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PMID: 17322880 Published · ppublish English Comparative Study Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Mapping autism risk loci using genetic linkage and chromosomal rearrangements.

Nature genetics ·Vol. 39 ·No. 3 ·2007-03-00 ·Pages 319-28

Autism Genome Project Consortium, Szatmari P, Paterson AD, Zwaigenbaum L, Roberts W, Brian J, Liu XQ, Vincent JB, Skaug JL, Thompson AP, Senman L, Feuk L, Qian C, Bryson SE, Jones MB, Marshall CR, Scherer SW, Vieland VJ, Bartlett C, Mangin LV, Goedken R, Segre A, Pericak-Vance MA, Cuccaro ML, Gilbert JR, Wright HH, Abramson RK, Betancur C, Bourgeron T, Gillberg C, Leboyer M, Buxbaum JD, Davis KL, Hollander E, Silverman JM, Hallmayer J, Lotspeich L, Sutcliffe JS, Haines JL, Folstein SE, Piven J, Wassink TH, Sheffield V, Geschwind DH, Bucan M, Brown WT, Cantor RM, Constantino JN, Gilliam TC, Herbert M, Lajonchere C, Ledbetter DH, Lese-Martin C, Miller J, Nelson S, Samango-Sprouse CA, Spence S, State M, Tanzi RE, Coon H, Dawson G, Devlin B, Estes A, Flodman P, Klei L, McMahon WM, Minshew N, Munson J, Korvatska E, Rodier PM, Schellenberg GD, Smith M, Spence MA, Stodgell C, Tepper PG, Wijsman EM, Yu CE, Rogé B, Mantoulan C, Wittemeyer K, Poustka A, Felder B, Klauck SM, Schuster C, Poustka F, Bölte S, Feineis-Matthews S, Herbrecht E, Schmötzer G, Tsiantis J, Papanikolaou K, Maestrini E, Bacchelli E, Blasi F, Carone S, Toma C, Van Engeland H, de Jonge M, Kemner C, Koop F, Koop F, Langemeijer M, Langemeijer M, Hijmans C, Hijimans C, Staal WG, Baird G, Bolton PF, Rutter ML, Weisblatt E, Green J, Aldred C, Wilkinson JA, Pickles A, Le Couteur A, Berney T, McConachie H, Bailey AJ, Francis K, Honeyman G, Hutchinson A, Parr JR, Wallace S, Monaco AP, Barnby G, Kobayashi K, Lamb JA, Sousa I, Sykes N, Cook EH, Guter SJ, Leventhal BL, Salt J, Lord C, Corsello C, Hus V, Weeks DE, Volkmar F, Tauber M, Fombonne E, Shih A, Meyer KJ

Abstract

Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,181 [corrected] families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12-p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs.

MeSH Terms
Autistic Disorder/diagnosis,genetics Chromosome Aberrations Chromosome Mapping Family Female Genetic Linkage Genetic Predisposition to Disease Genetic Testing/methods Genetic Variation Humans Lod Score Male Risk Factors
Authors & Affiliations
142 authors, click to expand affiliations / ORCID
Autism Genome Project Consortium
Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario L8N 3Z5, Canada.
