department of Child and Adolescent Psychiatry
46 Department of Psychiatry and Behavioral Sciences
47 Paediatric Neurodisability
48 SGDP - MRC Social, Genetic and Developmental Psychiatry Centre
49 Department of Psychiatry
50 Bloorview Research Institute
51 Division of Medical Genetics [Seattle]
52 Departments of Biostatistics and Medicine
53 Battelle Center for Mathematical Medicine
54 BioFIG
55 Pathology and Laboratory Medicine
56 Program in Genetics and Genomic Biology
57 ION - Institute of Neuroscience [Newcastle]
58 Department of Psychiatry
59 Division of Molecular Genome Analysis
60 Vanderbilt Brain Institute
61 Department of Molecular Physiology & Biophysics and Psychiatry
62 Department of Neurology
63 Utah Autism Research Program
64 Department of Developmental Neuroscience
65 Department of Psychiatry and Behavioral Sciences [Stanford]
66 Department of Neuroscience
67 Department of Psychiatry
68 Institute for Juvenile Research
69 Departments of Psychiatry, Genetics and Genomic Sciences
70 Department of Psychiatry
71 Seaver Autism Center for Research and Treatment
72 Friedman Brain Institute
73 The Mindich Child Health and Development Institute
74 Department of Neuroscience
75 NPS - Neuroscience Paris Seine
76 McLaughlin Centre
77 Department of Pediatrics
2 Seaver Autism Center for Research and Treatment
3 Department of Psychiatry
4 Department of Genetics and Genomic Sciences
5 The Mindich Child Health and Development Institute
6 The Icahn Institute for Genomics and Multiscale Biology
7 Friedman Brain Institute
8 Discipline of Psychiatry [Dublin]
9 Department of Psychiatry [Pittsburgh]
10 Department of Psychiatry
11 Department of Psychiatry and Behavioural Neurosciences
12 ACoRD - Academic Centre on Rare Diseases
13 National Children's Research Centre
14 The Wellcome Trust Centre for Human Genetics [Oxford]
15 INSA - Instituto Nacional de Saùde Dr Ricardo Jorge [Portugal]
16 Center for Biodiversity, Functional & Integrative Genomics
17 John P. Hussman Institute for Human Genomics
18 Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy
19 Children's University Hospital
20 Department of Pharmacy and Biotechnology
21 Department of Pediatrics
22 School of Education
23 Department of Psychiatry
24 Octogone - Octogone Unité de Recherche Interdisciplinaire
25 Autism Research Unit
26 UNDA - Unidade de Neurodesenvolvimento e Autismo
27 Institute for Biomedical Imaging and Life Science
28 Department of Pediatrics
29 CADB - Center for Autism and the Developing Brain
30 IMRB - Institut Mondor de Recherche Biomédicale
31 Service de psychiatrie
32 Foundation Fondamental
33 Institute of Health and Society
34 Institute for Juvenile Research and Department of Psychiatry
35 Manchester Academic Health Sciences Centre
36 Institute of Brain, Behaviour and Mental Health
37 National Centre for Medical Genetics
38 Gillberg Neuropsychiatry Centre [Göteborg, Sueden]
39 Disciplines of Genetics and Medicine
40 Génétique Humaine et Fonctions Cognitives
41 Service de psychopathologie de l'enfant et de l'adolescent
42 Department of Psychiatry and Behavioral Sciences
43 UPD7 - Université Paris Diderot - Paris 7
44 Institute of Psychiatry
45 Department of Child and Adolescent Psychiatry
46 Department of Psychiatry and Behavioral Sciences
47 Paediatric Neurodisability
48 SGDP - MRC Social, Genetic and Developmental Psychiatry Centre
49 Department of Psychiatry
50 Bloorview Research Institute
51 Division of Medical Genetics [Seattle]
52 Departments of Biostatistics and Medicine
53 Battelle Center for Mathematical Medicine
54 BioFIG
55 Pathology and Laboratory Medicine
56 Program in Genetics and Genomic Biology
57 ION - Institute of Neuroscience [Newcastle]
58 Department of Psychiatry
59 Division of Molecular Genome Analysis
60 Vanderbilt Brain Institute
61 Department of Molecular Physiology & Biophysics and Psychiatry
62 Department of Neurology
63 Utah Autism Research Program
64 Department of Developmental Neuroscience
65 Department of Psychiatry and Behavioral Sciences [Stanford]
66 Department of Neuroscience
67 Department of Psychiatry
68 Institute for Juvenile Research
69 Departments of Psychiatry, Genetics and Genomic Sciences
70 Department of Psychiatry
71 Seaver Autism Center for Research and Treatment
72 Friedman Brain Institute
73 The Mindich Child Health and Development Institute
74 Department of Neuroscience
75 NPS - Neuroscience Paris Seine
76 McLaughlin Centre
77 Department of Pediatrics
Jillian Casey
- Fonction : Auteur
Marion Leboyer
- Fonction : Auteur
- PersonId : 756830
- ORCID : 0000-0001-5473-3697
- IdRef : 089352475
Jonathan Green
- Fonction : Auteur
- PersonId : 763155
- ORCID : 0000-0002-5003-0203
Andrew Green
- Fonction : Auteur
Thomas Bourgeron
- Fonction : Auteur
- PersonId : 747963
- IdHAL : thomas-bourgeron
- ORCID : 0000-0001-8164-9220
- IdRef : 119761955
Catalina Betancur
- Fonction : Auteur
- PersonId : 13320
- IdHAL : catalina-betancur
- ORCID : 0000-0002-3327-4804
- IdRef : 180835750
Hakon Hakonarson
Connectez-vous pour contacter l'auteur
- Fonction : Auteur correspondant
- PersonId : 957590
Connectez-vous pour contacter l'auteur
Résumé
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≤4.16E-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.
Domaines
Génétique
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Hadley_Nat_Comms_2014-Supp_tables.pdf (159.4 Ko)
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Hadley_Nat_Comms_2014.pdf (761.91 Ko)
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