Hostname: page-component-848d4c4894-2pzkn Total loading time: 0 Render date: 2024-06-02T21:48:43.170Z Has data issue: false hasContentIssue false

Planning studies of etiology

Published online by Cambridge University Press:  01 January 2005

SHELLEY D. SMITH
Affiliation:
University of Nebraska Medical Center
COLLEEN A. MORRIS
Affiliation:
University of Nevada School of Medicine

Abstract

Knowledge of the environmental and genetic etiologies of complex cognitive disorders can guide strategies for diagnosis, prevention, and therapy, but disentangling the various causes can be very challenging. Two basic approaches can be used in identifying genetic factors, a top-down approach, in which phenotypic descriptions are used to discover genes that influence those phenotypes, and a bottom-up approach, comparing the phenotypic effects of genes that are known to cause syndromes that include cognitive disabilities. Thorough characterization of phenotypes throughout development is critical to both of these methods. These strategies have been applied to the characterization of genetic etiologies for reading disability, language disorders, attention-deficit hyperactivity disorder, and autism.

Type
Articles
Copyright
© 2005 Cambridge University Press

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Abecasis G. R., Cherny S. S., & Cardon L. R. 2001. The impact of genotyping error on family-based analysis of quantitative traits. European Journal of Human Genetics, 9, 130134.Google Scholar
American Psychiatric Association. 1994. Diagnostic and statistical manual of mental disorders (4th ed.) Washington, DC: Author.
Amir R. E., Van den Veyver I. B., Wan M., Tran C. Q., Francke U., & Zoghbi H. Y. 1999. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nature Genetics, 23, 185188.Google Scholar
Bespalova I. N., & Buxbaum J. D. 2003. Disease susceptibility genes for autism. Annals of Medicine, 35, 274281.Google Scholar
Bolton P. F., Dennis N. R., Browne C. E., Thomas N. S., Veltman M. W., Thompson R. J., & Jacobs P. 2001. The phenotypic manifestations of interstitial duplications of proximal 15q with special reference to the autistic spectrum disorders. American Journal of Medical Genetics, 105, 675685.Google Scholar
Bolton P. F., Park R. J., Higgins J. N., Griffiths P. D., & Pickles A. 2002. Neuro-epileptic determinants of autism spectrum disorders in tuberous sclerosis complex. Brain, 125, 12471255.Google Scholar
Borecki I. B., & Suarez B. K. 2001. Linkage and association: Basic concepts. Advances in Genetics, 42, 4566.Google Scholar
Botstein D., & Risch N. 2003. Discovering genotypes underlying human phenotypes: Past successes for mendelian disease, future approaches for complex disease. Nature Genetics, 33 (Suppl.), 228237.Google Scholar
Bundey S., Hardy C., Vickers S., Kilpatrick M. W., & Corbett J. A. 1994. Duplication of the 15q11–13 region in a patient with autism, epilepsy and ataxia. Developmental Medicine and Child Neurology, 36, 736742.Google Scholar
Buxbaum J. D., Silverman J. M., Smith C. J., Greenberg D. A., Kilifarski M., Reichert J., Cook E. H. Jr., Fang Y., Song C. Y., & Vitale R. 2002. Association between a GABRB3 polymorphism and autism. Molecular Psychiatry, 7, 311316.Google Scholar
Cardon L. R., & Fulker D. W. 1994. The power of interval mapping of quantitative trait loci, using selected sib pairs. American Journal of Human Genetics, 55, 825833.Google Scholar
Cassidy S. B., & Morris C. A. 2002. Behavioral phenotypes in genetic syndromes: genetic clues to human behavior. Advances in Pediatrics, 49, 5986.Google Scholar
