Abstract
We performed a high-density, single nucleotide polymorphism (SNP), genome-wide scan on a six-generation pedigree from Utah with seven affected males, diagnosed with autism spectrum disorder. Using a two-stage linkage design, we first performed a nonparametric analysis on the entire genome using a 10K SNP chip to identify potential regions of interest. To confirm potentially interesting regions, we eliminated SNPs in high linkage disequilibrium (LD) using a principal components analysis (PCA) method and repeated the linkage results. Three regions met genome-wide significance criteria after controlling for LD: 3q13.2–q13.31 (nonparametric linkage (NPL), 5.58), 3q26.31–q27.3 (NPL, 4.85) and 20q11.21–q13.12 (NPL, 5.56). Two regions met suggestive criteria for significance 7p14.1–p11.22 (NPL, 3.18) and 9p24.3 (NPL, 3.44). All five chromosomal regions are consistent with other published findings. Haplotype sharing results showed that five of the affected subjects shared more than a single chromosomal region of interest with other affected subjects. Although no common autism susceptibility genes were found for all seven autism cases, these results suggest that multiple genetic loci within these regions may contribute to the autism phenotype in this family, and further follow-up of these chromosomal regions is warranted.
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References
Bailey A, Le Couteur A, Gottesman I, Bolton P, Simonoff E, Yuzda E et al. Autism as a strongly genetic disorder: evidence from a British twin study. Psychol Med 1995; 25: 63–77.
Steffenburg S, Gillberg C, Hellgren L, Andersson L, Gillberg IC, Jakobsson G et al. A twin study of autism in Denmark, Finland, Iceland, Norway and Sweden. J Child Psychol Psychiatry 1989; 30: 405–416.
Bolton P, MacDonald H, Pickles A, Rios P, Goode S, Crowson M et al. A case-control family history study of autism. J Child Psychol Psychiatry 1994; 35: 877–900.
Lamb JA, Parr JR, Bailey AJ, Monaco AP . Autism: in search of susceptibility genes. Neuromolecular Med 2002; 2: 11–28.
Auranen M, Vanhala R, Varilo T, Ayers K, Kempas E, Ylisaukko-Oja T et al. A genomewide screen for autism-spectrum disorders: evidence for a major susceptibility locus on chromosome 3q25–27. Am J Hum Genet 2002; 71: 777–790.
Buxbaum JD, Silverman JM, Smith CJ, Kilifarski M, Reichert J, Hollander E et al. Evidence for a susceptibility gene for autism on chromosome 2 and for genetic heterogeneity. Am J Hum Genet 2001; 68: 1514–1520.
Liu J, Nyholt DR, Magnussen P, Parano E, Pavone P, Geschwind D et al. A genomewide screen for autism susceptibility loci. Am J Hum Genet 2001; 69: 327–340.
McCauley JL, Li C, Jiang L, Olson LM, Crockett G, Gainer K et al. Genome-wide and Ordered-Subset linkage analyses provide support for autism loci on 17q and 19p with evidence of phenotypic and interlocus genetic correlates. BMC Med Genet 2005; 6: 1.
Risch N, Spiker D, Lotspeich L, Nouri N, Hinds D, Hallmayer J et al. A genomic screen of autism: evidence for a multilocus etiology. Am J Hum Genet 1999; 65: 493–507.
Barrett S, Beck JC, Bernier R, Bisson E, Braun TA, Casavant TL et al. An autosomal genomic screen for autism. Collaborative linkage study of autism. Am J Med Genet 1999; 88: 609–615.
Cantor RM, Kono N, Duvall JA, Alvarez-Retuerto A, Stone JL, Alarcon M et al. Replication of autism linkage: fine-mapping peak at 17q21. Am J Hum Genet 2005; 76: 1050–1056.
International Molecular Genetic Study of Autism Consortium (IMGSAC). A genomewide screen for autism: strong evidence for linkage to chromosomes 2q, 7q, and 16p. Am J Hum Genet 2001; 69: 570–581.
