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Dense linkage disequilibrium mapping in the 15q11–q13 maternal expression domain yields evidence for association in autism

Molecular Psychiatry volume 8, pages 624–634 (2003)Cite this article

Abstract

Autism [MIM 209850] is a neurodevelopmental disorder exhibiting a complex genetic etiology with clinical and locus heterogeneity. Chromosome 15q11–q13 has been proposed to harbor a gene for autism susceptibility based on (1) maternal-specific chromosomal duplications seen in autism and (2) positive evidence for linkage disequilibrium (LD) at 15q markers in chromosomally normal autism families. To investigate and localize a potential susceptibility variant, we developed a dense single nucleotide polymorphism (SNP) map of the maternal expression domain in proximal 15q. We analyzed 29 SNPs spanning the two known imprinted, maternally expressed genes in the interval (UBE3A and ATP10C) and putative imprinting control regions. With a marker coverage of 1/10 kb in coding regions and 1/15 kb in large 5′ introns, this map was employed to thoroughly dissect LD in autism families. Two SNPs within ATP10C demonstrated evidence for preferential allelic transmission to affected offspring. The signal detected at these SNPs was stronger in singleton families, and an adjacent SNP demonstrated transmission distortion in this subset. All SNPs showing allelic association lie within islands of sequence homology between human and mouse genomes that may be part of an ancestral haplotype containing a functional susceptibility allele. The region was further explored for recombination hot spots and haplotype blocks to evaluate haplotype transmission. Five haplotype blocks were defined within this region. One haplotype within ATP10C displayed suggestive evidence for preferential transmission. Interpretation of these data will require replication across data sets, evaluation of potential functional effects of associated alleles, and a thorough assessment of haplotype transmission within ATP10C and neighboring genes. Nevertheless, these findings are consistent with the presence of an autism susceptibility locus in 15q11–q13.

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References

  1. Fombonne E . The epidemiology of autism: a review. Psychol Med 1999; 29: 769–786.

    Article  CAS  PubMed  Google Scholar 

  2. Folstein S, Rutter M . Infantile autism: a genetic study of 21 twin pairs. J Child Psychol Psychiatry 1977; 18: 297–321.

    Article  CAS  PubMed  Google Scholar 

  3. 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.

    Article  CAS  PubMed  Google Scholar 

  4. Folstein SE, Piven J . Etiology of autism: genetic influences. Pediatrics 1991; 87: 767–773.

    CAS  PubMed  Google Scholar 

  5. 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.

    Article  CAS  PubMed  Google Scholar 

  6. Folstein S . Twin and adoption studies in child and adolescent psychiatric disorders. Curr Opin Pediatr 1996; 8: 339–347.

    Article  CAS  PubMed  Google Scholar 

  7. Ledbetter DH, Ballabio A . Molecular cytogenetics of contiguous gene syndromes: mechanisms and consequences of gene dosage imbalance. In: Scriver CR, Beaud et al, Sly WS, Valle D (eds). The Metabolic and Molecular Basis of Inherited Disease, 7th edn. McGraw Hill: New York, 1995, pp 811–839.

    Google Scholar 

  8. Jiang YH, Tsai TF, Bressler J, Beaud et al. Imprinting in Angelman and Prader–Willi Syndromes. Curr Opin Genet Dev 1998; 8: 334–342.

    Article  CAS  PubMed  Google Scholar 

  9. Browne CE, Dennis NR, Maher E, Long FL, Nicholson JC, Sillibourne J et al. Inherited interstitial duplications of proximal 15q-genotype-phenotype correlations. Am J Hum Genet 1997; 61: 1342–1352.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Cook Jr EH, Lindgren V, Leventhal BL, Courchesne R, Lincoln A, Shulman C et al. Autism or atypical autism in maternally but not paternally derived proximal 15q duplication. Am J Hum Genet 1997; 60: 928–934.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Mao R, Jalal SM, Snow K, Michels VV, Szabo SM, Babovic-Vuksanovic D . Characteristics of two cases with dup(15)(q11.2–12): one of maternal and one of paternal origin. Genet Med 2000; 2: 131–135.

    Article  CAS  PubMed  Google Scholar 

  12. Bolton PF, Dennis NR, Browne CE, Thomas NS, Veltman MW, Thompson RJ et al. The phenotypic manifestations of interstitial duplications of proximal 15q with special reference to the autistic spectrum disorders. Am J Med Genet 2001; 105: 675–685.

    Article  CAS  PubMed  Google Scholar 

  13. Robinson WP, Binkert F, Gine R, Vazquez C, Muller W, Rosenkranz W et al. Clinical and molecular analysis of five inv dup(15) patients. Eur J Hum Genet 1993; 1: 37–50.