Chapman N. H., Raskind W. H., Thomson J. B., Berninger V. W., & Wijsman E. M. 2003. Segregation analysis of phenotypic components of learning disabilities. II. Phonological decoding. American Journal of Medical Genetics, 121B (1), 6070.Google Scholar
Cook E. H. Jr., Courchesne R. Y., Cox N. J., Lord C., Gonen D., Guter S. J., Lincoln A., Nix K., Haas R., Leventhal B. L., & Courchesne E. 1998. Linkage-disequilibrium mapping of autistic disorder, with 15q11–13 markers. American Journal of Human Genetics, 62, 10771083.Google Scholar
Cook E. H. Jr., Lindgren V., Leventhal B. L., Courchesne R., Lincoln A., Shulman C., Lord C., & Courchesne E. 1997. Autism or atypical autism in maternally but not paternally derived proximal 15q duplication. American Journal of Human Genetics, 60, 928934.Google Scholar
DeFries J. C., & Alarcón M. 1996. Genetics of specific reading disability. Mental Retardation and Developmental Disabilities Research Reviews, 2, 947.Google Scholar
Ewart A. K., Morris C. A., Atkinson D., Jin W., Sternes K., Spallone P., Stock A. D., Leppert M., & Keating M. T. 1993. Hemizygosity at the elastin locus in a developmental disorder, Williams syndrome. Nature Genetics, 5, 1116.Google Scholar
Fantes J. A., Mewborn S. K., Lese C. M., Hedrick J., Brown R. L., Dyomin V., Chaganti R. S., Christian S. L., & Ledbetter D. H. 2002. Organisation of the pericentromeric region of chromosome 15: At least four partial gene copies are amplified in patients with a proximal duplication of 15q. Journal of Medical Genetics, 39, 170177.Google Scholar
Faraone S. V., Biederman J., & Friedman D. 2000. Validity of DSM-IV subtypes of attention-deficit/hyperactivity disorder: A family study perspective. Journal of the American Academy of Child and Adolescent Psychiatry, 39, 300307.Google Scholar
Feingold E. 2001. Methods of linkage analysis of quantitative trait loci in humans. Theoretical Population Biology, 60, 167180.Google Scholar
Fisher S. E. 2003. Isolation of the genetic factors underlying speech and language disorders. In R. Plomin, J. C. DeFries, I. W. Craig, & P. McGuffin (Eds.), Behavioral genetics in the postgenomic era (pp. 205226). Washington, DC: American Psychological Association.
Fisher S. E. 2005. Dissection of molecular mechanisms underlying speech and language disorders. Applied Psycholinguistics, 26, 111128.Google Scholar
Fisher S. E., & DeFries J. C. 2002. Developmental dyslexia: Genetic dissection of a complex cognitive trait. Nature Reviews: Neuroscience, 3, 767780.Google Scholar
Forrest W. F., & Feingold E. 2000. Composite statistics for QTL mapping with moderately discordant sibling pairs. American Journal of Human Genetics, 66, 16421660.Google Scholar
Frangiskakis J. M., Ewart A. K., Morris C. A., Mervis C. B., Bertrand J., Robinson B. F., Klein B. P., Ensing G. J., Everett L. A., Green E. D., Proschel C., Gutowski N. J., Noble M., Atkinson D. L., Odelberg S. J., & Keating M. T. 1996. LIM-kinase1 hemizygosity implicated in impaired visuospatial constructive cognition. Cell, 86, 5969.Google Scholar
Gayán J., & Olson R. K. 2001. Genetic and environmental influences on orthographic and phonological skills in children with reading disabilities. Developmental Neuropsychology, 20, 483507.Google Scholar
Hauser E. R., & Pericak–Vance M. A. 2000. Genetic analysis for common complex disease. American Heart Journal, 140, S36S44.Google Scholar
Heo M., Faith M. S., & Allison D. B. 2002. Power and sample sizes for linkage with extreme sampling under an oligogenic model for quantitative traits. Behavioral Genetics, 32, 2336.Google Scholar
