Relative Burden of Large CNVs on a Range of Neurodevelopmental Phenotypes
While numerous studies have implicated copy number variants (CNVs) in a range of neurological phenotypes, the impact relative to disease severity has been difficult to ascertain due to small sample sizes, lack of phenotypic details, and heterogeneity in platforms used for discovery. Using a customized microarray enriched for genomic hotspots, we assayed for large CNVs among 1,227 individuals with various neurological deficits including dyslexia (376), sporadic autism (350), and intellectual disability (ID) (501), as well as 337 controls. We show that the frequency of large CNVs (>1 Mbp) is significantly greater for ID–associated phenotypes compared to autism (p = 9.58×10−11, odds ratio = 4.59), dyslexia (p = 3.81×10−18, odds ratio = 14.45), or controls (p = 2.75×10−17, odds ratio = 13.71). There is a striking difference in the frequency of rare CNVs (>50 kbp) in autism (10%, p = 2.4×10−6, odds ratio = 6) or ID (16%, p = 3.55×10−12, odds ratio = 10) compared to dyslexia (2%) with essentially no difference in large CNV burden among dyslexia patients compared to controls. Rare CNVs were more likely to arise de novo (64%) in ID when compared to autism (40%) or dyslexia (0%). We observed a significantly increased large CNV burden in individuals with ID and multiple congenital anomalies (MCA) compared to ID alone (p = 0.001, odds ratio = 2.54). Our data suggest that large CNV burden positively correlates with the severity of childhood disability: ID with MCA being most severely affected and dyslexics being indistinguishable from controls. When autism without ID was considered separately, the increase in CNV burden was modest compared to controls (p = 0.07, odds ratio = 2.33).
Vyšlo v časopise:
Relative Burden of Large CNVs on a Range of Neurodevelopmental Phenotypes. PLoS Genet 7(11): e32767. doi:10.1371/journal.pgen.1002334
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1002334
Souhrn
While numerous studies have implicated copy number variants (CNVs) in a range of neurological phenotypes, the impact relative to disease severity has been difficult to ascertain due to small sample sizes, lack of phenotypic details, and heterogeneity in platforms used for discovery. Using a customized microarray enriched for genomic hotspots, we assayed for large CNVs among 1,227 individuals with various neurological deficits including dyslexia (376), sporadic autism (350), and intellectual disability (ID) (501), as well as 337 controls. We show that the frequency of large CNVs (>1 Mbp) is significantly greater for ID–associated phenotypes compared to autism (p = 9.58×10−11, odds ratio = 4.59), dyslexia (p = 3.81×10−18, odds ratio = 14.45), or controls (p = 2.75×10−17, odds ratio = 13.71). There is a striking difference in the frequency of rare CNVs (>50 kbp) in autism (10%, p = 2.4×10−6, odds ratio = 6) or ID (16%, p = 3.55×10−12, odds ratio = 10) compared to dyslexia (2%) with essentially no difference in large CNV burden among dyslexia patients compared to controls. Rare CNVs were more likely to arise de novo (64%) in ID when compared to autism (40%) or dyslexia (0%). We observed a significantly increased large CNV burden in individuals with ID and multiple congenital anomalies (MCA) compared to ID alone (p = 0.001, odds ratio = 2.54). Our data suggest that large CNV burden positively correlates with the severity of childhood disability: ID with MCA being most severely affected and dyslexics being indistinguishable from controls. When autism without ID was considered separately, the increase in CNV burden was modest compared to controls (p = 0.07, odds ratio = 2.33).
