Abstract
Reviewers in the 1960s and early 1970s were skeptical about any substantial role for genetic factors in the etiology of autism. A realization that the 2% rate of autism in siblings (as estimated at that time) was far above the general population base rate, and that this suggested a possible high genetic liability, led to the first small-scale twin study of autism. The replicated evidence from both twin and family studies undertaken in the 1970s and 1980s indicated both strong genetic influences and the likelihood that they applied to a phenotype that was much broader than the traditional diagnostic category of autism. Medical and chromosomal findings also indicated genetic heterogeneity. Advances in molecular genetics led to genome-wide scans of affected relative pair samples with a positive log of the odds to base 10 score for a location on chromosome 7. The major remaining research challenges and the likely clinical benefits that should derive from genetic research are considered in relation to both current knowledge and that anticipated to emerge from research over the next decade.
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REFERENCES
Allison, D. B. (1997). Transmission-disequilibrium tests for quantitative traits. American Journal of Human Genetics, 60, 676-690.
August, G. J., Stewart, M. A., & Tsai, L. (1981). The incidence of cognitive disabilities in the siblings of autistic children. British Journal of Psychiatry, 138, 416-422.
Bailey, A., Bolton, P., Butler, L., Le Couteur, A., Murphy, M., Scott, S., Webb, T., & Rutter, M. (1993). Prevalence of the fragile X anomaly amongst autistic twins and singletons. Journal of Child Psychology and Psychiatry, 34, 673-688.
Bailey, A., Le Couteur, A., Gottesman, I., Bolton, P., Simonoff, E., Yuzda, F. Y., & Rutter, M. (1995). Autism as a strongly genetic disorder: Evidence from a British twin study. Psychological Medicine, 25, 63-77.
Bailey, A., Palferman, S., Heavey, L., & Le Couteur, A. (1998). Autism: The phenotype in relatives. Journal of Autism and Developmental Disorders, 28, 369-392.
Barcellos, L. F., Klitz, W., Field, L. L., Tobias, R., Bowcock, A. M., Wilson, R., Nelson, M. P., Nagatomi, J., & Thomson, G. (1997). Association mapping of disease loci, by use of a pooled DNA genomic screen. American Journal of Human Genetics, 61, 734-747.
Barlow, D. P. (1995). Gametic imprinting in mammals. Science, 270, 1610-1613.
Baron-Cohen, S. (1995). Mindblindness: An essay on autism and theory of mind. Cambridge, MA: MIT Press.
Bolton, P., Macdonald, H., Pickles, A., Rios, P., Goode, S., Crowson, M., Bailey, A., & Rutter, M. (1994). A case-control family history study of autism. Journal of Child Psychology and Psychiatry, 35, 877-900.
Bolton, P., Murphy, M., Macdonald, H., Whitlock, B., Pickles, A., & Rutter, M. (1997). Obstetric complications in autism: Consequences or causes of the condition? Journal of the American Academy of Child and Adolescent Psychiatry, 36, 272-281.
Bolton, P., Pickles, A., Murphy, M., & Rutter, M. (1998). Autistic, affective and other psychiatric disorders: Patterns of familial aggregation. Psychological Medicine, 28, 385-395.
Brown, P. O., & Hartwell, L. (1998). Genomics and human disease-variations on variation. Nature Genetics, 18, 90-93.
Brown, R., Hobson, R. P., & Lee, A. (1997). Are there autistic-like features in congenitally blind children? Journal of Child Psychology and Psychiatry, 38, 693-703.
Burmeister, M. (1999). Basic concepts in the study of diseases with complex genetics. Biological Psychiatry, 45, 522-532.
Capecchi, M. R. (1994). Targeted gene replacement. Scientific American, 270, 34-41.
Chakravarti, A. (1999). Population genetics-making sense out of sequence. Nature Genetics, 21, 56-60.
Chess, S. (1977). Follow-up report on autism in congenital rubella. Journal of Autism and Childhood Schizophrenia, 7, 69-81.
Chess, S., Korn, S. J., & Fernandez, P. B. (1971). Psychiatric disorders of children with congenital rubella. New York: Brunner/Mazel.