Szatmari Peter
Paterson Andrew D
Zwaigenbaum Lonnie
Roberts Wendy
Brian Jessica
Liu Xiao-Qing
Vincent John B
Skaug Jennifer L
Thompson Ann P
Senman Lili
Feuk Lars
Qian Cheng
Bryson Susan E
Jones Marshall B
Marshall Christian R
Scherer Stephen W
Vieland Veronica J
Bartlett Christopher
Mangin La Vonne
Goedken Rhinda
Segre Alberto
Pericak-Vance Margaret A
Cuccaro Michael L
Gilbert John R
Wright Harry H
Abramson Ruth K
Betancur Catalina
Bourgeron Thomas
Gillberg Christopher
Leboyer Marion
Buxbaum Joseph D
Davis Kenneth L
Hollander Eric
Silverman Jeremy M
Hallmayer Joachim
Lotspeich Linda
Sutcliffe James S
Haines Jonathan L
Folstein Susan E
Piven Joseph
Wassink Thomas H
Sheffield Val
Geschwind Daniel H
Bucan Maja
Brown W Ted
Cantor Rita M
Constantino John N
Gilliam T Conrad
Herbert Martha
Lajonchere Clara
Ledbetter David H
Lese-Martin Christa
Miller Janet
Nelson Stan
Samango-Sprouse Carol A
Spence Sarah
State Matthew
Tanzi Rudolph E
Coon Hilary
Dawson Geraldine
Devlin Bernie
Estes Annette
Flodman Pamela
Klei Lambertus
McMahon William M
Minshew Nancy
Munson Jeff
Korvatska Elena
Rodier Patricia M
Schellenberg Gerard D
Smith Moyra
Spence M Anne
Stodgell Chris
Tepper Ping Guo
Wijsman Ellen M
Yu Chang-En
Rogé Bernadette
Mantoulan Carine
Wittemeyer Kerstin
Poustka Annemarie
Felder Bärbel
Klauck Sabine M
Schuster Claudia
Poustka Fritz
Bölte Sven
Feineis-Matthews Sabine
Herbrecht Evelyn
Schmötzer Gabi
Tsiantis John
Papanikolaou Katerina
Maestrini Elena
Bacchelli Elena
Blasi Francesca
Carone Simona
Toma Claudio
Van Engeland Herman
de Jonge Maretha
Kemner Chantal
Koop Frederieke
Koop Frederike
Langemeijer Marjolein
Langemeijer Marjolijn
Hijmans Channa
Hijimans Channa
Staal Wouter G
Baird Gillian
Bolton Patrick F
Rutter Michael L
Weisblatt Emma
Green Jonathan
Aldred Catherine
Wilkinson Julie-Anne
Pickles Andrew
Le Couteur Ann
Berney Tom
McConachie Helen
Bailey Anthony J
Francis Kostas
Honeyman Gemma
Hutchinson Aislinn
Parr Jeremy R
Wallace Simon
Monaco Anthony P
Barnby Gabrielle
Kobayashi Kazuhiro
Lamb Janine A
Sousa Ines
Sykes Nuala
Cook Edwin H
Guter Stephen J
Leventhal Bennett L
Salt Jeff
Lord Catherine
Corsello Christina
Hus Vanessa
Weeks Daniel E
Volkmar Fred
Tauber Maïté
Fombonne Eric
Shih Andy
Meyer Kacie J
References (45)
45 references, click to expand
  1. Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome.
    Nat Genet. 2006 Sep;38(9):1038-42 PMID: 16906162
  2. Latent-class analysis of recurrence risks for complex phenotypes with selection and measurement error: a twin and family history study of autism.
    Am J Hum Genet. 1995 Sep;57(3):717-26 PMID: 7668301
  3. Pervasive developmental disorders in preschool children: confirmation of high prevalence.
    Am J Psychiatry. 2005 Jun;162(6):1133-41 PMID: 15930062
  4. Autism as a paradigmatic complex genetic disorder.
    Annu Rev Genomics Hum Genet. 2004;5:379-405 PMID: 15485354
  5. Principal components analysis corrects for stratification in genome-wide association studies.
    Nat Genet. 2006 Aug;38(8):904-9 PMID: 16862161
  6. Dissection of synapse induction by neuroligins: effect of a neuroligin mutation associated with autism.
    J Biol Chem. 2005 Jun 10;280(23):22365-74 PMID: 15797875
  7. Diagnostic genome profiling in mental retardation.
    Am J Hum Genet. 2005 Oct;77(4):606-16 PMID: 16175506
  8. Molecular genetics of autosomal-dominant demyelinating Charcot-Marie-Tooth disease.
    Neuromolecular Med. 2006;8(1-2):43-62 PMID: 16775366
  9. The broad autism phenotype: a complementary strategy for molecular genetic studies of autism.
    Am J Med Genet. 2001 Jan 8;105(1):34-5 PMID: 11424990
  10. The genetics of autistic disorders and its clinical relevance: a review of the literature.
    Mol Psychiatry. 2007 Jan;12(1):2-22 PMID: 17033636
  11. On a general class of conditional tests for family-based association studies in genetics: the asymptotic distribution, the conditional power, and optimality considerations.
