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Table of Contents
Vol. 70, No. 4, 2010
Issue release date: February 2011
Section title: Original Paper
Open Access Gateway
Hum Hered 2010;70:232–244

Increasing Genotype-Phenotype Model Determinism: Application to Bivariate Reading/Language Traits and Epistatic Interactions in Language-Impaired Families

Simmons T.R.a · Flax J.F.b, c · Azaro M.A.c · Hayter J.E.c · Justice L.M.d · Petrill S.A.e · Bassett A.S.f · Tallal P.b · Brzustowicz L.M.c · Bartlett C.W.a
aBattelle Center for Mathematical Medicine, Research Institute at Nationwide Children’s Hospital and Department of Pediatrics, Ohio State University, Columbus, Ohio, bCenter for Molecular and Behavioral Neuroscience, Rutgers University, Newark, N.J., cDepartment of Genetics, Rutgers University, Piscataway, N.J., dSchool of Teaching and Learning and eDepartment of Human Development and Family Science, Ohio State University, Columbus, Ohio, USA; fDepartment of Psychiatry, University of Toronto, and Schizophrenia Research Program, Queen Street Division, Centre for Addiction and Mental Health, Toronto, Ont., Canada
email Corresponding Author

Assistant Prof. Christopher W. Bartlett, PhD, Battelle Center for

Mathematical Medicine, Research Institute at Nationwide Children’s Hospital and Ohio State University, JW3926, 700 Children’s Drive, Columbus, OH 43205 (USA)