    Article  CAS  PubMed  Google Scholar 

  14. Wolpert CM, Menold MM, Bass MP, Qumsiyeh MB, Donnelly SL, Ravan SA et al. Three probands with autistic disorder and isodicentric chromosome 15. Am J Med Genet 2000; 96: 365–372.

    Article  CAS  PubMed  Google Scholar 

  15. Borgatti R, Piccinelli P, Passoni D, Dalpra L, Miozzo M, Micheli R et al. Relationship between clinical and genetic features in ‘inverted duplicated chromosome 15’ patients. Pediatr Neurol 2001; 24: 111–116.

    Article  CAS  PubMed  Google Scholar 

  16. Nicholls RD, Gottlieb W, Russell LB, Davda M, Horsthemke B, Rinchik EM . Evaluation of potential models for imprinted and nonimprinted components of human chromosome 15q11–q13 syndromes by fine-structure homology mapping in the mouse. Proc Natl Acad Sci USA 1993; 90: 2050–2054.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Nicholls RD, Saitoh S, Horsthemke B . Imprinting in Prader–Willi and Angelman–Syndromes. Trends Genet 1998; 14: 194–200.

    Article  CAS  PubMed  Google Scholar 

  18. Nicholls RD, Knepper JL . Genome organization, function, and imprinting in Prader-Willi and Angelman syndromes. Ann Rev Genomics Human Genet 2001; 2: 153–175.

    Article  CAS  Google Scholar 

  19. Buiting K, Barnicoat A, Lich C, Pembrey M, Malcolm S, Horsthemke B . Disruption of the bipartite imprinting center in a family with Angelman syndrome. Am J Hum Genet 2001; 68: 1290–1294.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Chamberlain SJ, Brannan CI . The Prader–Willi syndrome imprinting center activates the paternally expressed murine Ube3a antisense transcript but represses paternal Ube3a. Genomics 2001; 73: 316–322.

    Article  CAS  PubMed  Google Scholar 

  21. Han MK, Bethi M, Nurmi EL, Butler MG, Sutcliffe JS . Methylation of the UBE3A CpG island does not mediate transcriptional repression of the paternal allele in brain. Am J Hum Genet 1999; 65: A273.

    Google Scholar 

  22. Runte M, Huttenhofer A, Gross S, Kiefmann M, Horsthemke B, Buiting K . The IC-SNURF-SNRPN transcript serves as a host for multiple small nucleolar RNA species and as an antisense RNA for UBE3A. Hum Mol Genet 2001; 10: 2687–2700.

    Article  CAS  PubMed  Google Scholar 

  23. Albrecht U, Sutcliffe JS, Cattanach BM, Beechey CV, Armstrong D, Eichele G et al. Imprinted expression of the murine Angelman syndrome gene, Ube3a, in hippocampal and Purkinje neurons. Nat Genet 1997; 17: 75–78.

    Article  CAS  PubMed  Google Scholar 

  24. Rougeulle C, Glatt H, Lalande M . The Angelman syndrome candidate gene, UBE3A/E6-AP, is imprinted in brain. Nat Genet 1997; 17: 14–15.

    Article  CAS  PubMed  Google Scholar 

  25. Meguro M, Kashiwagi A, Mitsuya K, Nakao M, Kondo I, Saitoh S et al. A novel maternally expressed gene, ATP10C, encodes a putative aminophospholipid translocase associated with Angelman syndrome. Nat Genet 2001; 28: 19–20.

    CAS  PubMed  Google Scholar 

  26. Herzing LB, Kim SJ, Cook Jr EH, Ledbetter DH . The human aminophospholipid-transporting ATPase gene ATP10C maps adjacent to UBE3A and exhibits similar imprinted expression. Am J Hum Genet 2001; 68: 1501–1505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Fang P, Lev-Lehman E, Tsai TF, Matsuura T, Benton CS, Sutcliffe JS et al. The spectrum of mutations in UBE3A causing Angelman syndrome. Hum Mol Genet 1999; 8: 129–135.

    Article  CAS  PubMed  Google Scholar 

  28. Halleck MS, Lawler JJ, Blackshaw S, Gao L, Nagarajan P, Hacker C et al. Differential expression of putative transbilayer amphipath transporters. Physiol Genomics 1999; 1: 139–150.

