Home LiteratureArticle Details
PMID: 19404256 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Common genetic variants on 5p14.1 associate with autism spectrum disorders.

Nature ·Vol. 459 ·No. 7246 ·2009-05-28 ·Pages 528-33

Wang K, Zhang H, Ma D, Bucan M, Glessner JT, Abrahams BS, Salyakina D, Imielinski M, Bradfield JP, Sleiman PM, Kim CE, Hou C, Frackelton E, Chiavacci R, Takahashi N, Sakurai T, Rappaport E, Lajonchere CM, Munson J, Estes A, Korvatska O, Piven J, Sonnenblick LI, Alvarez Retuerto AI, Herman EI, Dong H, Hutman T, Sigman M, Ozonoff S, Klin A, Owley T, Sweeney JA, Brune CW, Cantor RM, Bernier R, Gilbert JR, Cuccaro ML, McMahon WM, Miller J, State MW, Wassink TH, Coon H, Levy SE, Schultz RT, Nurnberger JI, Haines JL, Sutcliffe JS, Cook EH, Minshew NJ, Buxbaum JD, Dawson G, Grant SF, Geschwind DH, Pericak-Vance MA, Schellenberg GD, Hakonarson H

Abstract

Autism spectrum disorders (ASDs) represent a group of childhood neurodevelopmental and neuropsychiatric disorders characterized by deficits in verbal communication, impairment of social interaction, and restricted and repetitive patterns of interests and behaviour. To identify common genetic risk factors underlying ASDs, here we present the results of genome-wide association studies on a cohort of 780 families (3,101 subjects) with affected children, and a second cohort of 1,204 affected subjects and 6,491 control subjects, all of whom were of European ancestry. Six single nucleotide polymorphisms between cadherin 10 (CDH10) and cadherin 9 (CDH9)-two genes encoding neuronal cell-adhesion molecules-revealed strong association signals, with the most significant SNP being rs4307059 (P = 3.4 x 10(-8), odds ratio = 1.19). These signals were replicated in two independent cohorts, with combined P values ranging from 7.4 x 10(-8) to 2.1 x 10(-10). Our results implicate neuronal cell-adhesion molecules in the pathogenesis of ASDs, and represent, to our knowledge, the first demonstration of genome-wide significant association of common variants with susceptibility to ASDs.

MeSH Terms
Autistic Disorder/genetics Brain/metabolism Cadherins/genetics Case-Control Studies Cell Adhesion/genetics Cell Adhesion Molecules, Neuronal/genetics Chromosomes, Human, Pair 5/genetics Cohort Studies Genetic Markers/genetics Genetic Predisposition to Disease/genetics Genetic Variation/genetics Genome-Wide Association Study Genotype Humans Polymorphism, Single Nucleotide/genetics Reproducibility of Results
Chemicals
CDH10 protein, human CDH9 protein, human Cadherins Cell Adhesion Molecules, Neuronal Genetic Markers
Authors & Affiliations
56 authors, click to expand affiliations / ORCID
Wang Kai
Center for Applied Genomics, Children's Hospital of Philadelphia, Pennsylvania 19104, USA.
Zhang Haitao
Ma Deqiong
Bucan Maja
Glessner Joseph T
Abrahams Brett S
Salyakina Daria
Imielinski Marcin
Bradfield Jonathan P
Sleiman Patrick M A
Kim Cecilia E
Hou Cuiping
Frackelton Edward
Chiavacci Rosetta
Takahashi Nagahide
Sakurai Takeshi
Rappaport Eric
Lajonchere Clara M
Munson Jeffrey
Estes Annette
Korvatska Olena
Piven Joseph
Sonnenblick Lisa I
Alvarez Retuerto Ana I
Herman Edward I
Dong Hongmei
Hutman Ted
Sigman Marian
Ozonoff Sally
Klin Ami
Owley Thomas
Sweeney John A
Brune Camille W
Cantor Rita M
Bernier Raphael
Gilbert John R
Cuccaro Michael L
McMahon William M
Miller Judith
State Matthew W
Wassink Thomas H
Coon Hilary
Levy Susan E
Schultz Robert T
Nurnberger John I
Haines Jonathan L
Sutcliffe James S
Cook Edwin H
Minshew Nancy J
Buxbaum Joseph D
Dawson Geraldine
Grant Struan F A
Geschwind Daniel H
Pericak-Vance Margaret A
Schellenberg Gerard D
Hakonarson Hakon
References (49)