Tel. +1 614 722 2688, Fax +1 614 355 2728



  1. Risch N: Linkage strategies for genetically complex traits. Ii. The power of affected relative pairs. Am J Hum Genet 1990;46:229–241.
  2. Tomblin JB, Records NL, Buckwalter P, Zhang X, Smith E, O’Brien M: Prevalence of specific language impairment in kindergarten children. J Speech Lang Hear Res 1997;40:1245–1260.
  3. Dale PS, Price TS, Bishop DV, Plomin R: Outcomes of early language delay: I. Predicting persistent and transient language difficulties at 3 and 4 years. J Speech Lang Hear Res 2003;46:544–560.
  4. Snowling M, Bishop DV, Stothard SE: Is preschool language impairment a risk factor for dyslexia in adolescence? J Child Psychol Psychiatry 2000;41:587–600.
  5. Whitehouse AJ, Line EA, Watt HJ, Bishop DV: Qualitative aspects of developmental language impairment relate to language and literacy outcome in adulthood. Int J Lang Commun Disord 2009:1–22.
  6. Leonard LB: Children with specific language impairment. Cambridge, MA, MIT Press, 1998.
  7. Tallal P, Piercy M: Defects of non-verbal auditory perception in children with developmental aphasia. Nature 1973;241:468–469.
  8. Tallal P, Piercy M: Developmental aphasia: impaired rate of non-verbal processing as a function of sensory modality. Neuropsychologia 1973;11:389–398.
  9. Wright BA, Lombardino LJ, King WM, Puranik CS, Leonard CM, Merzenich MM: Deficits in auditory temporal and spectral resolution in language-impaired children. Nature 1997;387:176–178.
  10. Wright BA, Bowen RW, Zecker SG: Nonlinguistic perceptual deficits associated with reading and language disorders. Curr Opin Neurobiol 2000;10:482–486.
  11. Witton C, Stein JF, Stoodley CJ, Rosner BS, Talcott JB: Separate influences of acoustic am and fm sensitivity on the phonological decoding skills of impaired and normal readers. J Cogn Neurosci 2002;14:866–874.
  12. Talcott JB, Witton C, McClean M, Hansen PC, Rees A, Green GG, Stein JF: Can sensitivity to auditory frequency modulation predict children’s phonological and reading skills? Neuroreport 1999;10:2045–2050.
  13. Witton C, Talcott JB, Hansen PC, Richardson AJ, Griffiths TD, Rees A, Stein JF, Green GG: Sensitivity to dynamic auditory and visual stimuli predicts nonword reading ability in both dyslexic and normal readers. Curr Biol 1998;8:791–797.
  14. Snowling MJ, Bishop DV, Stothard SE, Chipchase B, Kaplan C: Psychosocial outcomes at 15 years of children with a preschool history of speech-language impairment. J Child Psychol Psychiatry 2006;47:759–765.
  15. Reed MA: Speech perception and the discrimination of brief auditory cues in reading disabled children. J Exp Child Psychol 1989;48:270–292.
  16. Catts HW, Bridges MS, Little TD, Tomblin JB: Reading achievement growth in children with language impairments. J Speech Lang Hear Res 2008;51:1569–1579.
  17. Catts HW, Fey ME, Tomblin JB, Zhang X: A longitudinal investigation of reading outcomes in children with language impairments. J Speech Lang Hear Res 2002;45:1142–1157.
  18. Catts HW, Fey ME, Proctor-Williams K: The relationship between language and reading. Preliminary results from a longitudinal investigation. Logoped Phoniatr Vocol 2000;25:3–11.
  19. Catts HW: The relationship between speech-language impairments and reading disabilities. J Speech Hear Res 1993;36:948–958.
  20. Rice ML, Haney KR, Wexler K: Family histories of children with sli who show extended optional infinitives. J Speech Lang Hear Res 1998;41:419–432.