Philippe A, Martinez M, Guilloud-Bataille M, Gillberg C, Rastam M, Sponheim E et al. Genome-wide scan for autism susceptibility genes. Paris Autism Research International Sibpair Study. Hum Mol Genet 1999; 8: 805–812.
Shao Y, Wolpert CM, Raiford KL, Menold MM, Donnelly SL, Ravan SA et al. Genomic screen and follow-up analysis for autistic disorder. Am J Med Genet 2002; 114: 99–105.
Lauritsen MB, Als TD, Dahl HA, Flint TJ, Wang AG, Vang M et al. A genome-wide search for alleles and haplotypes associated with autism and related pervasive developmental disorders on the Faroe Islands. Mol Psychiatry 2006; 11: 37–46.
Schellenberg GD, Dawson G, Sung YJ, Estes A, Munson J, Rosenthal E et al. Evidence for multiple loci from a genome scan of autism kindreds. Mol Psychiatry 2006; 11: 1049–1060.
Szatmari P, Paterson AD, Zwaigenbaum L, Roberts W, Brian J, Liu XQ et al. Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat Genet 2007; 39: 319–328.
Folstein SE, Rosen-Sheidley B . Genetics of autism: complex aetiology for a heterogeneous disorder. Nat Rev Genet 2001; 2: 943–955.
Pickles A, Bolton P, Macdonald H, Bailey A, Le Couteur A, Sim CH et al. 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; 57: 717–726.
Jones MB, Szatmari P . A risk-factor model of epistatic interaction, focusing on autism. Am J Med Genet 2002; 114: 558–565.
Ma DQ, Whitehead PL, Menold MM, Martin ER, Ashley-Koch AE, Mei H et al. Identification of significant association and gene–gene interaction of GABA receptor subunit genes in autism. Am J Hum Genet 2005; 77: 377–388.
Trikalinos TA, Karvouni A, Zintzaras E, Ylisaukko-oja T, Peltonen L, Jarvela I et al. A heterogeneity-based genome search meta-analysis for autism-spectrum disorders. Mol Psychiatry 2006; 11: 29–36.
Stone JL, Merriman B, Cantor RM, Yonan AL, Gilliam TC, Geschwind DH et al. Evidence for sex-specific risk alleles in autism spectrum disorder. Am J Hum Genet 2004; 75: 1117–1123.
Molloy CA, Keddache M, Martin LJ . Evidence for linkage on 21q and 7q in a subset of autism characterized by developmental regression. Mol Psychiatry 2005; 10: 741–746.
Alarcon M, Cantor RM, Liu J, Gilliam TC, Geschwind DH . Evidence for a language quantitative trait locus on chromosome 7q in multiplex autism families. Am J Hum Genet 2002; 70: 60–71.
Bradford Y, Haines J, Hutcheson H, Gardiner M, Braun T, Sheffield V et al. Incorporating language phenotypes strengthens evidence of linkage to autism. Am J Med Genet 2001; 105: 539–547.
Sutcliffe JS, Delahanty RJ, Prasad HC, McCauley JL, Han Q, Jiang L et al. Allelic heterogeneity at the serotonin transporter locus (SLC6A4) confers susceptibility to autism and rigid-compulsive behaviors. Am J Hum Genet 2005; 77: 265–279.
Shao Y, Cuccaro ML, Hauser ER, Raiford KL, Menold MM, Wolpert CM et al. Fine mapping of autistic disorder to chromosome 15q11–q13 by use of phenotypic subtypes. Am J Hum Genet 2003; 72: 539–548.
Coon H, Matsunami N, Stevens J, Miller J, Pingree C, Camp NJ et al. Evidence for linkage on chromosome 3q25–27 in a large autism extended pedigree. Hum Hered 2006; 60: 220–226.
Lord C, Risi S, Lambrecht L, Cook Jr EH, Leventhal BL, DiLavore PC et al. 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; 30: 205–223.
Lord C, Rutter M, Le Couteur A . 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; 24: 659–685.
Wechsler D . Wechsler Adult Intelligence Scale—Third Edition. The Psychological Corporation: San Antonio, TX, 1997.
