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Population- and Family-Based Studies Associate the MTHFR Gene with Idiopathic Autism in Simplex Families

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Abstract

Two methylenetetrahydrofolate reductase gene (MTHFR) functional polymorphisms were studied in 205 North American simplex (SPX) and 307 multiplex (MPX) families having one or more children with an autism spectrum disorder. Case–control comparisons revealed a significantly higher frequency of the low-activity 677T allele, higher prevalence of the 677TT genotype and higher frequencies of the 677T-1298A haplotype and double homozygous 677TT/1298AA genotype in affected individuals relative to controls. Family-based association testing demonstrated significant preferential transmission of the 677T and 1298A alleles and the 677T-1298A haplotype to affected offspring. The results were not replicated in MPX families. The results associate the MTHFR gene with autism in SPX families only, suggesting that reduced MTHFR activity is a risk factor for autism in these families.

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References

  • American Academy of Pediatrics. (2001). American Academy of Pediatrics: The pediatrician’s role in the diagnosis and management of autistic spectrum disorder in children. Pediatrics, 107, 1221–1226.

    Article  Google Scholar 

  • Bailey, A., Phillips, W., & Rutter, M. (1996). Autism: Towards an integration of clinical, genetic, neuropsychological, and neurobiological perspectives. Journal of Child Psychology and Psychiatry, 37, 89–126.

    Article  PubMed  Google Scholar 

  • Bird, A. (2002). DNA methylation patterns and epigenetic memory. Genes and Development, 16, 6–21.

    Article  PubMed  Google Scholar 

  • Bittel, D. C., Kibiryeva, N., Sell, S. M., Strong, T. V., & Butler, M. G. (2007). Whole genome microarray analysis of gene expression in Prader-Willi syndrome. American Journal of Medical Genetics Part A, 143, 430–442.

    Article  PubMed  Google Scholar 

  • Boris, M., Goldblatt, A., Galanko, J., & James, S. L. (2004). Association of MTHFR variants with autism. Journal of American Physicians and Surgeons, 9, 106–108.

    Google Scholar 

  • Castro, R., Rivera, I., Ravasco, P., Camilo, M. E., Jakobs, C., Blom, H. J., et al. (2004). 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C → T and 1298A → C mutations are associated with DNA hypomethylation. Journal of Medical Genetics, 41, 454–458.

    Article  PubMed  Google Scholar 

  • Centers for Disease Control and Prevention (CDC). (2009). Prevalence of autism spectrum disorders—Autism and developmental disabilities monitoring network, United States, 2006. Surveillance summaries, morbidity and mortality weekly report, 58, SS-10, pp. 1–28.

  • Christian, S. L., Brune, C. W., Sudi, J., Kumar, R. A., Liu, S., Karamohamed, S., et al. (2008). Novel submicroscopic chromosomal abnormalities detected in autism spectrum disorder. Biological Psychiatry, 63, 1111–1117.

    Article  PubMed  Google Scholar 

  • Cohen, I. L., Gomez, T. R., Gonzalez, M. G., Lennon, E. M., Karmel, B. Z., & Gardner, J. M. (2010). Parent PDD behavior inventory profiles of young children classified according to autism diagnostic observation schedule-generic and autism diagnostic interview-revised criteria. Journal of Autism and Developmental Disorders, 40, 246–254.

    Article  PubMed  Google Scholar 

  • Cohen, I. L., & Sudhalter, V. (2005). The PDD behavior inventory. Lutz, FL: Psychological Assessment Resources, Inc.

    Google Scholar 

  • Davies, W., Isles, A. R., & Wilkinson, L. S. (2005). Imprinted gene expression in the brain. Neuroscience Biobehavioral Reviews, 29, 421–430.

    Article  Google Scholar 

  • Friso, S., Choi, S. W., Girelli, D., Mason, J. B., Dolnikowski, G. G., Bagley, P. J. et al. (2002). A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status. In Proceedings of the national academy of sciences USA, 99, pp. 5606–5611.