  21. Tallal P, Hirsch LS, Realpe-Bonilla T, Miller S, Brzustowicz LM, Bartlett C, Flax JF: Familial aggregation in specific language impairment. J Speech Lang Hear Res 2001;44:1172–1182.
  22. Tallal P, Ross R, Curtiss S: Familial aggregation in specific language impairment. J Speech Hear Disord 1989;54:167–173.
  23. Tomblin JB: Familial concentration of developmental language impairment. J Speech Hear Disord 1989;54:287–295.
  24. Van der Lely HK, Stollwerck L: A grammatical specific language impairment in children: an autosomal dominant inheritance? Brain Lang 1996;52:484–504.
  25. Bishop DV, North T, Donlan C: Genetic basis of specific language impairment: evidence from a twin study. Dev Med Child Neurol 1995;37:56–71.
  26. Tomblin JB, Buckwalter PR: Heritability of poor language achievement among twins. J Speech Lang Hear Res 1998;41:188–199.
  27. DeThorne LS, Petrill SA, Hayiou-Thomas ME, Plomin R: Low expressive vocabulary: higher heritability as a function of more severe cases. J Speech Lang Hear Res 2005;48:792–804.
  28. Bishop DV: The role of genes in the etiology of specific language impairment. J Commun Disord 2002;35:311–328.
  29. Kovas Y, Hayiou-Thomas ME, Oliver B, Dale PS, Bishop DV, Plomin R: Genetic influences in different aspects of language development: the etiology of language skills in 4.5-year-old twins. Child Dev 2005;76:632–651.
  30. Colledge E, Bishop DV, Koeppen-Schomerus G, Price TS, Happe FG, Eley TC, Dale PS, Plomin R: The structure of language abilities at 4 years: a twin study. Dev Psychol 2002;38:749–757.
  31. Bartlett CW, Flax JF, Logue MW, Smith BJ, Vieland VJ, Tallal P, Brzustowicz LM: Examination of potential overlap in autism and language loci on chromosomes 2, 7, and 13 in two independent samples ascertained for specific language impairment. Hum Hered 2004;57:10–20.
  32. Bartlett CW, Flax JF, Logue MW, Vieland VJ, Bassett AS, Tallal P, Brzustowicz LM: A major susceptibility locus for specific language impairment is located on 13q21. Am J Hum Genet 2002;71:45–55.
  33. The SLI Consortium: A genomewide scan identifies two novel loci involved in specific language impairment. Am J Hum Genet 2002;70:384–398.
  34. The SLI Consortium: Highly significant linkage to the sli1 locus in an expanded sample of individuals affected by specific language impairment. Am J Hum Genet 2004;74:1225–1238.
  35. Monaco AP: Multivariate linkage analysis of specific language impairment (sli). Ann Hum Genet 2007;71:660–673.
  36. Newbury DF, Winchester L, Addis L, Paracchini S, Buckingham LL, Clark A, Cohen W, Cowie H, Dworzynski K, Everitt A, Goodyer IM, Hennessy E, Kindley AD, Miller LL, Nasir J, O’Hare A, Shaw D, Simkin Z, Simonoff E, Slonims V, Watson J, Ragoussis J, Fisher SE, Seckl JR, Helms PJ, Bolton PF, Pickles A, Conti-Ramsden G, Baird G, Bishop DV, Monaco AP: Cmip and atp2c2 modulate phonological short-term memory in language impairment. Am J Hum Genet 2009;85:264– 272.
  37. Vernes SC, Newbury DF, Abrahams BS, Winchester L, Nicod J, Groszer M, Alarcon M, Oliver PL, Davies KE, Geschwind DH, Monaco AP, Fisher SE: A functional genetic link between distinct developmental language disorders. N Engl J Med 2008;359:2337–2345.
  38. Lai CS, Fisher SE, Hurst JA, Vargha-Khadem F, Monaco AP: A forkhead-domain gene is mutated in a severe speech and language disorder. Nature 2001;413:519–523.
  39. Lai CS, Gerrelli D, Monaco AP, Fisher SE, Copp AJ: Foxp2 expression during brain development coincides with adult sites of pathology in a severe speech and language disorder. Brain 2003;126:1120–1127.

