Networks of Neuronal Genes Affected by Common and Rare Variants in Autism Spectrum Disorders
Autism spectrum disorders (ASD) are neurodevelopmental disorders with phenotypic and genetic heterogeneity. Recent studies have reported rare and de novo mutations in ASD, but the allelic architecture of ASD remains unclear. To assess the role of common and rare variations in ASD, we constructed a gene co-expression network based on a widespread survey of gene expression in the human brain. We identified modules associated with specific cell types and processes. By integrating known rare mutations and the results of an ASD genome-wide association study (GWAS), we identified two neuronal modules that are perturbed by both rare and common variations. These modules contain highly connected genes that are involved in synaptic and neuronal plasticity and that are expressed in areas associated with learning and memory and sensory perception. The enrichment of common risk variants was replicated in two additional samples which include both simplex and multiplex families. An analysis of the combined contribution of common variants in the neuronal modules revealed a polygenic component to the risk of ASD. The results of this study point toward contribution of minor and major perturbations in the two sub-networks of neuronal genes to ASD risk.
Vyšlo v časopise:
Networks of Neuronal Genes Affected by Common and Rare Variants in Autism Spectrum Disorders. PLoS Genet 8(3): e32767. doi:10.1371/journal.pgen.1002556
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1002556
Souhrn
Autism spectrum disorders (ASD) are neurodevelopmental disorders with phenotypic and genetic heterogeneity. Recent studies have reported rare and de novo mutations in ASD, but the allelic architecture of ASD remains unclear. To assess the role of common and rare variations in ASD, we constructed a gene co-expression network based on a widespread survey of gene expression in the human brain. We identified modules associated with specific cell types and processes. By integrating known rare mutations and the results of an ASD genome-wide association study (GWAS), we identified two neuronal modules that are perturbed by both rare and common variations. These modules contain highly connected genes that are involved in synaptic and neuronal plasticity and that are expressed in areas associated with learning and memory and sensory perception. The enrichment of common risk variants was replicated in two additional samples which include both simplex and multiplex families. An analysis of the combined contribution of common variants in the neuronal modules revealed a polygenic component to the risk of ASD. The results of this study point toward contribution of minor and major perturbations in the two sub-networks of neuronal genes to ASD risk.
Zdroje
1. HallmayerJClevelandSTorresAPhillipsJCohenB 2011 Genetic Heritability and Shared Environmental Factors Among Twin Pairs With Autism. Arch Gen Psychiatry 68 1095 1102 doi:10.1001/archgenpsychiatry.2011.76
2. BaileyALe CouteurAGottesmanIBoltonPSimonoffE 1995 Autism as a strongly genetic disorder: evidence from a British twin study. Psychol Med 25 63 77
3. RonaldAHoekstraRA 2011 Autism spectrum disorders and autistic traits: a decade of new twin studies. Am J Med Genet B Neuropsychiatr Genet 156B 255 274 doi:10.1002/ajmg.b.31159
4. AbrahamsBSGeschwindDH 2008 Advances in autism genetics: on the threshold of a new neurobiology. Nat Rev Genet 9 341 355 doi:10.1038/nrg2346
5. O'RoakBJStateMW 2008 Autism genetics: strategies, challenges, and opportunities. Autism Res 1 4 17 doi:10.1002/aur.3
6. WangKZhangHMaDBucanMGlessnerJT 2009 Common genetic variants on 5p14.1 associate with autism spectrum disorders. Nature 459 528 533 doi:10.1038/nature07999
7. WeissLAArkingDE 2009 A genome-wide linkage and association scan reveals novel loci for autism. Nature 461 802 808 doi:10.1038/nature08490
8. SebatJLakshmiBMalhotraDTrogeJLese-MartinC 2007 Strong Association of De Novo Copy Number Mutations with Autism. Science 316 445 449 doi:10.1126/science.1138659
9. PintoDPagnamentaATKleiLAnneyRMericoD 2010 Functional impact of global rare copy number variation in autism spectrum disorders. Nature 466 368 372 doi:10.1038/nature09146