    Article  CAS  PubMed  Google Scholar 

  29. Ancans J, Tobin DJ, Hoogduijn MJ, Smit NP, Wakamatsu K, Thody AJ . Melanosomal pH controls rate of melanogenesis, eumelanin/phaeomelanin ratio and melanosome maturation in melanocytes and melanoma cells. Exp Cell Res 2001; 268: 26–35.

    Article  CAS  PubMed  Google Scholar 

  30. Bass MP, Menold MM, Wolpert CM, Donnelley SI, Ravan SA, Hauser ER et al. Genetic studies in autistic disorder and chromosome 15. Neurogenetics 2000; 2: 219–226.

    Article  CAS  PubMed  Google Scholar 

  31. 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.

    Article  PubMed  Google Scholar 

  32. 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.

    Article  CAS  PubMed  Google Scholar 

  33. Philippe A, Martinez M, Guilloud-Bataille M, Gillberg C, Rastam M, Sponheim E et al. Genome-wide scan for autism susceptibility genes. Hum Mol Genet 1999; 8: 805–812.

    Article  CAS  PubMed  Google Scholar 

  34. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. IMGSAC. A full genome screen for autism with evidence for linkage to a region on chromosome 7q. International Molecular Genetic Study of Autism Consortium. Hum Mol Genet 1998; 7: 571–578.

  36. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Cook EH, Courchesne RY, Cox NJ, Lord C, Gonen D, Guter SJ et al. Linkage–disequilibrium mapping of autistic disorder, With 15q11–13 Markers. Am J Hum Genet 1998; 62: 1077–1083.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Martin ER, Menold MM, Wolpert CM, Bass MP, Donnelly SL, Ravan SA et al. Analysis of linkage disequilibrium in gamma-aminobutyric acid receptor subunit genes in autistic disorder. Am J Med Genet 2000; 96: 43–48.

    Article  PubMed  Google Scholar 

  39. Buxbaum JD, Silverman JM, Smith CJ, Greenberg DA, Kilifarski M, Reichert J et al. Association between a GABRB3 polymorphism and autism. Mol Psychiatry 2002; 7: 311–316.

    Article  CAS  PubMed  Google Scholar 

  40. Salmon B, Hallmayer J, Rogers T, Kalaydjieva L, Petersen PB, Nicholas P et al. Absence of linkage and linkage disequilibrium to chromosome 15q11–q13 markers in 139 multiplex families with autism. Am J Med Genet 1999; 88: 551–556.

    Article  CAS  PubMed  Google Scholar 

  41. Maestrini E, Lai C, Marlow A, Matthews N, Wallace S, Bailey A et al. Serotonin transporter (5-HTT) and gamma-aminobutyric acid receptor subunit beta3 (GABRB3) gene polymorphisms are not associated with autism in the IMGSA families. The International Molecular Genetic Study of Autism Consortium. Am J Med Genet 1999; 88: 492–496.

    Article  CAS  PubMed  Google Scholar 

  42. Nurmi EL, Bradford Y, Chen Y, Hall J, Arnone B, Gardiner MB et al. Linkage disequilibrium at the Angelman syndrome gene UBE3A in autism families. Genomics 2001; 77: 105–113.

    Article  CAS  PubMed  Google Scholar 

  43. Labuda D, Krajinovic M, Richer C, Skoll A, Sinnett H, Yotova V et al. Rapid detection of CYP1A1, CYP2D6, and NAT variants by multiplex polymerase chain reaction and allele-specific oligonucleotide assay. Anal Biochem 1999; 275: 84–92.

    Article  CAS  PubMed  Google Scholar 

  44. Nordfors L, Jansson M, Sandberg G, Lavebratt C, Sengul S, Schalling M et al. Large-scale genotyping of single nucleotide polymorphisms by pyrosequencing and validation against the 5′nuclease Taqman assay. Hum Mutat 2002; 19: 395–401.

    Article  CAS  PubMed  Google Scholar 

  45. Hsu TM, Chen X, Duan S, Miller RD, Kwok PY . Universal SNP genotyping assay with fluorescence polarization detection. Biotechniques 2001; 31: 560, 562, 564–568, 570.

    Article  CAS  PubMed  Google Scholar 

  46. Sobel E, Lange K . Descent graphs in pedigree analysis: applications to haplotyping, location scores, and marker-sharing statistics. Am J Hum Genet 1996; 58: 1323–1337.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Abecasis GR, Cookson WO . GOLD—graphical overview of linkage disequilibrium. Bioinformatics 2000; 16: 182–183.