    Genet Epidemiol. 2002 Aug;23(2):165-80 PMID: 12214309
  12. Allegro, a new computer program for multipoint linkage analysis.
    Nat Genet. 2000 May;25(1):12-3 PMID: 10802644
  13. Hereditary motor and sensory neuropathy (HMSN) IA, developmental delay and autism related disorder in a boy with duplication (17)(p11.2p12).
    Genet Couns. 2004;15(1):73-80 PMID: 15083703
  14. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders.
    Nat Genet. 2007 Jan;39(1):25-7 PMID: 17173049
  15. Reduced N-acetylaspartate levels in mice lacking aralar, a brain- and muscle-type mitochondrial aspartate-glutamate carrier.
    J Biol Chem. 2005 Sep 2;280(35):31333-9 PMID: 15987682
  16. Stoppage rules and genetic studies of autism.
    J Autism Dev Disord. 1988 Mar;18(1):31-40 PMID: 3372457
  17. X-linked mental retardation and autism are associated with a mutation in the NLGN4 gene, a member of the neuroligin family.
    Am J Hum Genet. 2004 Mar;74(3):552-7 PMID: 14963808
  18. Neuroligins determine synapse maturation and function.
    Neuron. 2006 Sep 21;51(6):741-54 PMID: 16982420
  19. Global variation in copy number in the human genome.
    Nature. 2006 Nov 23;444(7118):444-54 PMID: 17122850
  20. Molecular mechanism for duplication 17p11.2- the homologous recombination reciprocal of the Smith-Magenis microdeletion.
    Nat Genet. 2000 Jan;24(1):84-7 PMID: 10615134
  21. High frequency of neurexin 1beta signal peptide structural variants in patients with autism.
    Neurosci Lett. 2006 Nov 27;409(1):10-3 PMID: 17034946
  22. Increased serum levels of glutamate in adult patients with autism.
    Prog Neuropsychopharmacol Biol Psychiatry. 2006 Dec 30;30(8):1472-7 PMID: 16863675
  23. Variance calculations for identity-by-descent estimation.
    Am J Hum Genet. 2006 Jun;78(6):914-21 PMID: 16685643
  24. Postmortem brain abnormalities of the glutamate neurotransmitter system in autism.
    Neurology. 2001 Nov 13;57(9):1618-28 PMID: 11706102
  25. Detection of large-scale variation in the human genome.
    Nat Genet. 2004 Sep;36(9):949-51 PMID: 15286789
  26. Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2.
    Nat Neurosci. 2005 Dec;8(12):1727-34 PMID: 16286931
  27. Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism.
    Nat Genet. 2003 May;34(1):27-9 PMID: 12669065
  28. Merlin--rapid analysis of dense genetic maps using sparse gene flow trees.
    Nat Genet. 2002 Jan;30(1):97-101 PMID: 11731797
  29. PedCheck: a program for identification of genotype incompatibilities in linkage analysis.
    Am J Hum Genet. 1998 Jul;63(1):259-66 PMID: 9634505
  30. The UCLA-University of Utah epidemiologic survey of autism: prevalence.
    Am J Psychiatry. 1989 Feb;146(2):194-9 PMID: 2783539
  31. Neurexins induce differentiation of GABA and glutamate postsynaptic specializations via neuroligins.
    Cell. 2004 Dec 29;119(7):1013-26 PMID: 15620359
  32. Fragile X syndrome and autism at the intersection of genetic and neural networks.
    Nat Neurosci. 2006 Oct;9(10):1221-5 PMID: 17001341
  33. A genomic screen of autism: evidence for a multilocus etiology.
    Am J Hum Genet. 1999 Aug;65(2):493-507 PMID: 10417292
  34. Searching for ways out of the autism maze: genetic, epigenetic and environmental clues.
    Trends Neurosci. 2006 Jul;29(7):349-58 PMID: 16808981
  35. Autism as a strongly genetic disorder: evidence from a British twin study.
    Psychol Med. 1995 Jan;25(1):63-77 PMID: 7792363
  36. Characterization of multilocus linkage disequilibrium.
    Genet Epidemiol. 2005 Apr;28(3):193-206 PMID: 15637716
  37. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results.