Clegg, J., Hollis, C., & Rutter, M. (1999, June). Developmental language disorders: A longitudinal study of cognitive, social, and psychiatric functioning. Paper presented at the biannual meeting of the International Society for the Study of Child and Adolescent Psychopathology, Barcelona, Spain.
Cook, E. H., 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, 1037-1083.
Cook, E. H. J., 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, 928-934.
Crabbe, J. C., Belknap, J. K., & Buck, K. J. (1994). Genetic animal models of alcohol and drug abuse. Science, 264, 1715-1723.
Daniels, J., Holmans, J., Williams, N., Turic, D., McGuffin, P., Plomin, R., & Owen, M. J. (1998). A simple method for analyzing microsatellite allele image patterns generated from DNA pools and its application to allelic association studies. American Journal of Human Genetics, 62, 1189-1197.
Davis, J. O., & Bracha, H. S. (1996). Prenatal growth markers in schizophrenia: A monozygotic co-twin control study. American Journal of Psychiatry, 153, 1166-1172.
DeLong, R., & Nohria, C. (1994). Psychiatric family history and neurological disease in autistic spectrum disorders. Developmental Medicine and Child Neurology, 36, 441-448.
Dykens, E. M., & Volkmar, F. (1997). Medical conditions associated with autism. In D. J. Cohen & F. R. Volkmar (Eds.), Handbook of autism and pervasive developmental disorders (pp. 388-410). New York: Wiley.
Fisher, S. E., Vargha-Khadem, F., Watkins, K. E., Monaco, A. P., & Pembrey, M. E. (1998). Localisation of a gene implicated in a severe speech and language disorder. Nature Genetics, 18, 168-170.
Fisher, S. E., Marlow, A. J., Lamb, J., Maestrini, E., Williams, D. F., Richardson, A. J., Weeks, D. E., Stein, J. F., & Monaco, A. P. (1999). A quantitative-trait locus on chromosome 6p influences different aspects of developmental dyslexia. American Journal of Human Genetics, 64, 146-156.
Folstein, S. E., & Piven, J. (1991). Etiology of autism: Genetic influences. Pediatrics, 87, 767-773.
Folstein, S., & Rutter, M. (1977a). Genetic influences and infantile autism. Nature, 265, 726-728.
Folstein, S., & Rutter, M. (1977b). Infantile autism: A genetic study of 21 pairs. Journal of Child Psychology and Psychiatry, 18, 297-321.
Fombonne, E., Bolton, P., Prior, J., Jordan, H., & Rutter, M. (1997). A family study of autism: Cognitive patterns and levels in parents and siblings. Journal of Child Psychology and Psychiatry, 38, 667-683.
Frith, U., & Happé, F. (1994). Autism: Beyond “theory of mind.” Cognition, 50, 115-132.
Fulker, D. W., & Cherny, S. S. (1996). An improved multipoint sib-pair analysis of quantitative traits. Behavior Genetics, 26, 527-532.
Gayán, J., Smith, S. D., Cherny, S. S., Cardon, L. R., Fulker, D. W., Brower, A. M., Olson, R. K., Pennington, B. F., & DeFries, J. C. (1999). Quantitative trait locus for specific language and reading deficits on chromosome 6p. American Journal of Human Genetics, 64, 157-164.
Gillberg, C., & Wahlström, J. (1985). Chromosome abnormalities in infantile autism and other childhood psychoses: A population study of 66 cases. Developmental Medicine and Child Neurology, 27, 293-304.
Goodman, R. (1991). Growing together and growing apart: The nongenetic forces on children in the same family. In P. McGuffin and R. Murray (Eds.), The new genetics of mental illness (pp. 212-224). Oxford, England: Heinemann Medical.
Griffith, E. M., Pennington, B. F., Wehner, E. A., & Rogers, S. J. (1999). Executive functions in young children with autism. Child Development, 70, 817-832.
Grigorenko, E. L., Wood, F. B., Meyer, M. S., Hart, L. A., Speed, W. C., Shuster, A., & Pauls, D. L. (1997). Susceptibility loci for distinct components of developmental dyslexia on chromosomes 6 and 15. American Journal of Human Genetics, 60, 27-39.
Gurling, H. M. D., Bolton, P. F., Vincent, J., Melmer, G., & Rutter, M. (1997). Molecular and cytogenetic investigations of the fragile X region including the Frax A and Frax E CGG trinucleotide repeat sequences in families multiplex for autism and related phenotypes. Human Heredity, 47, 254-262.