Hosking L., Lumsden S., Lewis K., Yeo A., McCarthy L., Bansal A., Riley J., Purvis I., & Xu C. F. 2004. Detection of genotyping errors by Hardy–Weinberg equilibrium testing. European Journal of Human Genetics, 12, 395399.Google Scholar
Humphrey A., Higgins J. N., Yates J. R., & Bolton P. F. 2004. Monozygotic twins with tuberous sclerosis discordant for the severity of developmental deficits. Neurology, 62, 795798.Google Scholar
Jamain S., Quach H., Betancur C., Rastam M., Colineaux C., Gillberg I. C., Soderstrom H., Giros B., Leboyer M., Gillberg C., Bourgeron T., & Paris Autism Research International Sibpair Study. 2003. Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nature Genetics, 34, 2729.Google Scholar
Kang H., Qin Z. S., Niu T., & Liu J. S. 2004. Incorporating genotyping uncertainty in haplotype inference for single-nucleotide polymorphisms. American Journal of Human Genetics, 74, 495510.Google Scholar
Kang S. J., Gordon D., & Finch S. J. 2004. What SNP genotyping errors are most costly for genetic association studies? Genetic Epidemiology, 26, 132141.Google Scholar
Kau A. S., Tierney E., Bukelis I., Stump M. H., Kates W. R., Trescher W. H., & Kaufmann W. E. 2004. Social behavior profile in young males with fragile X syndrome: Characteristics and specificity. American Journal of Medical Genetics, 126A, 917.Google Scholar
Kaufmann W. E., Cooper K. L., Mostofsky S. H., Capone G. T., Kates W. R., Newschaffer C. J., Bukelis I., Stump M. H., Jann A. E., & Lanham D. C. 2003. Specificity of cerebellar vermian abnormalities in autism: A quantitative magnetic resonance imaging study. Journal of Child Neurology, 18, 463470.Google Scholar
Kishino T., Lalande M., & Wagstaff J. 1997. UBE3A/E6-AP mutations cause Angelman syndrome. Nature Genetics, 15, 7073.Google Scholar
Lai C. S., Fisher S. E., Hurst J. A., Vargha–Khadem F., & Monaco A. P. 2001. A forkhead-domain gene is mutated in a severe speech and language disorder. Nature, 413, 519523.Google Scholar
Longo I., Russo L., Meloni I., Ricci I., Ariani F., Pescucci C., Giordano C. T., Canitano R., Hayek G., Zappella M., Neri G., Renieri A., & Gurrieri F. 2004, April 7. Three Rett patients with both MECP2 mutation and 15q11–13 rearrangements. European Journal of Human Genetics.Google Scholar
Marlow A. J., Fisher S. E., Francks C., MacPhie I. L., Cherny S. S., Richardson A. J., Talcott J. B., Stein J. F., Monaco A. P., & Cardon L. R. 2003. Use of multivariate linkage analysis for dissection of a complex cognitive trait. Journal of Human Genetics, 72, 561570.Google Scholar
Matsuura T., Sutcliffe J. S., Fang P., Galjaard R. J., Jiang Y. H., Benton C. S., Rommens J. M., & Beaudet A. L. 1997. De novo truncating mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman syndrome. Nature Genetics, 15, 7477.Google Scholar
McGuffin P. 2000. The quantitative and molecular genetics of human intelligence. Novartis Foundation Symposia, 233, 243255.Google Scholar
Mervis C. B., Robinson B. F., Bertrand J., Morris C. A., Klein–Tasman B. P., & Armstrong S. C. 2000. The Williams syndrome cognitive profile. Brain and Cognition, 44, 604628.Google Scholar
Morris C. A., & Mervis C. B. 2000. Williams syndrome and related disorders. Annual Review of Genomics and Human Genetics, 1, 461484.Google Scholar
Morris C. A., Mervis C. B., Hobart H. H., Gregg R. G., Bertrand J., Ensing G. J., Sommer A., Moore C. A., Hopkin R. J., Spallone P. A., Keating M. T., Osborne L., Kimberley K. W., & Stock A. D. 2003. GTF2I hemizygosity implicated in mental retardation in Williams syndrome: Genotype–phenotype analysis of five families with deletions in the Williams syndrome region. American Journal of Medical Genetics, 123A, 4559.Google Scholar