    Nat Genet. 1995 Nov;11(3):241-7 PMID: 7581446
  38. Best linear unbiased allele-frequency estimation in complex pedigrees.
    Biometrics. 2004 Jun;60(2):359-67 PMID: 15180661
  39. Developmental expression of glutamate transporters and glutamate dehydrogenase in astrocytes of the postnatal rat hippocampus.
    Hippocampus. 2004;14(8):975-85 PMID: 15390174
  40. Evidence for sex-specific risk alleles in autism spectrum disorder.
    Am J Hum Genet. 2004 Dec;75(6):1117-23 PMID: 15467983
  41. A combined linkage-physical map of the human genome.
    Am J Hum Genet. 2004 Dec;75(6):1143-8 PMID: 15486828
  42. Analysis of IMGSAC autism susceptibility loci: evidence for sex limited and parent of origin specific effects.
    J Med Genet. 2005 Feb;42(2):132-7 PMID: 15689451
  43. On the twin risk in autism.
    Am J Hum Genet. 2002 Oct;71(4):941-6 PMID: 12297988
  44. Correcting for multiple analyses in genomewide linkage studies.
    Ann Hum Genet. 2001 Nov;65(Pt 6):577-82 PMID: 11851987
  45. Combining information from multiple sources in the diagnosis of autism spectrum disorders.
    J Am Acad Child Adolesc Psychiatry. 2006 Sep;45(9):1094-103 PMID: 16926617
Article Info
Journal
Nature genetics
Abbr.
Nat Genet
ISSN
1061-4036
DOI
10.1038/ng1985
Published
2007-03-00
Epub
2007-00-18
Pages
319-28
Language
English
Region
United States
NLM ID
9216904
PMCID
PMC4867008
Subset
IM
Grants
NIMH NIH HHS · MH64547 · United States
NCRR NIH HHS · M01-RR00064 · United States
NINDS NIH HHS · R01 NS049261 · United States
NIMH NIH HHS · MH066673 · United States
NIMH NIH HHS · R37 MH057881 · United States
NINDS NIH HHS · NS049261 · United States
NCRR NIH HHS · M01 RR06022 · United States
NINDS NIH HHS · P01 NS026630 · United States
NIMH NIH HHS · MH061009 · United States
NIMH NIH HHS · R01 MH061009 · United States
NIMH NIH HHS · K02 MH01389 · United States
NICHD NIH HHS · U19HD34565 · United States
NINDS NIH HHS · R01 NS042165 · United States
NIMH NIH HHS · MH52708 · United States
NIMH NIH HHS · R01 MH057881 · United States
Autism Speaks · AS1489 · United States
NINDS NIH HHS · NS042165 · United States
NINDS NIH HHS · NS036738 · United States
NICHD NIH HHS · U19 HD035476 · United States
NICHD NIH HHS · U19 HD035482 · United States
NIMH NIH HHS · K05 MH01196 · United States
NICHD NIH HHS · 5 U19 HD035476 · United States
NICHD NIH HHS · P50 HD055784 · United States
NIMH NIH HHS · R01 MH064547 · United States
NIMH NIH HHS · R01 MH081754 · United States
NIMH NIH HHS · R01 MH093725 · United States
NIMH NIH HHS · MH057881 · United States
NINDS NIH HHS · R01 NS043550 · United States
NIMH NIH HHS · U54 MH066673-020001 · United States
NIMH NIH HHS · MH55135 · United States
Wellcome Trust · United Kingdom
Medical Research Council · G0601030 · United Kingdom
NCRR NIH HHS · M01 RR000064 · United States
NINDS NIH HHS · NS026630 · United States
NIMH NIH HHS · U54 MH066673 · United States
NICHD NIH HHS · U19 HD35482 · United States
Telethon · GGP030227 · Italy
NINDS NIH HHS · NS043550 · United States
NCRR NIH HHS · M01 RR006022 · United States
Databases
GEO
GSE6754
Corrections
ErratumIn
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External Links
PubMed source DOI: 10.1038/ng1985 PMC Full Text View journal details
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