Hanson, D. R., & Gottesman, I. (1976). The genetics, if any, of infantile autism and childhood schizophrenia. Journal of Autism and Schizophrenia, 6, 209-233.
Happé, F. G. E. (1994). An advanced test of theory of mind: Understanding of story characters' thoughts and feelings by able autistic, mentally handicapped and normal children and adults. Journal of Autism and Developmental Disorders, 24, 129-154.
Heavey, L., Phillips, W., Baron-Cohen, S., & Rutter, M. (in press). The Awkward Moments Test: A naturalistic measure of social understanding in autism. Journal of Autism and Developmental Disorders.
Hughes, C., Leboyer, M., & Bouvard, M. (1997). Executive function in parents of children with autism. Psychological Medicine, 27, 209-220.
Hughes, C., Plumet, M.-H., & Leboyer, M. (1999). Towards a cognitive phenotype for autism: Increased prevalence of executive dysfunction and superior spatial span amongst siblings of children with autism. Journal of Child Psychology and Psychiatry, 40, 705-718.
International Molecular Genetic Study of Autism Consortium (1998). A full genome screen for autism with evidence for linkage to a region on chromosome 7q. Human Molecular Genetics, 7, 571-578.
Kanner, L. (1943). Autistic disturbances of affective contact. Nervous Child, 2, 217-250.
Klauck, S. M., Poustka, F., Benner, A., Lesch, K.-P., & Poustka, A. (1997). Serotonin transporter (5-HTT) gene variants associated with autism? Human Molecular Genetics, 6, 2244-2248.
Kruglyak, L., & Lander, E. S. (1995). Complete multipoint sib-pair analysis of qualitative and quantitative traits. American Journal of Human Genetics, 57, 439-454.
Kurnit, D. M., Layton, W. M., & Matthysse, S. (1987). Genetics, chance and morphogenesis. American Journal of Human Genetics, 41, 979-995.
Landa, R., Piven, J., Wzorek, M., Gayle, J. O., Chase, G. A., & Folstein, S. E. (1992). Social language use in parents of autistic individuals. Psychological Medicine, 22, 245-254.
Landa, R., Wzorek, M., Piven, J., Folstein, S. E., & Isaacs, C. (1991). Spontaneous narrative discourse characteristics of parents of autistic individuals. Journal of Speech and Hearing Research, 34, 1339-1345.
Lander, E. S. (1999). Array of hope. Nature Genetics, 21, 3-4.
Le Couteur, A., Bailey, A. J., Goode, S., Pickles, A., Robertson, S., Gottesman, I., & Rutter, M. (1996). A broader phenotype of autism: The clinical spectrum in twins. Journal of Child Psychology and Psychiatry, 37, 785-801.
Le Couteur, A., Rutter, M., Lord, C., Rios, P., Robertson, S., Holdgrafer, M., & McLennan, J. (1989). Autism Diagnostic Interview: A standardized investigator-based instrument. Journal of Autism and Developmental Disorders, 19, 363-387.
Lord, C., Rutter, M., Goode, S., Heemsbergen, J., Jordan, H., & Mawhood, L. (1989). Autism Diagnostic Observation Schedule: A standardized observation of communicative and social behavior. Journal of Autism and Developmental Disorders, 24, 659-685.
Maestrini, E., Lai, C., Marlow, A., Matthews, N., Wallace, S., Bailey, A., Cook, E., Weeks, D. E., Monaco, A. P., & International Molecular Genetic Study of Autism Consortium (1999). Serotonin transporter (5-HTT) and g-aminobutyric acid receptor subunit b3 (GABRB3) gene polymorphisms are not associated with autism in the IMGSA families. American Journal of Medical Genetics (Neuropsychiatric Genetics), 88, 492-496.
Maestrini, E., Marlow, A. J., Weeks, D. E., & Monaco, A. P. (1998). Molecular genetic investigations of autism. Journal of Autism and Developmental Disorders, 28, 439-449.
Malhotra, A. K., & Goldman, D. (1999). Benefits and pitfalls encountered in psychiatric genetic association studies. Biological Psychiatry, 45, 544-550.