Zdroje
1. SharpAJHansenSSelzerRRChengZReganR 2006 Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome. Nat Genet 38 1038 1042
2. de VriesBBPfundtRLeisinkMKoolenDAVissersLE 2005 Diagnostic genome profiling in mental retardation. Am J Hum Genet 77 606 616
3. MarshallCRNoorAVincentJBLionelACFeukL 2008 Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet 82 477 488
4. SebatJLakshmiBMalhotraDTrogeJLese-MartinC 2007 Strong association of de novo copy number mutations with autism. Science 316 445 449
5. International Schizophrenia Consortium 2008 Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 455 237 241
6. WalshTMcClellanJMMcCarthySEAddingtonAMPierceSB 2008 Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science 320 539 543
7. CraddockNHurlesMECardinNPearsonRDPlagnolV 2010 Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls. Nature 464 713 720
8. GrozevaDKirovGIvanovDJonesIRJonesL 2010 Rare copy number variants: a point of rarity in genetic risk for bipolar disorder and schizophrenia. Arch Gen Psychiatry 67 318 327
9. HelbigIMeffordHCSharpAJGuipponiMFicheraM 2009 15q13.3 microdeletions increase risk of idiopathic generalized epilepsy. Nat Genet 41 160 162
10. MeffordHCMuhleHOstertagPvon SpiczakSBuysseK 2010 Genome-wide copy number variation in epilepsy: novel susceptibility loci in idiopathic generalized and focal epilepsies. PLoS Genet 6 e1000962 doi:10.1371/journal.pgen.1000962
11. WilliamsNMZaharievaIMartinALangleyKMantripragadaK 2010 Rare chromosomal deletions and duplications in attention-deficit hyperactivity disorder: a genome-wide analysis. Lancet 376 1401 1408
12. EliaJGaiXXieHMPerinJCGeigerE 2010 Rare structural variants found in attention-deficit hyperactivity disorder are preferentially associated with neurodevelopmental genes. Mol Psychiatry 15 637 646
13. WechslerD 1991 Wechsler intelligence scale for children - third edition (WISC-III) San Antonio The Psychological Corporation
14. BaileyJAGuZClarkRAReinertKSamonteRV 2002 Recent segmental duplications in the human genome. Science 297 1003 1007
15. ZhangJFeukLDugganGEKhajaRSchererSW 2006 Development of bioinformatics resources for display and analysis of copy number and other structural variants in the human genome. Cytogenet Genome Res 115 205 214
16. PenningtonBF 1990 The genetics of dyslexia. J Child Psychol Psychiatry 31 193 201
17. MeffordHCCooperGMZerrTSmithJDBakerC 2009 A method for rapid, targeted CNV genotyping identifies rare variants associated with neurocognitive disease. Genome Res
18. KirovGGrozevaDNortonNIvanovDMantripragadaKK 2009 Support for the involvement of large copy number variants in the pathogenesis of schizophrenia. Hum Mol Genet 18 1497 1503
19. StefanssonHRujescuDCichonSPietilainenOPIngasonA 2008 Large recurrent microdeletions associated with schizophrenia. Nature 455 232 236
20. de KovelCGTrucksHHelbigIMeffordHCBakerC 2010 Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies. Brain 133 23 32
21. ParacchiniSScerriTMonacoAP 2007 The genetic lexicon of dyslexia. Annu Rev Genomics Hum Genet 8 57 79
22. KumarRAKaraMohamedSSudiJConradDFBruneC 2008 Recurrent 16p11.2 microdeletions in autism. Hum Mol Genet 17 628 638
23. WeissLAShenYKornJMArkingDEMillerDT 2008 Association between microdeletion and microduplication at 16p11.2 and autism. N Engl J Med 358 667 675
24. PhelanMCRogersRCSaulRAStapletonGASweetK 2001 22q13 deletion syndrome. Am J Med Genet 101 91 99
25. GajeckaMMackayKLShafferLG 2007 Monosomy 1p36 deletion syndrome. Am J Med Genet C Semin Med Genet 145C 346 356