    External Resources

  40. MacDermot KD, Bonora E, Sykes N, Coupe AM, Lai CS, Vernes SC, Vargha-Khadem F, McKenzie F, Smith RL, Monaco AP, Fisher SE: Identification of foxp2 truncation as a novel cause of developmental speech and language deficits. Am J Hum Genet 2005;76:1074–1080.
  41. Meaburn E, Dale PS, Craig IW, Plomin R: Language-impaired children: no sign of the foxp2 mutation. Neuroreport 2002;13:1075–1077.
  42. Newbury DF, Bonora E, Lamb JA, Fisher SE, Lai CS, Baird G, Jannoun L, Slonims V, Stott CM, Merricks MJ, Bolton PF, Bailey AJ, Monaco AP: Foxp2 is not a major susceptibility gene for autism or specific language impairment. Am J Hum Genet 2002;70:1318–1327.
  43. Vernes SC, Macdermot KD, Monaco AP, Fisher SE: Assessing the impact of FOXP1 mutations on developmental verbal dyspraxia. Eur J Hum Genet 2009;17:1354–1358.
  44. De Thorne LS, Hart SA, Petrill SA, Deater-Deckard K, Thompson LA, Schatschneider C, Davison MD: Children’s history of speech-language difficulties: Genetic influences and associations with reading-related measures. J Speech Lang Hear Res 2006;49:1280–1293.
  45. Bartlett CW, Vieland VJ: Two novel quantitative trait linkage analysis statistics based on the posterior probability of linkage: application to the coga families. BMC Genet 2005;6(suppl 1):S121.
  46. Vieland VJ, Huang Y, Bartlett C, Davies TF, Tomer Y: A multilocus model of the genetic architecture of autoimmune thyroid disorder, with clinical implications. Am J Hum Genet 2008;82:1349–1356.
  47. Vieland VJ, Huang J: Reply to Cordell and Farrall. Am J Hum Genet 2003;73:1471–1473.
  48. Vieland VJ, Huang J: Two-locus heterogeneity cannot be distinguished from two-locus epistasis on the basis of affected-sib-pair data. Am J Hum Genet 2003;73:223–232.
  49. Simmons TR, Weaver PJ, Andrews-Bryant T, Flax JF, Tallal P, Bartlett CW, Brzustowicz LM: Multivariate genetic analysis of specific language impairment (sli) in extended pedigrees: the relationship between reading and language measures on 13q21: American Society of Human Genetics. Philadelphia, Pennsylvania, 2008, Abstract program number 1830.
  50. Hariri AR, Goldberg TE, Mattay VS, Kolachana BS, Callicott JH, Egan MF, Weinberger DR: Brain-derived neurotrophic factor val66met polymorphism affects human memory-related hippocampal activity and predicts memory performance. J Neurosci 2003;23:6690–6694.
  51. Tyler WJ, Alonso M, Bramham CR, Pozzo-Miller LD: From acquisition to consolidation: on the role of brain-derived neurotrophic factor signaling in hippocampal- dependent learning. Learn Mem 2002;9:224–237.
  52. Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A, Zaitsev E, Gold B, Goldman D, Dean M, Lu B, Weinberger DR: The bdnf val66met polymorphism affects activity-dependent secretion of bdnf and human memory and hippocampal function. Cell 2003;112:257–269.
  53. Komulainen P, Pedersen M, Hanninen T, Bruunsgaard H, Lakka TA, Kivipelto M, Hassinen M, Rauramaa TH, Pedersen BK, Rauramaa R: BDNF is a novel marker of cognitive function in ageing women: the DR’s EXTRA study. Neurobiol Learn Mem 2008;90:596–603.
  54. Miyajima F, Ollier W, Mayes A, Jackson A, Thacker N, Rabbitt P, Pendleton N, Horan M, Payton A: Brain-derived neurotrophic factor polymorphism val66met influences cognitive abilities in the elderly. Genes Brain Behav 2008;7:411–417.
  55. Hammil DD, Brown VL, Larsen SC, Wiederhold JL: Test of adolescent language-2. Austin, TX, Pro-Ed, 1987.
  56. Hammil DD, Newcomer PL: Test of language development-2, intermediate. Austin, TX, Pro-Ed, 1988.
  57. Newcomer PL, Hammil DD: Test of language development-2, primary. Austin, TX, Pro-Ed, 1988.
  58. Wechsler D: Wechsler intelligence scale for children-revised. San Antonio, TX, The Psychological Corporation, 1974.
  59. Wechsler D: Wechsler adult intelligence scale-revised. San Antonio, TX, The Psychological Corporation, 1981.
  60. Wechsler D: Wechsler pre-school and primary scale of intelligence -revised. San Antonio, TX, The Psychological Corporation, 1989.
  61. Wechsler D: Wechsler abrreviated scale of intelligence. San Antonio, TX, The Psychological Corporation, 1999.
  62. Woodcock RW: Woodcock reading mastery tests-revised. Minnesota, American Guidance Service, Inc., 1987.
  63. The International HapMap Consortium: The international hapmap project. Nature 2003;426:789–796.
  64. Sherry ST, Ward MH, Kholodov M, Baker J, Phan L, Smigielski EM, Sirotkin K: Dbsnp: The NCBI database of genetic variation. Nucleic Acids Research 2001;29:308–311.
  65. Kuhn RM, Karolchik D, Zweig AS, Wang T, Smith KE, Rosenbloom KR, Rhead B, Raney BJ, Pohl A, Pheasant M, Meyer L, Hsu F, Hinrichs AS, Harte RA, Giardine B, Fujita P, Diekhans M, Dreszer T, Clawson H, Barber GP, Haussler D, Kent WJ: The UCSC genome browser database: Update 2009. Nucleic Acids Res 2009;37:D755–D761.
  66. Kong X, Murphy K, Raj T, He C, White PS, Matise TC: A combined linkage-physical map of the human genome. Am J Hum Genet 2004;75:1143–1148.
  67. Bruse S, Moreau M, Azaro M, Zimmerman R, Brzustowicz L: Improvements to bead-based oligonucleotide ligation SNP genotyping assays. Biotechniques 2008;45:559–571.
  68. O’Connell JR, Weeks DE: Pedcheck: a program for identifying genotype incompatibilities in linkage analysis. Am J Hum Genet 1997;63:259–266.
  69. Sobel E, Sengul H, Weeks DE: Multipoint estimation of identity-by-descent probabilities at arbitrary positions among marker loci on general pedigrees. Hum Hered 2001;52:121–131.
  70. 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.
  71. Sobel E, Papp JC, Lange K: Detection and integration of genotyping errors in statistical genetics. Am J Hum Genet 2002;70:496–508.
  72. Mukhopadhyay N, Almasy L, Schroeder M, Mulvihill WP, Weeks DE: Mega2, a data-handling program for facilitating genetic linkage and association analyses. Am J Hum Genet 1999;65:A436.