Wechsler D . Manual for the Wechsler Intelligence Scale for Children—Third Edition. The Psychological Corporation: San Antonio, TX, 1991.
Elliott CD . Differential Ability Scales. The Psychological Corporation: San Antonio, TX, 1990.
Jorde LB . Inbreeding in the Utah Mormons: an evaluation of estimates based on pedigrees, isonymy, and migration matrices. Ann Hum Genet 1989; 53 (Part 4): 339–355.
Jorde LB . Consanguinity and prereproductive mortality in the Utah Mormon population. Hum Hered 2001; 52: 61–65.
Matsuzaki H, Loi H, Dong S, Tsai YY, Fang J, Law J et al. Parallel genotyping of over 10 000 SNPs using a one-primer assay on a high-density oligonucleotide array. Genome Res 2004; 14: 414–425.
Mukhopadhyay N, Almasy L, Schroeder M, Mulvihill WP, Weeks DE . Mega2: data-handling for facilitating genetic linkage and association analyses. Bioinformatics 2005; 21: 2556–2557.
Thomas A . GMCheck: Bayesian error checking for pedigree genotypes and phenotypes. Bioinformatics 2005; 21: 3187–3188.
Thomas A, Gutin A, Abkevich V, Bansai A . Multipoint linkage analysis by blocked (Gibbs) sampling. Stats Comp 2000; 10: 259–269.
Abkevich V, Camp NJ, Hensel CH, Neff CD, Russell DL, Hughes DC et al. Predisposition locus for major depression at chromosome 12q22–12q23.2. Am J Hum Genet 2003; 73: 1271–1281.
Camp NJ, Farnham JM, Cannon Albright LA . Genomic search for prostate cancer predisposition loci in Utah pedigrees. Prostate 2005; 65: 365–374.
Camp NJ, Lowry MR, Richards RL, Plenk AM, Carter C, Hensel CH et al. Genome-wide linkage analyses of extended Utah pedigrees identifies loci that influence recurrent, early-onset major depression and anxiety disorders. Am J Med Genet B Neuropsychiatr Genet 2005; 135: 85–93.
Camp NJ, Neuhausen SL, Tiobech J, Polloi A, Coon H, Myles-Worsley M . Genomewide multipoint linkage analysis of seven extended Palauan pedigrees with schizophrenia, by a Markov-chain Monte Carlo method. Am J Hum Genet 2001; 69: 1278–1289.
Thomas A, Camp NJ . Maximum likelihood estimates of allele frequencies and error rates from samples of related individuals by gene counting. Bioinformatics 2006; 22: 771–772.
Schaid DJ, Guenther JC, Christensen GB, Hebbring S, Rosenow C, Hilker CA et al. Comparison of microsatellites versus single-nucleotide polymorphisms in a genome linkage screen for prostate cancer-susceptibility Loci. Am J Hum Genet 2004; 75: 948–965.
Amos CI, Chen WV, Lee A, Li W, Kern M, Lundsten R et al. High-density SNP analysis of 642 Caucasian families with rheumatoid arthritis identifies two new linkage regions on 11p12 and 2q33. Genes Immun 2006; 7: 277–286.
Horne BD, Camp NJ . Principal component analysis for selection of optimal SNP-sets that capture intragenic genetic variation. Genet Epidemiol 2004; 26: 11–21.
Lander E, Kruglyak L . Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 1995; 11: 241–247.
Ray A, Weeks DE . No convincing evidence of linkage for restless legs syndrome on chromosome 9p. Am J Hum Genet 2005; 76: 705–707; author reply 7–10.
Terwilliger JD, Speer M, Ott J . Chromosome-based method for rapid computer simulation in human genetic linkage analysis. Genet Epidemiol 1993; 10: 217–224.
Martineau J, Herault J, Petit E, Guerin P, Hameury L, Perrot A et al. Catecholaminergic metabolism and autism. Dev Med Child Neurol 1994; 36: 688–697.
