Abstract
Autism is a common neurodevelopmental disorder with a significant genetic component and locus heterogeneity. To date, 12 microsatellite genome screens have been performed using various data sets of sib-pair families (parents and affected children) resulting in numerous regions of potential linkage across the genome. However, no universal region or consistent candidate gene from these regions has emerged. The use of large, extended pedigrees is a recognized powerful approach to identify significant linkage results, as these families potentially contain more potential linkage information than sib-pair families. A genome-wide linkage analysis was performed on 26 extended autism families (65 affected, 184 total individuals). Each family had two to four affected individuals comprised of either avuncular or cousin pairs. For analysis, we used a high-density single-nucleotide polymorphism genotyping assay, the Affymetrix GeneChip Human Mapping 10K array. Two-point analysis gave peak heterogeneity limit of detection (HLOD) of 2.82 at rs2877739 on chromosome 14q. Suggestive linkage evidence (HLOD>2) from a two-point analysis was also found on chromosomes 1q, 2q, 5q, 6p,11q and 12q. Chromosome 12q was the only region showing significant linkage evidence by multipoint analysis with a peak HLOD=3.02 at rs1445442. In addition, this linkage evidence was enhanced significantly in the families with only male affected (multipoint HLOD=4.51), suggesting a significant gender-specific effect in the etiology of autism. Chromosome-wide haplotype analyses on chromosome 12 localized the potential autism gene to a 4 cM region shared among the affected individuals across linked families. This novel linkage peak on chromosome 12q further supports the hypothesis of substantial locus heterogeneity in autism.
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References
Yeargin-Allsopp M, Rice C, Karapurkar T, Doernberg N, Boyle C, Murphy C . Prevalence of autism in a US metropolitan area. JAMA 2003; 289: 49–55.
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.
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.
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 Allied Disciplines 1994; 35: 877–900.
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.
Folstein SE, Rosen-Sheidley B . Genetics of autism: complex aetiology for a heterogeneous disorder. Nat Rev Genet 2001; 2: 943–955.
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.
Pritchard JK . Are rare variants responsible for susceptibility to complex diseases? Am J Hum Genet 2001; 69: 124–137.
International Molecular Genetic Study of Autism Consortium. A full genome screen for autism with evidence for linkage to a region on chromosome 7q. Hum Mol Genet 1998; 7: 571–578.
International Molecular Genetic Study of Autism Consortium. A genomewide screen for autism: strong evidence for linkage to chromosomes 2q, 7q, and 16p. Am J Hum Genet 2001; 69: 570–581.
Collaborative Linkage Study of Autism. An autosomal genomic screen for autism. Am J Med Genet 2001; 105: 609–615.
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.
Meyers RM, Risch N, Spiker D, Lotspeich L . A full genome screen for susceptibility genes to autism by linkage analysis in ninety multiplex families. Am J Hum Genet 1998; 63: A302.
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.
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.
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.
Yonan AL, Alarcon M, Cheng R, Magnusson PKE, Spence SJ, Palmer AA et al. A genomewide screen of 345 families for autism-susceptibility loci. Am J Hum Genet 2003; 73: 886–897.
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.
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.
Santangelo SL, Tsatsanis K . What is known about autism: genes, brain, and behavior. Am J Pharmacogenomics 2005; 5: 71–92.
Ott J . Analysis of Human Genetic Linkage, 1st edn. The Johns Hopkins University Press: Baltimore, 1985.
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.
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.
Buxbaum JD, Silverman J, Keddache M, Smith CJ, Hollander E, Ramoz N et al. Linkage analysis for autism in a subset families with obsessive-compulsive behaviors: evidence for an autism susceptibility gene on chromosome 1 and further support for susceptibility genes on chromosome 6 and 19. Mol Psychiatry 2004; 9: 144–150.
Buxbaum J . The genetics of autism spectrum disorders. Medscape: Psychiatry and Mental Health 10(2). 12-29-2005.
Terwilliger JD, Goring HH . Gene mapping in the 20th and 21st centuries: statistical methods, data analysis and experimental design. Hum Biol 2000; 72: 63–132.
Hodge SE . Do bilineal pedigrees represent a problem for linkage analysis? Basic principles and simulation results for single-gene diseases with no heterogeneity. Genet Epidemiol 1992; 9: 191–206.
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.
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.
Middleton FA, Pato MT, Gentile KL, Morley CP, Zhao X, Eisener AF et al. Genomewide linkage analysis of bipolar disorder by use of a high-density single-nucleotide-polymorphism (SNP) genotyping assay: a comparison with microsatellite marker assays and finding of significant linkage to chromosome 6q22. Am J Hum Genet 2004; 74: 886–897.
Sawcer SJ, Maranian M, Singlehurst S, Yeo T, Compston A, Daly MJ et al. Enhancing linkage analysis of complex disorders: an evaluation of high-density genotyping. Hum Mol Genet 2004; 13: 1943–1949.
Sawcer S, Ban M, Maranian M, Yeo TW, Compston A, Kirby A et al. A high-density screen for linkage in multiple sclerosis –International multiple sclerosis genetics consortium. Am J Hum Genet 2005; 77: 454–467.
Lord C, Pickles A, McLennan J, Rutter M, Bregman J, Folstein S et al. Diagnosing autism: analyses of data from the Autism Diagnostic Interview. J Autism Dev Disord 1997; 27: 501–517.