49 references, click to expand
  1. Molecular cytogenetic analysis and resequencing of contactin associated protein-like 2 in autism spectrum disorders.
    Am J Hum Genet. 2008 Jan;82(1):165-73 PMID: 18179895
  2. GenePaint.org: an atlas of gene expression patterns in the mouse embryo.
    Nucleic Acids Res. 2004 Jan 1;32(Database issue):D552-6 PMID: 14681479
  3. The autism diagnostic observation schedule-generic: a standard measure of social and communication deficits associated with the spectrum of autism.
    J Autism Dev Disord. 2000 Jun;30(3):205-23 PMID: 11055457
  4. Molecular genetics of autism spectrum disorder.
    Mol Psychiatry. 2004 Sep;9(9):819-32 PMID: 15197396
  5. Effects of familial risk factors and place of birth on the risk of autism: a nationwide register-based study.
    J Child Psychol Psychiatry. 2005 Sep;46(9):963-71 PMID: 16108999
  6. Whole-genome association study of bipolar disorder.
    Mol Psychiatry. 2008 Jun;13(6):558-69 PMID: 18317468
  7. Autism: the first firm finding = underconnectivity?
    Epilepsy Behav. 2007 Aug;11(1):20-4 PMID: 17531541
  8. Cortical activation and synchronization during sentence comprehension in high-functioning autism: evidence of underconnectivity.
    Brain. 2004 Aug;127(Pt 8):1811-21 PMID: 15215213
  9. PennCNV: an integrated hidden Markov model designed for high-resolution copy number variation detection in whole-genome SNP genotyping data.
    Genome Res. 2007 Nov;17(11):1665-74 PMID: 17921354
  10. Advances in autism genetics: on the threshold of a new neurobiology.
    Nat Rev Genet. 2008 May;9(5):341-55 PMID: 18414403
  11. Practical aspects of imputation-driven meta-analysis of genome-wide association studies.
    Hum Mol Genet. 2008 Oct 15;17(R2):R122-8 PMID: 18852200
  12. Autism Diagnostic Interview-Revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders.
    J Autism Dev Disord. 1994 Oct;24(5):659-85 PMID: 7814313
  13. Identifying autism loci and genes by tracing recent shared ancestry.
    Science. 2008 Jul 11;321(5886):218-23 PMID: 18621663
  14. Tissue-specific genetic control of splicing: implications for the study of complex traits.
    PLoS Biol. 2008 Dec 23;6(12):e1 PMID: 19222302
  15. A genome-wide association study of autism reveals a common novel risk locus at 5p14.1.
    Ann Hum Genet. 2009 May;73(Pt 3):263-73 PMID: 19456320
  16. A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism.
    Am J Hum Genet. 2008 Jan;82(1):160-4 PMID: 18179894
  17. Recent advances in the genetics of autism.
    Biol Psychiatry. 2007 Feb 15;61(4):429-37 PMID: 16996486
  18. Is autism a disconnection disorder?
    Lancet Neurol. 2004 Oct;3(10):577 PMID: 15380151
  19. Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes.
    Genome Res. 2005 Aug;15(8):1034-50 PMID: 16024819
  20. The genetics of autistic disorders and its clinical relevance: a review of the literature.
    Mol Psychiatry. 2007 Jan;12(1):2-22 PMID: 17033636
  21. The autism genetic resource exchange: a resource for the study of autism and related neuropsychiatric conditions.
    Am J Hum Genet. 2001 Aug;69(2):463-6 PMID: 11452364
  22. Pathway-based approaches for analysis of genomewide association studies.
    Am J Hum Genet. 2007 Dec;81(6):1278-83 PMID: 17966091
  23. Why the frontal cortex in autism might be talking only to itself: local over-connectivity but long-distance disconnection.