    External Resources

  73. Wigginton JE, Abecasis GR: Pedstats: descriptive statistics, graphics and quality assessment for gene mapping data. Bioinformatics 2005;21:3445–3447.
  74. 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.
  75. Govil M, Segre AM, Vieland VJ: Mlip: Using multiple processors to compute the posterior probability of linkage. BMC Bioinformatics 2008;9(suppl 6):S2.
  76. Seok SC, Evans M, Vieland VJ: Fast and accurate calculation of a computationally intensive statistic for mapping disease genes. J Comput Biol 2009;16:659–676.
  77. Wang K, Huang J, Vieland VJ: The consistency of the posterior probability of linkage. Ann Hum Genet 2000;64:533–553.
  78. Huang J, Vieland VJ: Comparison of ‘model-free’ and ‘model-based’ linkage statistics in the presence of locus heterogeneity: single data set and multiple data set applications. Human Heredity 2001;51:217–225.
  79. Vieland VJ, Wang K, Huang J: Power to detect linkage based on multiple sets of data in the presence of locus heterogeneity: comparative evaluation of model-based linkage methods for affected sib pair data. Hum Hered 2001;51:199–208.
  80. Logue MW, Vieland VJ: A new method for computing the multipoint posterior probability of linkage. Hum Hered 2004;57:90–99.
  81. Yang X, Huang J, Logue MW, Vieland VJ: The posterior probability of linkage allowing for linkage disequilibrium and a new estimate of disequilibrium between a trait and a marker. Hum Hered 2005;59:210–219.
  82. Bartlett CW, Vieland VJ: Accumulating quantitative trait linkage evidence across multiple datasets using the posterior probability of linkage. Genet Epidemiol 2007;31:91–102.
  83. Huang Y, Bartlett CW, Segre AM, O’Connell JR, Mangin L, Vieland VJ: Exploiting gene ×gene interaction in linkage analysis. BMC Proc 2007;1 Suppl 1:S64.
  84. Logue M, Vieland VJ, Goedken R, Crowe R: Bayesian analysis of a previously published genome screen for panic disorder reveals new and compelling evidence for linkage to chromsome 7. Am J Med Genet B (Neuropsychiat Genet) 2003;121B:95–99.
  85. Bartlett CW, Vieland VJ, Bartlett J, Bell JT, Bhattacharjee S, Clerget-Darpoux F, Bush WS, Edwards TL, Gao G, Halder I, Huang Y, Kotti S, Larkin EK, Li H, Motsinger AA, Mukhopadhyay N, Namkung J, Park T, Ritchie MD, Stein CM, Zhou JY: Discussing gene-gene interaction: warning – translating equations to English may result in jabberwocky. Genet Epidemiol 2007;31 Suppl 1:S61–67.
  86. Vieland VJ: Bayesian linkage analysis, or: how I learned to stop worrying and love the posterior probability of linkage. Am J Hum Genet 1998;63:947–954.
  87. Logue MW, Vieland VJ, Goedken RJ, Crowe RR: Bayesian analysis of a previously published genome screen for panic disorder reveals new and compelling evidence for linkage to chromosome 7. Am J Med Genet B Neuropsychiatr Genet 2003;121B:95–99.
  88. Baddeley A: Working memory and language: an overview. J Commun Disord 2003;36:189–208.
  89. Harlaar N, Hayiou-Thomas ME, Dale PS, Plomin R: Why do preschool language abilities correlate with later reading? A twin study. J Speech Lang Hear Res 2008;51:688–705.
  90. Bailey PJ, Snowling MJ: Auditory processing and the development of language and literacy. Br Med Bull 2002;63:135–146.
  91. Bishop DV, Snowling MJ: Developmental dyslexia and specific language impairment: same or different? Psychol Bull 2004;130:858–886.
  92. Larkin RF, Snowling MJ: Comparing phonological skills and spelling abilities in children with reading and language impairments. Int J Lang Commun Disord 2008;43:111–124.
  93. Chen ZY, Jing D, Bath KG, Ieraci A, Khan T, Siao CJ, Herrera DG, Toth M, Yang C, McEwen BS, Hempstead BL, Lee FS: Genetic variant BDNF (val66met) polymorphism alters anxiety-related behavior. Science 2006;314:140–143.
  94. Newbury DF, Bishop DV, Monaco AP: Genetic influences on language impairment and phonological short-term memory. Trends Cogn Sci 2005;9:528–534.
  95. Tallal P: Improving language and literacy is a matter of time. Nat Rev Neurosci 2004;5:721–728.
  96. Catts H, Adlorf S, Weismer S: Language deficits in poor comprehenders: a case for the simple view of reading. J Speech Hear Res 2006;49:278–293.

    External Resources

  97. Catts HW, Adlof SM, Hogan TP, Weismer SE: Are specific language impairment and dyslexia distinct disorders? J Speech Lang Hear Res 2005;48:1378–1396.
  98. Archibald LM, Gathercole SE: Short-term and working memory in specific language impairment. Int J Lang Commun Disord 2006;41:675–693.
  99. Baddeley A, Wilson BA: A developmental deficit in short-term phonological memory: implications for language and reading. Memory 1993;1:65–78.
  100. Leonard LB, Ellis Weismer S, Miller CA, Francis DJ, Tomblin JB, Kail RV: Speed of processing, working memory, and language impairment in children. J Speech Lang Hear Res 2007;50:408–428.
  101. Montgomery JW, Evans JL: Complex sentence comprehension and working memory in children with specific language impairment. J Speech Lang Hear Res 2009;52:269–288.
  102. Brzustowicz LM, Hodgkinson KA, Chow EW, Honer WG, Bassett AS: Location of a major susceptibility locus for familial schizophrenia on chromosome 1q21-q22. Science 2000;288:678–682.