Merriman, T. R., Eaves, I. A., Twells, R. C. J., Merriman, M. E., Danoy, P. A. C., Muxworthy, C. E., Hunter, K. M. D., Cox, R. D., Cucca, F., McKinney, P. A., Shield, J. P. H., Baum, J. D., Tuomilehto, J., Tuomilehto-Wolf, E., Ionesco-Tirgoviste, C., Joner, G., Thorsby, E., Undlien, D. E., Pociot, F., Nerup, J., Rønningen, K. S., Bain, S. C., & Todd, J. A. (1997). Transmission of haplotypes of microsatellite markers rather than single marker alleles in the mapping of a putative type 1 diabetes susceptibility gene (IDDM6). Human Molecular Genetics, 7, 517-524.
Merriman, T., Twells, R., Merriman, M., Eaves, I., Cox, R., Cucca, F., McKinney, P., Shield, J., Baum, D., Bosi, E., Pozzilli, P., Nisticò, L., Buzzetti, R., Joner, G., Rønningen, K., Thorsby, E., Undlien, D., Pociot, F., Nerup, J., Bain, S., Barnett, A., & Todd, J. (1998). Evidence by allelic association-dependent methods for a type 1 diabetes polygene (IDDM6) on chromosome 18q21. Human Molecular Genetics, 6, 1003-1010.
Meyers, C., Elias, S., & Arrabal, P. (1995). Congenital anomalies and pregnancy loss. In L. G. Keith, E. Papiernik, D. M. Keith, & B. Luke (Eds.), Multiple pregnancy: Epidemiology, gestation and perinatal outcome (pp. 73-92). New York: Parthenon.
Molenaar, P. C. M., Boomsma, D. I., & Dolan, C. V. (1993). A third source of developmental differences. Behavior Genetics, 23, 519-524.
Murphy, M., Bolton, P., Pickles, A. Fombonne, E., Piven, J., & Rutter, M. (1999). Personality traits in the relatives of autistic probands. Manuscript submitted for publication.
Ozonoff, S., Rogers, S. J., Farnham, J. M., & Pennington, B. F. (1993). Can standard measures identify subclinical markers of autism? Journal of Autism and Developmental Disorders, 23, 429-441.
Philippe, A., Martinez, M., Guilloud-Bataille, M., Gillberg, C., Råstam, M., Sponterm, E., Coleman, M., Zapella, M., Aschauser, H., van Malldergerme, L., Penet, C., Feingoll, J., Brice, A., Leboyer, M., & Paris Autism Research International Sibpair Study (1999). Genome-wide scan for autism susceptibility genes. Human Molecular Genetics, 8, 805-812.
Pickles, A., Bolton, P., Macdonald, H., Bailey, A., Le Couteur, A., Sim, L., & Rutter, M. (1995). Latent class analysis of recurrence risk for complex phenotypes with selection and measurement error: A twin and family history study of autism. American Journal of Human Genetics, 57, 717-726.
Pickles, A., Starr, E., Kazak, S., Bolton, P., Papanikolau, K., Bailey, A. J., Goodman, R., & Rutter, M. (in press). Variable expression of the autism broader phenotype: Findings from extended pedigrees. Journal of Child Psychology and Psychiatry.
Piven, J., Chase, G. A., Landa, R., Wzorek, M., Gayle, J., Cloud, D., & Folstein, S. (1991). Psychiatric disorders in the parents of autistic individuals. Journal of the American Academy of Child and Adolescent Psychiatry, 30, 471-478.
Piven, J., Gayle, J., Chase, J., Fink, B., Landa, R., Wrozek, M. & Folstein, S. (1990). A family history study of neuropsychiatric disorders in the adult siblings of autistic individuals. Journal of the American Academy of Child and Adolescent Psychiatry, 29, 177-183.
Piven, J., & Palmer, P. (1997). Cognitive deficits in parents from multiple-incidence autism families. Journal of Child Psychology and Psychiatry, 38, 1011-1022.
Piven, J., Palmer, P., Jacobi, D., Childress, D., & Arndt, S. (1997). The broader autism phenotype: Evidence from a family study of multiple-incidence autism families. American Journal of Psychiatry, 154, 185-190.