10. SandersSJErcan-SencicekAGHusVLuoRMurthaMT 2011 Multiple Recurrent De Novo CNVs, Including Duplications of the 7q11.23 Williams Syndrome Region, Are Strongly Associated with Autism. Neuron 70 863 885 doi:10.1016/j.neuron.2011.05.002
11. BerkelSMarshallCRWeissBHoweJRoethR 2010 Mutations in the SHANK2 synaptic scaffolding gene in autism spectrum disorder and mental retardation. Nat Genet 42 489 491 doi:10.1038/ng.589
12. LevyDRonemusMYamromBLeeY-haLeottaA 2011 Rare De Novo and Transmitted Copy-Number Variation in Autistic Spectrum Disorders. Neuron 70 886 897 doi:10.1016/j.neuron.2011.05.015
13. SchaafCPZoghbiHY 2011 Solving the autism puzzle a few pieces at a time. Neuron 70 806 808 doi:10.1016/j.neuron.2011.05.025
14. WalshCAEngleEC 2010 Allelic diversity in human developmental neurogenetics: insights into biology and disease. Neuron 68 245 253 doi:10.1016/j.neuron.2010.09.042
15. GilmanSRIossifovILevyDRonemusMWiglerM 2011 Rare De Novo Variants Associated with Autism Implicate a Large Functional Network of Genes Involved in Formation and Function of Synapses. Neuron 70 898 907 doi:10.1016/j.neuron.2011.05.021
16. GaiXXieHMPerinJCTakahashiNMurphyK 2011 Rare structural variation of synapse and neurotransmission genes in autism. Molecular Psychiatry Available:http://www.nature.com/mp/journal/vaop/ncurrent/full/mp201110a.html. Accessed 11 December 2011
17. SakaiYShawCADawsonBCDugasDVAl-MohtasebZ 2011 Protein interactome reveals converging molecular pathways among autism disorders. Sci Transl Med 3 86ra49 doi:10.1126/scitranslmed.3002166
18. ZhangBHorvathS 2005 A general framework for weighted gene co-expression network analysis. Stat Appl Genet Mol Biol 4 Article17 doi:10.2202/1544-6115.1128
19. OldhamMCKonopkaGIwamotoKLangfelderPKatoT 2008 Functional organization of the transcriptome in human brain. Nat Neurosci 11 1271 1282 doi:10.1038/nn.2207
20. VoineaguIWangXJohnstonPLoweJKTianY 2011 Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature 474 380 384 doi:10.1038/nature10110
21. CahoyJDEmeryBKaushalAFooLCZamanianJL 2008 A Transcriptome Database for Astrocytes, Neurons, and Oligodendrocytes: A New Resource for Understanding Brain Development and Function. The Journal of Neuroscience 28 264 278 doi:10.1523/JNEUROSCI.4178-07.2008
22. MargolinJFFriedmanJRMeyerWKVissingHThiesenHJ 1994 Krüppel-associated boxes are potent transcriptional repression domains. Proceedings of the National Academy of Sciences 91 4509 4513
23. ShannonPMarkielAOzierOBaligaNSWangJT 2003 Cytoscape: A Software Environment for Integrated Models of Biomolecular Interaction Networks. Genome Research 13 2498 2504 doi:10.1101/gr.1239303
24. PringleNPYuW-PHowellMColvinJSOrnitzDM 2003 Fgfr3 expression by astrocytes and their precursors: evidence that astrocytes and oligodendrocytes originate in distinct neuroepithelial domains. Development 130 93 102 doi:10.1242/dev.00184
25. SchwabJMFreiEKlusmanISchnellLSchwabME 2001 AIF-1 expression defines a proliferating and alert microglial/macrophage phenotype following spinal cord injury in rats. Journal of Neuroimmunology 119 214 222 doi:16/S0165-5728(01)00375-7
26. TomaselloEVivierE 2005 KARAP/DAP12/TYROBP: three names and a multiplicity of biological functions. European Journal of Immunology 35 1670 1677 doi:10.1002/eji.200425932
27. LeeJ-KMcCoyMKHarmsASRuhnKAGoldSJ 2008 Regulator of G-Protein Signaling 10 Promotes Dopaminergic Neuron Survival via Regulation of the Microglial Inflammatory Response. The Journal of Neuroscience 28 8517 8528 doi:10.1523/JNEUROSCI.1806-08.2008
28. StreitWJ 2001 Microglia and macrophages in the developing CNS. Neurotoxicology 22 619 624
29. Del Rio-HortegaP 1932 Microglia. PenfieldW Cytology and cellular pathology of the nervous system P.B. Hoeber 481 534
30. OkatyBWMillerMNSuginoKHempelCMNelsonSB 2009 Transcriptional and Electrophysiological Maturation of Neocortical Fast-Spiking GABAergic Interneurons. The Journal of Neuroscience 29 7040 7052 doi:10.1523/JNEUROSCI.0105-09.2009
31. RudyBMcBainCJ 2001 Kv3 channels: voltage-gated K+ channels designed for high-frequency repetitive firing. Trends Neurosci 24 517 526