Newbury D. F., Bonora E., Lamb J. A., Fisher S. E., Lai C. S., Baird G., Jannoun L., Slonims V., Stott C. M., Merricks M. J., Bolton P. F., Bailey A. J., & Monaco A. P., and the International Molecular Genetic Study of Autism Consortium. 2002. FOXP2 is not a major susceptibility gene for autism or specific language impairment. American Journal of Human Genetics, 70, 13181327.Google Scholar
Nurmi E. L., Bradford Y., Chen Y., Hall J., Arnone B., Gardiner M. B., Hutcheson H. B., Gilbert J. R., Pericak–Vance M. A., Copeland–Yates S. A., Michaelis R. C., Wassink T. H., Santangelo S. L., Sheffield V. C., Piven J., Folstein S. E., Haines J. L., & Sutcliffe J. S. 2001. Linkage disequilibrium at the Angelman syndrome gene UBE3A in autism families. Genomics, 77, 105113.Google Scholar
Nurmi E. L., Amin T., Olson L. M., Jacobs M. M., McCauley J. L., Lam A. Y., Organ E. L., Folstein S. E., Haines J. L., & Sutcliffe J. S. 2003. Dense linkage disequilibrium mapping in the 15q11–q13 maternal expression domain yields evidence for association in autism. Molecular Psychiatry, 8, 624634.Google Scholar
Nurmi E. L., Dowd M., Tadevosyan–Leyfer O., Haines J. L., Folstein S. E., & Sutcliffe J. S. 2003. Exploratory subsetting of autism families based on savant skills improves evidence of genetic linkage to 15q11–q13. Journal of the American Academy of Child and Adolescent Psychiatry, 42, 856863.Google Scholar
O'Brien E. K., Zhang X., Nishimura C., Tomblin J. B., & Murray J. C. 2003. Association of specfic language impairment (SLI) to the region of 7q31. American Journal of Human Genetics, 72, 15361543.Google Scholar
Ott J., & Bhat A. 1999. Linkage analysis in heterogeneous and complex traits. European Child and Adolescent Psychiatry, 8 (Suppl. 3), 4346.Google Scholar
Pauls D. L., Alsobrook J. P. II, Goodman W., Rasmussen S., & Leckman J. F. 1995. A family study of obsessive–compulsive disorder. American Journal of Psychiatry, 152, 7684.Google Scholar
Pauls D. L., Hurst C. R., Kruger S. D., Leckman J. F., Kidd K. K., & Cohen D. J. 1986. Gilles de la Tourette's syndrome and attention deficit disorder with hyperactivity. Evidence against a genetic relationship. Archives of General Psychiatry, 43, 11771179.Google Scholar
Pericak–Vance M. A. 2003. The genetics of autistic disorder. In R. Plomin, J. C. DeFries, I. W. Craig, & P. McGuffin (Eds.), Behavioral genetics in the postgenomic era (pp. 267288). Washington, DC: American Psychological Association.
Pericak–Vance M. A., Wolpert C. M., Menold M. M., Bass M. P., DeLong G. R., Beaty L. M., Zimmerman A., Potter N., Gilbert J. R., Vance J. M., Wright H. H., Abramson R. K., & Cuccaro L. M. 1997. Linkage evidence supports the involvement of chromosome 15 in autistic disorder. American Journal of Human Genetics, 61 (Suppl.), A40.Google Scholar
Philofsky A., Hepburn S. L., Hayes A., Hagerman R., & Rogers S. J. 2004. Linguistic and cognitive functioning and autism symptoms in young children with fragile X syndrome. American Journal of Mental Retardation, 109, 208218.Google Scholar
Plomin R., & Walker S. O. 2003. Genetics and educational psychology. British Journal of Educational Psychology, 73, 314.Google Scholar
Raskind W. H., Hsu L., Berninger V. W., Thomson J. B., & Wijsman E. M. 2000. Familial aggregation of dyslexia phenotypes. Behavioral Genetics, 30, 385396.Google Scholar
Raymond D. V. 2003. Abnormal mental development. In D. L. Rimoin, J. M. Connor, R. E. Pyeritz, & B. R. Korf (Eds.), Emery and Rimoin's principles and practices in medical genetics (4th ed., pp. 10461065) New York: Churchill Livingston.