    Article  CAS  PubMed  Google Scholar 

  48. Martin ER, Kaplan NL, Weir BS . Tests for linkage and association in nuclear families. Am J Hum Genet 1997; 61: 439–448.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Martin ER, Monks SA, Warren LL, Kaplan NL . A test for linkage and association in general pedigrees: the pedigree disequilibrium test. Am J Hum Genet 2000; 67: 146–154.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Clayton D . A generalization of the transmission/disequilibrium test for uncertain-haplotype transmission. Am J Hum Genet 1999; 65: 1170–1177.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Dubchak I, Brudno M, Loots GG, Pachter L, Mayor C, Rubin EM et al. Active conservation of noncoding sequences revealed by three-way species comparisons. Genome Res 2000; 10: 1304–1306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Mayor C, Brudno M, Schwartz JR, Poliakov A, Rubin EM, Frazer KA et al. VISTA: visualizing global DNA sequence alignments of arbitrary length. Bioinformatics 2000; 16: 1046–1047.

    Article  CAS  PubMed  Google Scholar 

  53. Risch N, Merikangas K . The future of genetic studies of complex human diseases. Science 1996; 273: 1516–1517.

    Article  CAS  PubMed  Google Scholar 

  54. Risch NJ . Searching for genetic determinants in the new millennium. Nature 2000; 405: 847–856.

    Article  CAS  PubMed  Google Scholar 

  55. Rioux JD, Daly MJ, Silverberg MS, Lindblad K, Steinhart H, Cohen Z et al. Genetic variation in the 5q31 cytokine gene cluster confers susceptibility to Crohn disease. Nat Genet 2001; 29: 223–228.

    Article  CAS  PubMed  Google Scholar 

  56. Collins FS, Guyer MS, Charkravarti A . Variations on a theme: cataloging human DNA sequence variation. Science 1997; 278: 1580–1581.

    Article  CAS  PubMed  Google Scholar 

  57. Kruglyak L . Prospects for whole-genome linkage disequilibrium mapping of common disease genes. Nat Genet 1999; 22: 139–144.

    Article  CAS  PubMed  Google Scholar 

  58. Boehnke M . A look at linkage disequilibrium. Nat Genet 2000; 25: 246–247.

    Article  CAS  PubMed  Google Scholar 

  59. Pritchard JK, Przeworski M . Linkage disequilibrium in humans: models and data. Am J Hum Genet 2001; 69: 1–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Hewett D, Samuelsson L, Polding J, Enlund F, Smart D, Cantone K et al. Identification of a psoriasis susceptibility candidate gene by linkage disequilibrium mapping with a localized single nucleotide polymorphism map. Genomics 2002; 79: 305–314.

    Article  CAS  PubMed  Google Scholar 

  61. Kim SJ, Herzing LB, Veenstra-VanderWeele J, Lord C, Courchesne R, Leventhal BL et al. Mutation screening and transmission disequilibrium study of ATP10C in autism. Am J Med Genet 2002; 114: 137–143.

    Article  PubMed  Google Scholar 

  62. Ardlie KG, Kruglyak L, Seielstad M . Patterns of linkage disequilibrium in the human genome. Nat Rev Genet 2002; 3: 299–309.

    Article  CAS  PubMed  Google Scholar 

  63. Tabor HK, Risch N, Myers RM . Candidate-gene approaches for studying complex genetic traits: practical considerations. Nat Rev Genet 2002; 3: 1–7.

    Article  Google Scholar 

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Acknowledgements

This work was supported by an award from the National Alliance for Autism Research and NIH grant MH61009 to JSS and grant MH55135 to SEF. ELN is supported by the Medical Scientist Training Program at VU. Grant MH55284 to Joseph Piven supported recruitment of the 27 singelton families through the University of Iowa CLSA site. We acknowledge the contributions of the Vanderbilt Program in Human Genetics DNA Resources Core in providing materials for this study.

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Authors and Affiliations

  1. Department of Molecular Physiology and Biophysics, Program in Human Genetics, Vanderbilt University, Nashville, TN, USA

    E L Nurmi, T Amin, L M Olson, J L McCauley, A Y Lam, E L Organ, J L Haines & J S Sutcliffe

  2. Center for Molecular Neuroscience, Vanderbilt University, Nashville, TN, USA

    E L Nurmi, M M Jacobs, J L Haines & J S Sutcliffe

  3. Department of Psychiatry, Tufts University School of Medicine and New England Medical Center, Boston, MA, USA

    S E Folstein

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  1. E L Nurmi
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Nurmi, E., Amin, T., Olson, L. et al. Dense linkage disequilibrium mapping in the 15q11–q13 maternal expression domain yields evidence for association in autism. Mol Psychiatry 8, 624–634 (2003). https://doi.org/10.1038/sj.mp.4001283

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