Piven, J., Wzorek, M., Landa, R., Lainhart, J., Bolton, P., Chase, G. A., & Folstein, S. (1994). Personality characteristics of the parents of autistic individuals. Psychological Medicine, 24, 783-795.
Pocock, S. J. (1983). Clinical trials: A practical approach. Chichester, England: Wiley.
Risch, N., & Merikangas, K. (1996). The future of genetic studies of complex human diseases. Science, 273, 1516-1517.
Rutter, M. (1967). Psychotic disorders in early childhood. In A. J. Coppen and A. Walk (Eds.), Recent Developments in Schizophrenia (pp.133-158). Ashford, Kent: Headley Bros/RMPA.
Rutter, M. (1994). Psychiatric genetics: Research challenges and pathways forward. American Journal of Medical Genetics (Neuropsychiatric Genetics), 54, 185-198.
Rutter, M. (1999a). Psychosocial adversity and child psychopathology. British Journal of Psychiatry, 174, 480-493.
Rutter, M. (1999b). The Emanuel Miller Memorial Lecture 1998. Autism: Two-way interplay between research and clinical work. Journal of Child and Adolescent Psychiatry, 40, 169-188.
Rutter, M., Andersen-Wood, L., Beckett, C., Bredenkamp, D., Castle, J., Groothues, C., Kreppner, J., Keaveney, L., Lord, C., O'Connor, T. G., & English and Romanian Adoptee (ERA) Study Team (1999). Quasi-autistic patterns following severe early global privation. Journal of Child Psychology and Psychiatry, 40, 537-549.
Rutter, M., Bailey, A., Bolton, P., & Le Couteur, A. (1994). Autism and known medical conditions: Myth and substance. Journal of Child Psychology and Psychiatry, 35, 311-322.
Rutter, M., Dunn, J., Plomin, R., Simonoff, E., Pickles, A., Maughan, B., Ormel, J., Meyer, J., & Eaves, L. (1997). Integrating nature and nurture: Implications of person-environment correlations and interactions of developmental psychopathology. Development and Psychopathology, 9, 335-364.
Rutter, M., Silberg, J., O'Connor, T., & Simonoff, E. (1999a). Genetics and child psychiatry: I. Advances in quantitative and molecular genetics. Journal of Child Psychology and Psychiatry, 40, 3-18.
Rutter, M., Silberg, J., O'Connor, T., & Simonoff, E. (1999b). Genetics and child psychiatry: II. Empirical research findings. Journal of Child Psychology and Psychiatry, 40, 19-55.
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, 327-336.
Sibilia, M., & Wagner, E. F. (1996). Transgenic animals. European Review, 4, 371-392.
Smalley, S. L. (1998). Autism and tuberous sclerosis. Journal of Autism and Developmental Disorders, 28, 407-414.
Smalley, S. L., McCracken, J., & Tanguay, P. (1995). Autism, affective disorders and social phobia. American Journal of Medical Genetics, 60, 19-26.
Spielman, R. S., & Ewens, W. J. (1996). Invited editorial: The TDT and other family-based tests for linkage disequilibrium and association. American Journal of Human Genetics, 59, 983-989.
Starr, L., Kazak, S., Pickles, A., Tomlins, M., Bailey, A., & Rutter, M. (1999). Family genetic study of autism associated with profound mental retardation. Submitted for publication.
Steffenburg, S., Gillberg, C., Hellgren, L., Andersson, L., Gillberg, I., Jakobsson, G., & Bohman, M. (1989). A twin study of autism in Denmark, Finland, Iceland, Norway and Sweden. Journal of Child Psychology and Psychiatry, 30, 405-416.
Wahlsten, D. (1999). Single-gene influences on brain and behavior. Annual Review of Psychology, 50, 599-624.
Watson, S. J., & Akil, H. (1999). Gene chips and arrays revealed: A primer on their power and their uses. Biological Psychiatry, 45, 533-543.
Watson, J. D., Gilman, M., Witkowski, J., & Zoller, M. (1992). Recombinant DNA (2nd ed.). New York: Scientific American Books.
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Rutter, M. Genetic Studies of Autism: From the 1970s into the Millennium. J Abnorm Child Psychol 28, 3–14 (2000). https://doi.org/10.1023/A:1005113900068
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DOI: https://doi.org/10.1023/A:1005113900068