Rutter M, LeCouteur A, Lord C . Autism Diagnostic Interview, Revised (ADI-R). Western Psychological Services: Los Angeles, CA, 2003.
Sparrow SS, Balla D, Cicchetti D . Vineland Adaptive Behavior Scales, Interview edn. AGS Publishing: Circle Pines, MN, 1984.
O'Connell JR, Weeks DE . PedCheck: a program for identification of genotype incompatibilities in linkage analysis. Am J Hum Genet 1998; 63: 259–266.
Epstein MP, Duren WL, Boehnke M . Improved inference of relationship for pairs of individuals. Am J Hum Genet 2000; 67: 1219–1231.
Boehnke M, Cox NJ . Accurate inference of relationships in sib-pair linkage studies. Am J Hum Genet 1997; 61: 423–429.
Lathrop GM, Lalouel JM, Julier C, Ott J . Strategies for multilocus linkage analysis in humans. Proc Natl Acad Sci USA 1984; 81: 3443–3446.
Schaffer AA, Gupta SK, Shriram K, Cottingham RW . Avoiding recomputation in linkage analysis. Hum Hered 1994; 44: 225–237.
Ott J . Linkage analysis and family classification under heterogeneity. Ann Hum Genet 1983; 47 (Part 4): 311–320.
Abecasis GR, Cherny SS, Cookson WO, Cardon LR . Merlin – rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 2002; 30: 97–101.
Abecasis GR, Wigginton JE . Handling marker-marker linkage disequilibrium: pedigree analysis with clustered markers. Am J Hum Genet 2005; 77: 754–767.
Abecasis GR, Cherny SS, Cookson WO, Cardon LR . Merlin – rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 2002; 30: 97–101.
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.
Xu H, Gregory SG, Hauser ER, Stenger JE, Pericak-Vance MA, Vance JM, Zuchner S, Hauser MA . SNP selector: a web tool for selecting SNPs for genetic association studies. Bioinformatics 2005; 21: 4181–4186.
Kong A, Gudbjartsson DF, Sainz J, Jonsdottir GM, Gudjonsson SA, Richardsson B et al. A high-resolution recombination map of the human genome. Nat Genet 2002; 31: 241–247.
Broman KW . Estimation of allele frequencies with data on sibships. Genet Epidemiol 2001; 20: 307–315.
Whittemore AS, Halpern J . A class of tests for linkage using affected pedigree members. Biometrics 1994; 50: 118–127.
McPeek MS, Strahs A . Assignment of linkage disequilibrium by the decay of haplotype sharing with application to fine-scale genetic mapping. Am J Hum Genet 1999; 65: 858–875.
Ott J . Analysis of Human Genetic Linkage, 3rd edn. The Johns Hopkins University Press: Baltimore, Maryland, 1999.
Lander E, Kruglyak L . Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 1995; 11: 241–247.
Kruglyak L, Daly MJ . Linkage thresholds for two-stage genome scans. Am J Hum Genet 1998; 62: 994–997.
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.
Baron M . Optimal ascertainment strategies to detect linkage to common disease alleles. Am J Hum Genet 1999; 64: 1243–1248.
Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 1993; 261: 921–923.
Namjou B, Nath SK, Kilpatrick J, Kelly JA, Reid J, James JA et al. Stratification of pedigrees multiplex for systemic lupus erythematosus and for self-reported rheumatoid arthritis detects a systemic lupus erythematosus susceptibility gene (SLER1) at 5p15.3. Arthritis Rheum 2002; 46: 2937–2945.
Kim SJ, Young LJ, Gonen D, Veenstra-VanderWeele J, Courchesne R, Courchesne E et al. Transmission disequilibrium testing of arginine vasopressin receptor 1A (AVPR1A) polymorphisms in autism. Mol Psychiatry 2002; 7: 503–507.
Wassink TH, Brzustowicz LM, Bartlett CW, Szatmari P . The search for autism disease genes. Ment Retard Dev Disabil Res Rev 2004; 10: 272–283.
Acknowledgements
We thank the patients with autism, and the family members who agreed to participate in this study, as well as the personnel of the CHG at DUMC, for their input on this project. We also thank Drs Robert Delong and Gordon Worley for referring patients and their families to the study. We thank the Translational Genomics Research Institute (TGen) for their generosity and effort in performing the Affymetrix chip assays. This research was supported, in part, by National Institutes of Health (NIH) program project Grant NS26630, and Grants R01 NS36768, R01 AG20135 and R01 NS42165; by the National Alliance of Autism Research (NAAR); and by a gift from the Hussman Foundation. The research conducted in this study complies with current US laws. We also gratefully acknowledge the resources provided by the AGRE consortium and the participating Autism Genetic Resource Exchange (AGRE) families. The AGRE is a program of Cure Autism Now (CAN). This work used the core resources of the GCRC (MO1 RR-00095) and the CHGR at VUMC and the CHG at DUMC.
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Ma, D., Cuccaro, M., Jaworski, J. et al. Dissecting the locus heterogeneity of autism: significant linkage to chromosome 12q14. Mol Psychiatry 12, 376–384 (2007). https://doi.org/10.1038/sj.mp.4001927
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DOI: https://doi.org/10.1038/sj.mp.4001927
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