Auranen M, Varilo T, Alen R, Vanhala R, Ayers K, Kempas E et al. Evidence for allelic association on chromosome 3q25–27 in families with autism spectrum disorders originating from a subisolate of Finland. Mol Psychiatry 2003; 8: 879–884.
Ylisaukko-oja T, Alarcon M, Cantor RM, Auranen M, Vanhala R, Kempas E et al. Search for autism loci by combined analysis of Autism Genetic Resource Exchange and Finnish families. Ann Neurol 2006; 59: 145–155.
Limprasert P, Zhong N, Dobkin C, Brown WT . Polymorphism of FXR1 showing lack of association with autism. Am J Med Genet 1997; 74: 453–454.
Ylisaukko-oja T, Rehnstrom K, Auranen M, Vanhala R, Alen R, Kempas E et al. Analysis of four neuroligin genes as candidates for autism. Eur J Hum Genet 2005; 13: 1285–1292.
Wolpert CM, Donnelly SL, Cuccaro ML, Hedges DJ, Poole CP, Wright HH et al. De novo partial duplication of chromosome 7p in a male with autistic disorder. Am J Med Genet 2001; 105: 222–225.
Rodier PM, Ingram JL, Tisdale B, Croog VJ . Linking etiologies in humans and animal models: studies of autism. Reprod Toxicol 1997; 11: 417–422.
Ingram JL, Stodgell CJ, Hyman SL, Figlewicz DA, Weitkamp LR, Rodier PM . Discovery of allelic variants of HOXA1 and HOXB1: genetic susceptibility to autism spectrum disorders. Teratology 2000; 62: 393–405.
Conciatori M, Stodgell CJ, Hyman SL, O'Bara M, Militerni R, Bravaccio C et al. Association between the HOXA1 A218G polymorphism and increased head circumference in patients with autism. Biol Psychiatry 2004; 55: 413–419.
Ronald A, Happe F, Bolton P, Butcher LM, Price TS, Wheelwright S et al. Genetic heterogeneity between the three components of the autism spectrum: a twin study. J Am Acad Child Adolesc Psychiatry 2006; 45: 691–699.
Lamb JA, Barnby G, Bonora E, Sykes N, Bacchelli E, Blasi F et al. Analysis of IMGSAC autism susceptibility loci: evidence for sex limited and parent of origin specific effects. J Med Genet 2005; 42: 132–137.
Boyles AL, Scott WK, Martin ER, Schmidt S, Li YJ, Ashley-Koch A et al. Linkage disequilibrium inflates type I error rates in multipoint linkage analysis when parental genotypes are missing. Hum Hered 2005; 59: 220–227.
Sellick GS, Webb EL, Allinson R, Matutes E, Dyer MJ, Jonsson V et al. A high-density SNP genomewide linkage scan for chronic lymphocytic leukemia-susceptibility loci. Am J Hum Genet 2005; 77: 420–429.
John S, Shephard N, Liu G, Zeggini E, Cao M, Chen W et al. Whole-genome scan, in a complex disease, using 11 245 single-nucleotide polymorphisms: comparison with microsatellites. Am J Hum Genet 2004; 75: 54–64.
Acknowledgements
This work was supported by R01 MH069359, 5 U19 HD035476 (one of the NICHD Collaborative Programs of Excellence in Autism), the Utah Autism Foundation and by GCRC grant number M01-RR00064 from the National Center for Research Resources. Partial support for all datasets within the Utah Population Database (UPDB) was provided by the University of Utah Huntsman Cancer Institute. We thank Dr Sally Ozonoff for assistance with diagnoses of subjects, and our staff whose countless hours of work have made this study possible. We also greatly appreciate the time and effort given by the family members who participated in this study.
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Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/
Utah Population Database (UPDB), http://www.hci.utah.edu/groups/ppr/
HapMap, http://www.hapmap.org/
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Allen-Brady, K., Miller, J., Matsunami, N. et al. A high-density SNP genome-wide linkage scan in a large autism extended pedigree. Mol Psychiatry 14, 590–600 (2009). https://doi.org/10.1038/mp.2008.14
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DOI: https://doi.org/10.1038/mp.2008.14
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