32. HowardMAVolkovIOMirskyRGarellPCNohMD 2000 Auditory cortex on the human posterior superior temporal gyrus. The Journal of Comparative Neurology 416 79 92 doi:10.1002/(SICI)1096-9861(20000103)416:1<79::AID-CNE6>3.0.CO;2-2
33. DumRPStrickPL 2003 An Unfolded Map of the Cerebellar Dentate Nucleus and its Projections to the Cerebral Cortex. Journal of Neurophysiology 89 634 639 doi:10.1152/jn.00626.2002
34. RezakMBeneventoLA 1979 A comparison of the organization of the projections of the dorsal lateral geniculate nucleus, the inferior pulvinar and adjacent lateral pulvinar to primary visual cortex (area 17) in the macaque monkey. Brain Research 167 19 40 doi:10.1016/0006-8993(79)90260-9
35. BaizerJUngerleiderLDesimoneR 1991 Organization of visual inputs to the inferior temporal and posterior parietal cortex in macaques. The Journal of Neuroscience 11 168 190
36. ZekiSWatsonJLueckCFristonKKennardC 1991 A direct demonstration of functional specialization in human visual cortex. The Journal of Neuroscience 11 641 649
37. PenfieldBoldreyE 1937 Somatic Motor and Sensory Representation in the Cerebral Cortex of Man As Studied By Electrical Stimulation. Brain 60 389 443 doi:10.1093/brain/60.4.389
38. ZhangBKohYHBecksteadRBBudnikVGanetzkyB 1998 Synaptic Vesicle Size and Number Are Regulated by a Clathrin Adaptor Protein Required for Endocytosis. Neuron 21 1465 1475 doi:10.1016/S0896-6273(00)80664-9
39. BrackmannMSchuchmannSAnandRBraunewellK-H 2005 Neuronal Ca2+ sensor protein VILIP-1 affects cGMP signalling of guanylyl cyclase B by regulating clathrin-dependent receptor recycling in hippocampal neurons. Journal of Cell Science 118 2495 2505 doi:10.1242/jcs.02376
40. FassioAPatryLCongiaSOnofriFPitonA 2011 SYN1 loss-of-function mutations in autism and partial epilepsy cause impaired synaptic function. Human Molecular Genetics 20 2297 2307 doi:10.1093/hmg/ddr122
41. SalaünCJamesDJGreavesJChamberlainLH 2004 Plasma membrane targeting of exocytic SNARE proteins. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1693 81 89 doi:10.1016/j.bbamcr.2004.05.008
42. RegadTRothMBredenkampNIllingNPapalopuluN 2007 The neural progenitor-specifying activity of FoxG1 is antagonistically regulated by CKI and FGF. Nat Cell Biol 9 531 540 doi:10.1038/ncb1573
43. SubramanianLSarkarAShettyASMuralidharanBPadmanabhanH 2011 Transcription factor Lhx2 is necessary and sufficient to suppress astrogliogenesis and promote neurogenesis in the developing hippocampus. Proceedings of the National Academy of Sciences 108 E265 E274 doi:10.1073/pnas.1101109108
44. HernandezM-CAndres-BarquinPJMartinezSBulfoneARubensteinJLR 1997 ENC-1: A Novel MammalianKelch-Related Gene Specifically Expressed in the Nervous System Encodes an Actin-Binding Protein. The Journal of Neuroscience 17 3038 3051
45. MokalledMHJohnsonAKimYOhJOlsonEN 2010 Myocardin-related transcription factors regulate the Cdk5/Pctaire1 kinase cascade to control neurite outgrowth, neuronal migration and brain development. Development 137 2365 2374 doi:10.1242/dev.047605
46. WilliamsMEWilkeSADaggettADavisEOttoS 2011 Cadherin-9 Regulates Synapse-Specific Differentiation in the Developing Hippocampus. Neuron 71 640 655 doi:10.1016/j.neuron.2011.06.019
47. KimS-YChungHSSunWKimH 2007 Spatiotemporal expression pattern of non-clustered protocadherin family members in the developing rat brain. Neuroscience 147 996 1021 doi:10.1016/j.neuroscience.2007.03.052
48. ShenLNamHSongPMooreHAndersonSA 2006 FoxG1 haploinsufficiency results in impaired neurogenesis in the postnatal hippocampus and contextual memory deficits. Hippocampus 16 875 890 doi:10.1002/hipo.20218
49. O'SullivanNCPickeringMDi GiacomoDLoscherJSMurphyKJ 2010 Mkl Transcription Cofactors Regulate Structural Plasticity in Hippocampal Neurons. Cerebral Cortex 20 1915 1925 doi:10.1093/cercor/bhp262
50. KimSYMoJWHanSChoiSYHanSB 2010 The expression of non-clustered protocadherins in adult rat hippocampal formation and the connecting brain regions. Neuroscience 170 189 199 doi:10.1016/j.neuroscience.2010.05.027
51. RaychaudhuriSKornJMMcCarrollSAAltshulerDSklarP 2010 Accurately Assessing the Risk of Schizophrenia Conferred by Rare Copy-Number Variation Affecting Genes with Brain Function. PLoS Genet 6 e1001097 doi:10.1371/journal.pgen.1001097
52. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls 2007 Nature 447 661 678 doi:10.1038/nature05911
53. AnneyRKleiLPintoDReganRConroyJ 2010 A genome-wide scan for common alleles affecting risk for autism. Human Molecular Genetics 19 4072 4082 doi:10.1093/hmg/ddq307
54. WuJYKubanKCKAllredEShapiroFDarrasBT 2005 Association of Duchenne muscular dystrophy with autism spectrum disorder. J Child Neurol 20 790 795
55. HoltRBarnbyGMaestriniEBacchelliEBrocklebankD 2010 Linkage and candidate gene studies of autism spectrum disorders in European populations. Eur J Hum Genet 18 1013 1019 doi:10.1038/ejhg.2010.69
56. CarayolJSaccoRToresFRousseauFLewinP 2011 Converging Evidence for an Association of ATP2B2 Allelic Variants with Autism in Male Subjects. Biological Psychiatry 70 880 887 doi:10.1016/j.biopsych.2011.05.020
57. The International Schizophrenia Consortium 2009 Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460 748 752 doi:10.1038/nature08185
58. SohalVSZhangFYizharODeisserothK 2009 Parvalbumin neurons and gamma rhythms enhance cortical circuit performance. Nature 459 698 702 doi:10.1038/nature07991
59. MorillonBLehongreKFrackowiakRSJDucorpsAKleinschmidtA 2010 Neurophysiological origin of human brain asymmetry for speech and language. Proceedings of the National Academy of Sciences 107 18688 18693 doi:10.1073/pnas.1007189107
60. GiraudA-LKleinschmidtAPoeppelDLundTEFrackowiakRSJ 2007 Endogenous Cortical Rhythms Determine Cerebral Specialization for Speech Perception and Production. Neuron 56 1127 1134 doi:10.1016/j.neuron.2007.09.038
61. LeceaLdedel RíoJSorianoE 1995 Developmental expression of parvalbumin mRNA in the cerebral cortex and hippocampus of the rat. Molecular Brain Research 32 1 13 doi:10.1016/0169-328X(95)00056-X
62. FungSJWebsterMJSivagnanasundaramSDuncanCElashoffM 2010 Expression of Interneuron Markers in the Dorsolateral Prefrontal Cortex of the Developing Human and in Schizophrenia. Am J Psychiatry 167 1479 1488 doi:10.1176/appi.ajp.2010.09060784
63. MorrowEMYooS-YFlavellSWKimT-KLinY 2008 Identifying Autism Loci and Genes by Tracing Recent Shared Ancestry. Science 321 218 223 doi:10.1126/science.1157657
64. WestAEGreenbergME 2011 Neuronal Activity–Regulated Gene Transcription in Synapse Development and Cognitive Function. Cold Spring Harbor Perspectives in Biology 3 Available:http://cshperspectives.cshlp.org/content/3/6/a005744.abstract. Accessed 27 September 2011
65. EhningerDSilvaAJ 2009 Genetics and neuropsychiatric disorders: Treatment during adulthood. Nat Med 15 849 850 doi:10.1038/nm0809-849
66. EhningerDLiWFoxKStrykerMPSilvaAJ 2008 Reversing Neurodevelopmental Disorders in Adults. Neuron 60 950 960 doi:10.1016/j.neuron.2008.12.007
67. LangfelderPHorvathS 2008 WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics 9 559 doi:10.1186/1471-2105-9-559
68. MillerJAHorvathSGeschwindDH 2010 Divergence of human and mouse brain transcriptome highlights Alzheimer disease pathways. Proceedings of the National Academy of Sciences 107 12698 12703 doi:10.1073/pnas.0914257107
69. GhazalpourADossSZhangBWangSPlaisierC 2006 Integrating Genetic and Network Analysis to Characterize Genes Related to Mouse Weight. PLoS Genet 2 e130 doi:10.1371/journal.pgen.0020130
70. HuangDWShermanBTLempickiRA 2008 Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protocols 4 44 57 doi:10.1038/nprot.2008.211
71. WangKLiMBucanM 2007 Pathway-Based Approaches for Analysis of Genomewide Association Studies. Am J Hum Genet 81 1278 1283
72. PurcellSNealeBTodd-BrownKThomasLFerreiraMAR 2007 PLINK: A Tool Set for Whole-Genome Association and Population-Based Linkage Analyses. The American Journal of Human Genetics 81 559 575 doi:10.1086/519795
73. AndersonCAPetterssonFHClarkeGMCardonLRMorrisAP 2010 Data quality control in genetic case-control association studies. Nat Protocols 5 1564 1573 doi:10.1038/nprot.2010.116
74. FraleyC 1999 MCLUST: Software for Model-Based Cluster Analysis. Journal of Classification 16 297 306 doi:10.1007/s003579900058
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Genetika Reprodukčná medicínaČlánok vyšiel v časopise
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