    Curr Opin Neurobiol. 2005 Apr;15(2):225-30 PMID: 15831407
  24. Evolution and functional classification of vertebrate gene deserts.
    Genome Res. 2005 Jan;15(1):137-45 PMID: 15590943
  25. Structural variation of chromosomes in autism spectrum disorder.
    Am J Hum Genet. 2008 Feb;82(2):477-88 PMID: 18252227
  26. Genome-wide analyses of human perisylvian cerebral cortical patterning.
    Proc Natl Acad Sci U S A. 2007 Nov 6;104(45):17849-54 PMID: 17978184
  27. X-APL: an improved family-based test of association in the presence of linkage for the X chromosome.
    Am J Hum Genet. 2007 Jan;80(1):59-68 PMID: 17160894
  28. Disruption of neurexin 1 associated with autism spectrum disorder.
    Am J Hum Genet. 2008 Jan;82(1):199-207 PMID: 18179900
  29. Autism: the quest for the genes.
    Expert Rev Mol Med. 2007 Sep 03;9(24):1-15 PMID: 17764594
  30. Multiple prostate cancer risk variants on 8q24.
    Nat Genet. 2007 May;39(5):579-80 PMID: 17460686
  31. Identification of novel autism candidate regions through analysis of reported cytogenetic abnormalities associated with autism.
    Mol Psychiatry. 2006 Jan;11(1):1, 18-28 PMID: 16205736
  32. The human cadherin-10 gene: complete coding sequence, predominant expression in the brain, and mapping on chromosome 5p13-14.
    FEBS Lett. 1999 Jun 11;452(3):328-34 PMID: 10386616
  33. Cadherins in the central nervous system.
    Prog Neurobiol. 2000 Aug;61(6):611-48 PMID: 10775799
  34. Association between microdeletion and microduplication at 16p11.2 and autism.
    N Engl J Med. 2008 Feb 14;358(7):667-75 PMID: 18184952
  35. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls.
    Nature. 2007 Jun 7;447(7145):661-78 PMID: 17554300
  36. Identification of loci associated with schizophrenia by genome-wide association and follow-up.
    Nat Genet. 2008 Sep;40(9):1053-5 PMID: 18677311
  37. Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene.
    Am J Hum Genet. 2008 Jan;82(1):150-9 PMID: 18179893
  38. Neuroanatomy of autism.
    Trends Neurosci. 2008 Mar;31(3):137-45 PMID: 18258309
  39. The UCSC Genome Browser Database: update 2009.
    Nucleic Acids Res. 2009 Jan;37(Database issue):D755-61 PMID: 18996895
  40. Mapping autism risk loci using genetic linkage and chromosomal rearrangements.
    Nat Genet. 2007 Mar;39(3):319-28 PMID: 17322880
  41. Recurrent 16p11.2 microdeletions in autism.
    Hum Mol Genet. 2008 Feb 15;17(4):628-38 PMID: 18156158
  42. Autism spectrum disorders: developmental disconnection syndromes.
    Curr Opin Neurobiol. 2007 Feb;17(1):103-11 PMID: 17275283
  43. Strong association of de novo copy number mutations with autism.
    Science. 2007 Apr 20;316(5823):445-9 PMID: 17363630
  44. Autism as a strongly genetic disorder: evidence from a British twin study.
    Psychol Med. 1995 Jan;25(1):63-77 PMID: 7792363
  45. The XVth World Congress of Psychiatric Genetics, October 7-11, 2007: Rapporteur summaries of oral presentations.
    Am J Med Genet B Neuropsychiatr Genet. 2008 Mar 5;147B(2):233-77 PMID: 18297693
  46. fMRI investigation of working memory for faces in autism: visual coding and underconnectivity with frontal areas.
    Cereb Cortex. 2008 Feb;18(2):289-300 PMID: 17517680
  47. A test for linkage and association in general pedigrees: the pedigree disequilibrium test.
    Am J Hum Genet. 2000 Jul;67(1):146-54 PMID: 10825280
  48. Multiple loci with different cancer specificities within the 8q24 gene desert.
    J Natl Cancer Inst. 2008 Jul 2;100(13):962-6 PMID: 18577746
  49. Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder.