26. Abd El-AzizMMBarraganIO'DriscollCAGoodstadtLPrigmoreE 2008 EYS, encoding an ortholog of Drosophila spacemaker, is mutated in autosomal recessive retinitis pigmentosa. Nat Genet 40 1285 1287
27. CollinRWLittinkKWKleveringBJvan den BornLIKoenekoopRK 2008 Identification of a 2 Mb human ortholog of Drosophila eyes shut/spacemaker that is mutated in patients with retinitis pigmentosa. Am J Hum Genet 83 594 603
28. MaestriniEPagnamentaATLambJABacchelliESykesNH 2010 High-density SNP association study and copy number variation analysis of the AUTS1 and AUTS5 loci implicate the IMMP2L-DOCK4 gene region in autism susceptibility. Mol Psychiatry 15 954 968
29. PetekEWindpassingerCVincentJBCheungJBorightAP 2001 Disruption of a novel gene (IMMP2L) by a breakpoint in 7q31 associated with Tourette syndrome. Am J Hum Genet 68 848 858
30. PagnamentaATBacchelliEde JongeMVMirzaGScerriTS 2010 Characterization of a family with rare deletions in CNTNAP5 and DOCK4 suggests novel risk loci for autism and dyslexia. Biol Psychiatry 68 320 328
31. Hannula-JouppiKKaminen-AholaNTaipaleMEklundRNopola-HemmiJ 2005 The axon guidance receptor gene ROBO1 is a candidate gene for developmental dyslexia. PLoS Genet 1 e50 doi:10.1371/journal.pgen.0010050
32. Nopola-HemmiJTaipaleMHaltiaTLehesjokiAEVoutilainenA 2000 Two translocations of chromosome 15q associated with dyslexia. J Med Genet 37 771 775
33. TaipaleMKaminenNNopola-HemmiJHaltiaTMyllyluomaB 2003 A candidate gene for developmental dyslexia encodes a nuclear tetratricopeptide repeat domain protein dynamically regulated in brain. Proc Natl Acad Sci U S A 100 11553 11558
34. BuonincontriRBacheISilahtarogluAElbroCNielsenAM 2011 A cohort of balanced reciprocal translocations associated with dyslexia: identification of two putative candidate genes at DYX1. Behav Genet 41 125 133
35. O'RoakBJDeriziotisPLeeCVivesLSchwartzJJ 2011 Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nat Genet 43 585 589
36. HamdanFFDaoudHRochefortDPitonAGauthierJ 2010 De novo mutations in FOXP1 in cases with intellectual disability, autism, and language impairment. Am J Hum Genet 87 671 678
37. HornDKapellerJRivera-BruguesNMoogULorenz-DepiereuxB 2010 Identification of FOXP1 deletions in three unrelated patients with mental retardation and significant speech and language deficits. Hum Mutat 31 E1851 1860
38. TeramitsuIKudoLCLondonSEGeschwindDHWhiteSA 2004 Parallel FoxP1 and FoxP2 expression in songbird and human brain predicts functional interaction. J Neurosci 24 3152 3163
39. VernesSCNewburyDFAbrahamsBSWinchesterLNicodJ 2008 A functional genetic link between distinct developmental language disorders. N Engl J Med 359 2337 2345
40. FirthHVRichardsSMBevanAPClaytonSCorpasM 2009 DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources. Am J Hum Genet 84 524 533
41. BonagliaMCCicconeRGimelliGGimelliSMarelliS 2008 Detailed phenotype-genotype study in five patients with chromosome 6q16 deletion: narrowing the critical region for Prader-Willi-like phenotype. Eur J Hum Genet 16 1443 1449
42. HolderJLJrButteNFZinnAR 2000 Profound obesity associated with a balanced translocation that disrupts the SIM1 gene. Hum Mol Genet 9 101 108
43. JamainSBetancurCQuachHPhilippeAFellousM 2002 Linkage and association of the glutamate receptor 6 gene with autism. Mol Psychiatry 7 302 310
44. StrungaruMHDinuIWalterMA 2007 Genotype-phenotype correlations in Axenfeld-Rieger malformation and glaucoma patients with FOXC1 and PITX2 mutations. Invest Ophthalmol Vis Sci 48 228 237
45. BallifBCTheisenACoppingerJGowansGCHershJH 2008 Expanding the clinical phenotype of the 3q29 microdeletion syndrome and characterization of the reciprocal microduplication. Mol Cytogenet 1 8