Repetto G. M., White L. M., Bader P. J., Johnson D., & Knoll J. H. 1998. Interstitial duplications of chromosome region 15q11–q13: Clinical and molecular characterization. American Journal Medical Genetics, 79, 8289.Google Scholar
Risch N., & Merikangas K. 1996. The future of genetic studies of complex human diseases. Science, 273, 15161517.Google Scholar
Risch N. J., & Zhang H. 1996. Mapping quantitative trait loci with extreme discordant sib pairs: Sampling considerations. American Journal of Human Genetics, 58, 836843.Google Scholar
Rogers S. J., Wehner D. E., & Hagerman R. 2001. The behavioral phenotype in fragile X: Symptoms of autism in very young children with fragile X syndrome, idiopathic autism, and other developmental disorders. Journal of Developmental and Behavioral Pediatrics, 22, 409417.Google Scholar
Samaco R. C., Nagarajan R. P., Braunschweig D., & LaSalle J. M. 2004. Multiple pathways regulate MeCP2 expression in normal brain development and exhibit defects in autism-spectrum disorders. Human Molecular Genetics, 13, 629639.Google Scholar
Schroer R. J., Phelan M. C., Michaelis R. C., Crawford E. C., Skinner S. A., Cuccaro M., Simensen R. J., Bishop J., Skinner C., Fender D., & Stevenson R. E. 1998. Autism and maternally derived aberrations of chromosome 15q. American Journal of Medical Genetics, 76, 327336.Google Scholar
Sham P. 2003. Recent developments in quantitative trait loci analysis. (2003). In D. L. Rimoin, J. M. Connor, R. E. Pyeritz, & B. R. Korf (Eds.), Emery and Rimoin's principles and practices in medical genetics (4th ed., pp. 4154). New York: Churchill Livingston.
Shao Y., Cuccaro M. L., Hauser E. R., Raiford K. L., Menold M. M., Wolpert C. M., Ravan S. A., Elston L., Decena K., Donnelly S. L., Abramson R. K., Wright H. H., DeLong G. R., Gilbert J. R., & Pericak–Vance M. A. 2003. Fine mapping of autistic disorder to chromosome 15q11–q13 by use of phenotypic subtypes. American Journal of Human Genetics, 72, 539548.Google Scholar
SLI Consortium. 2002. A genomewide scan identifies two novel loci involved in specific language impairment. American Journal of Human Genetics, 70, 384398.
Smalley S. L., McGough J. J., Del'Homme M., NewDelman J., Gordon E., Kim T., Liu A., & McCracken J. T. 2000. Familial clustering of symptoms and disruptive behaviors in multiplex families with attention-deficit/hyperactivity disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 39, 11351143.Google Scholar
Smith S. D. 2004. Localization and identification of genes influencing language and learning disorders. In M. L. Rice & S. F. Warren (Eds.), Developmental language disorder: From phenotype to etiologies. Hillsdale, NJ: Erlbaum.
Steffenburg S., Gillberg C. L., Steffenburg U., & Kyllerman M. 1996. Autism in Angelman syndrome: A population-based study. Pediatric Neurology, 14, 131136.Google Scholar
Taipale M., Kaminen N., Nopola–Hemmi J., Haltia T., Myllyluoma B., Lyytinen H., Muller K., Kaaranen M., Lindsberg P. J., Hannula–Jouppi K., & Kere J. 2003. A candidate gene for developmental dyslexia encodes a nuclear tetratricopeptide repeat domain protein dynamically regulated in brain. Proceedings of the National Academy of Sciences USA, 100, 1155311558.Google Scholar
Todd R. D., Rasmussen E. R., Neuman R. J., Reich W., Hudziak J. J., Bucholz K. K., Madden P. A., & Heath A. 2001. Familiality and heritability of subtypes of attention deficit hyperactivity disorder in a population sample of adolescent female twins. American Journal of Psychiatry, 158, 18911898.Google Scholar
Vink J. M., & Boomsma D. I. 2002. Gene finding strategies. Biological Psychology, 61, 5371.Google Scholar
Walz N. C., Byars A. W., Egelhoff J. C., & Franz D. N. 2002. Supratentorial tuber location and autism in tuberous sclerosis complex. Journal of Child Neurology, 17, 830832.Google Scholar
Watson P., Black G., Ramsden S., Barrow M., Super M., Kerr B., & Clayton–Smith J. 2001. Angelman syndrome phenotype associated with mutations in MECP2, a gene encoding a methyl CpG binding protein. Journal of Medical Genetics, 38, 224228.Google Scholar
Zoghbi H. Y. 2003. Postnatal neurodevelopmental disorders: Meeting at the synapse? Science, 302, 826830.Google Scholar