    Nat Genet. 2008 Sep;40(9):1056-8 PMID: 18711365
Article Info
Journal
Nature
Abbr.
Nature
ISSN
1476-4687
DOI
10.1038/nature07999
Published
2009-05-28
Epub
2009-00-28
Pages
528-33
Language
English
Region
England
NLM ID
0410462
PMCID
PMC2943511
Subset
IM
Grants
NIMH NIH HHS · MH0666730 · United States
NINDS NIH HHS · NS049261 · United States
NIMH NIH HHS · R01 MH081754-01 · United States
NICHD NIH HHS · N01-HD-4-3368 · United States
NINDS NIH HHS · R01 NS036768 · United States
NICHD NIH HHS · P50 HD055748 · United States
NICHD NIH HHS · P50 HD055784 · United States
NCRR NIH HHS · UL1-RR024134-03 · United States
NIMH NIH HHS · R01 MH064547-01 · United States
NIMH NIH HHS · MH69359 · United States
NIMH NIH HHS · R01 MH064547-04 · United States
NIMH NIH HHS · U54 MH066673 · United States
NIMH NIH HHS · R01 MH064547-05 · United States
NIMH NIH HHS · U24 MH081810 · United States
NICHD NIH HHS · P50 HD055782 · United States
NIMH NIH HHS · MH64547 · United States
NICHD NIH HHS · P50 HD055784-020002 · United States
NINDS NIH HHS · R01 NS049261 · United States
NICHD NIH HHS · P50 HD055782-01 · United States
NCRR NIH HHS · M01-RR00064 · United States
NINDS NIH HHS · P01 NS026630 · United States
NICHD NIH HHS · N01-HD-4-3383 · United States
NICHD NIH HHS · P50 HD055784-01 · United States
NIMH NIH HHS · MH080647 · United States
NIMH NIH HHS · MH061009 · United States
NIMH NIH HHS · R01 MH061009 · United States
NIMH NIH HHS · MH081754 · United States
NIMH NIH HHS · R01 MH081754-02 · United States
NCRR NIH HHS · UL1 RR024134-01 · United States
NINDS NIH HHS · R01 NS049261-01A2 · United States
NIMH NIH HHS · 1U24MH081810 · United States
NICHD NIH HHS · P50 HD055784-010002 · United States
NINDS NIH HHS · NS26630 · United States
NIMH NIH HHS · R01 MH061009-01A1 · United States
NIMH NIH HHS · R01 MH068398 · United States
NIMH NIH HHS · R01 MH064547-01S1 · United States
NIMH NIH HHS · R01 MH069359-01A2 · United States
NINDS NIH HHS · R01 NS036768-06 · United States
NIMH NIH HHS · R01 MH080647-11 · United States
NIMH NIH HHS · R01 MH064547-03 · United States
NIMH NIH HHS · R01 MH064547-02 · United States
NICHD NIH HHS · P50 HD055751 · United States
Medical Research Council · United Kingdom
NICHD NIH HHS · P50 HD055751-01 · United States
NIMH NIH HHS · U54 MH066673-01A10001 · United States
NIMH NIH HHS · R01 MH064547 · United States
NIMH NIH HHS · R01 MH080647 · United States
NICHD NIH HHS · HD055784 · United States
NIMH NIH HHS · R01 MH081754 · United States
NICHD NIH HHS · P50 HD055784-030002 · United States
NIMH NIH HHS · R01 MH069359 · United States
NINDS NIH HHS · NS36768 · United States
NINDS NIH HHS · P01 NS026630-109001 · United States
NIMH NIH HHS · R01 MH064547-02S1 · United States
NICHD NIH HHS · HD055782-01 · United States
NCRR NIH HHS · M01 RR000064 · United States
NCRR NIH HHS · UL1 RR024134 · United States
NICHD NIH HHS · HD055751 · United States
External Links
PubMed source DOI: 10.1038/nature07999 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2