46. LisiECHamoshADohenyKFSquibbEJacksonB 2008 3q29 interstitial microduplication: a new syndrome in a three-generation family. Am J Med Genet A 146A 601 609
47. CardosoCLeventerRJWardHLToyo-OkaKChungJ 2003 Refinement of a 400-kb critical region allows genotypic differentiation between isolated lissencephaly, Miller-Dieker syndrome, and other phenotypes secondary to deletions of 17p13.3. Am J Hum Genet 72 918 930
48. NagamaniSCZhangFShchelochkovOABiWOuZ 2009 Microdeletions including YWHAE in the Miller-Dieker syndrome region on chromosome 17p13.3 result in facial dysmorphisms, growth restriction, and cognitive impairment. J Med Genet 46 825 833
49. ItsaraACooperGMBakerCGirirajanSLiJ 2009 Population analysis of large copy number variants and hotspots of human genetic disease. Am J Hum Genet 84 148 161
50. RaskindW 2001 Current understanding of the genetic basis of reading and spelling disability. Learning Disability Quarterly 24 141 157
51. BakkalogluBO'RoakBJLouviAGuptaARAbelsonJF 2008 Molecular cytogenetic analysis and resequencing of contactin associated protein-like 2 in autism spectrum disorders. Am J Hum Genet 82 165 173
52. de la BarraFSkoknicVAlliendeARaimannECortesF 1986 [Twins with autism and mental retardation associated with balanced (7;20) chromosomal translocation]. Rev Chil Pediatr 57 549 554
53. HuangXLZouYSMaherTANewtonSMilunskyJM 2010 A de novo balanced translocation breakpoint truncating the autism susceptibility candidate 2 (AUTS2) gene in a patient with autism. Am J Med Genet A 152A 2112 2114
54. KalscheuerVMFitzPatrickDTommerupNBuggeMNiebuhrE 2007 Mutations in autism susceptibility candidate 2 (AUTS2) in patients with mental retardation. Hum Genet 121 501 509
55. SultanaRYuCEYuJMunsonJChenD 2002 Identification of a novel gene on chromosome 7q11.2 interrupted by a translocation breakpoint in a pair of autistic twins. Genomics 80 129 134
56. FletcherJShaywitzSShaywitzB 1999 Comorbidity of learning and attention disorders. Separate but equal. Pediatr Clin North Am 46 885 897
57. WillcuttEGPenningtonBFOlsonRKDeFriesJC 2007 Understanding comorbidity: a twin study of reading disability and attention-deficit/hyperactivity disorder. Am J Med Genet B Neuropsychiatr Genet 144B 709 714
58. WillcuttEGBetjemannRSMcGrathLMChhabildasNAOlsonRK 2010 Etiology and neuropsychology of comorbidity between RD and ADHD: the case for multiple-deficit models. Cortex 46 1345 1361
59. BedogniFHodgeRDNelsonBRFrederickEAShibaN 2010 Autism susceptibility candidate 2 (Auts2) encodes a nuclear protein expressed in developing brain regions implicated in autism neuropathology. Gene Expr Patterns 10 9 15
60. GreenREKrauseJBriggsAWMaricicTStenzelU 2010 A draft sequence of the Neandertal genome. Science 328 710 722
61. LevyDRonemusMYamromBLeeYHLeottaA 2011 Rare de novo and transmitted copy-number variation in autistic spectrum disorders. Neuron 70 886 897
62. PintoDPagnamentaATKleiLAnneyRMericoD 2010 Functional impact of global rare copy number variation in autism spectrum disorders. Nature 466 368 372
63. 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
64. GirirajanSRosenfeldJACooperGMAntonacciFSiswaraP 2010 A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay. Nat Genet 42 203 209
65. KimHGKishikawaSHigginsAWSeongISDonovanDJ 2008 Disruption of neurexin 1 associated with autism spectrum disorder. Am J Hum Genet 82 199 207
66. SzatmariPPatersonADZwaigenbaumLRobertsWBrianJ 2007 Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat Genet 39 319 328
67. GlessnerJTWangKCaiGKorvatskaOKimCE 2009 Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature 459 569 573
68. BucanMAbrahamsBSWangKGlessnerJTHermanEI 2009 Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes. PLoS Genet 5 e1000536 doi:10.1371/journal.pgen.1000536
69. NoorAWhibleyAMarshallCRGianakopoulosPJPitonA 2010 Disruption at the PTCHD1 Locus on Xp22.11 in Autism spectrum disorder and intellectual disability. Sci Transl Med 2 49ra68
70. BrkanacZChapmanNHIgoRPJrMatsushitaMMNielsenK 2008 Genome Scan of a Nonword Repetition Phenotype in Families with Dyslexia: Evidence for Multiple Loci. Behav Genet
71. RubensteinKMatsushitaMBerningerVWRaskindWHWijsmanEM 2011 Genome scan for spelling deficits: effects of verbal IQ on models of transmission and trait gene localization. Behav Genet 41 31 42
72. BerningerV 2006 A developmental approach to learning disabilities. SiegelIRenningerA Handbook of Child Psychology, Vol IV, Child Psychology and Practice New York John Wiley and Sons 420 452
73. FischbachGDLordC 2010 The Simons Simplex Collection: a resource for identification of autism genetic risk factors. Neuron 68 192 195
74. LordCRisiSLambrechtLCookEHJrLeventhalBL 2000 The autism diagnostic observation schedule-generic: a standard measure of social and communication deficits associated with the spectrum of autism. J Autism Dev Disord 30 205 223
75. LordCRutterMLe CouteurA 1994 Autism Diagnostic Interview-Revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. J Autism Dev Disord 24 659 685
76. MoldinSO 2003 NIMH Human Genetics Initiative: 2003 update. Am J Psychiatry 160 621 622
77. KesslerRCUstunTB 2004 The World Mental Health (WMH) Survey Initiative Version of the World Health Organization (WHO) Composite International Diagnostic Interview (CIDI). Int J Methods Psychiatr Res 13 93 121
78. TalatiAFyerAJWeissmanMM 2008 A comparison between screened NIMH and clinically interviewed control samples on neuroticism and extraversion. Mol Psychiatry 13 122 130
79. BaumAEAkulaNCabaneroMCardonaICoronaW 2008 A genome-wide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder. Mol Psychiatry 13 197 207
80. LiBLealSM 2008 Methods for detecting associations with rare variants for common diseases: application to analysis of sequence data. Am J Hum Genet 83 311 321
81. Simon-SanchezJScholzSFungHCMatarinMHernandezD 2007 Genome-wide SNP assay reveals structural genomic variation, extended homozygosity and cell-line induced alterations in normal individuals. Hum Mol Genet 16 1 14
82. AlbertMADanielsonERifaiNRidkerPM 2001 Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a randomized trial and cohort study. JAMA 286 64 70
83. SimonJALinFHulleySBBlanchePJWatersD 2006 Phenotypic predictors of response to simvastatin therapy among African-Americans and Caucasians: the Cholesterol and Pharmacogenetics (CAP) Study. Am J Cardiol 97 843 850
84. MelzerDPerryJRHernandezDCorsiAMStevensK 2008 A genome-wide association study identifies protein quantitative trait loci (pQTLs). PLoS Genet 4 e1000072 doi:10.1371/journal.pgen.1000072
85. CooperGMCoeBPGirirajanSRosenfeldJAVuTH 2011 A copy number variation morbidity map of developmental delay. Nat Genet 43 838 846
86. SelzerRRRichmondTAPofahlNJGreenRDEisPS 2005 Analysis of chromosome breakpoints in neuroblastoma at sub-kilobase resolution using fine-tiling oligonucleotide array CGH. Genes Chromosomes Cancer 44 305 319
87. DayNHemmaplardhAThurmanREStamatoyannopoulosJANobleWS 2007 Unsupervised segmentation of continuous genomic data. Bioinformatics 23 1424 1426
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2011 Číslo 11
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