  • Friso, S., Girelli, D., Trabetti, E., Olivieri, O., Guarini, P., Pignatti, P. F., et al. (2005). The MTHFR 1298A > C polymorphism and genomic DNA methylation in human lymphocytes. Cancer Epidemiology, Biomarkers and Prevention, 14, 938–943.

    Article  PubMed  Google Scholar 

  • Frosst, P., Blom, H. J., Milos, R., Goyette, P., Sheppard, C. A., Matthews, R. G., et al. (1995). A candidate genetic risk factor for vascular disease: A common mutation in methylenetetrahydrofolate reductase. Nature Genetics, 10, 111–113.

    Article  PubMed  Google Scholar 

  • Ghosh, R. P., Horowitz-Scherer, R. A., Nikitina, T., Gierasch, L. M., & Woodcock, C. L. (2008). Rett syndrome-causing mutations in human MeCP2 result in diverse structural changes that impact folding and DNA interactions. Journal of Biological Chemistry, 283, 20523–20534.

    Article  PubMed  Google Scholar 

  • Goos, L. M., & Silverman, I. (2001). The influence of genomic imprinting on brain development and behavior. Evolution and Human Behavior, 22, 385–407.

    Article  Google Scholar 

  • Hogart, A., Nagarajan, R. P., Patzel, K. A., Yasui, D. H., & Lasalle, J. M. (2007). 15q11-13 GABAA receptor genes are normally biallelically expressed in brain yet are subject to epigenetic dysregulation in autism-spectrum disorders. Human Molecular Genetics, 16, 691–703.

    Article  PubMed  Google Scholar 

  • Isles, A. R., & Wilkinson, L. S. (2000). Imprinted genes, cognition and behavior. Trends in Cognitive Sciences, 4, 309–318.

    Article  PubMed  Google Scholar 

  • James, S. J., Melnyk, S., Jernigan, S., Cleves, M. A., Halsted, C. H., Wong, D. H., et al. (2006). Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism. American Journal of Medical Genetics Part B Neuropsychiatric Genetics, 141B, 947–956.

    Article  Google Scholar 

  • James, S. J., Melnyk, S., Jernigan, S., Hubanks, A., Rose, S., & Gaylor, D. W. (2008). Abnormal transmethylation/transsulfuration Metabolism and DNA hypomethylation among parents of children with autism. Journal of Autism and Developmental Disorders, 38, 1966–1975.

    Article  PubMed  Google Scholar 

  • Jiang, Y. H., Sahoo, T., Michaelis, R. C., Bercovich, D., Bressler, J., Kashork, C. D., et al. (2004). A mixed epigenetic/genetic model for oligogenic inheritance of autism with a limited role for UBE3A. American Journal Medical Genetics Part A, 131, 1–10.

    Article  Google Scholar 

  • Kimura, M., Umegaki, K., Higuchi, M., Thomas, P., & Fenech, M. (2004). Methylenetetrahydrofolate reductase C677T polymorphism, folic acid and riboflavin are important determinants of genome stability in cultured human lymphocytes. Journal of Nutrition, 134, 48–56.

    PubMed  Google Scholar 

  • Kotsopoulos, J., Zhang, W. W., Zhang, S., McCready, D., Trudeau, M., Zhang, P., et al. (2008). Polymorphisms in folate metabolizing enzymes and transport proteins and the risk of breast cancer. Breast Cancer Research and Treatment, 112, 585–593.

    Article  PubMed  Google Scholar 

  • Krepischi, A. C., Kok, F., & Otto, P. G. (1998). X chromosome-inactivation patterns in patients with Rett syndrome. Human Genetics, 102, 319–321.

    Article  PubMed  Google Scholar 

  • Laird, N. M., Horvath, S., & Xu, X. (2000). Implementing a unified approach to family-based tests of association. Genetic Epidemiology, 19(1), S36–S42.

    Article  PubMed  Google Scholar 

  • Liu, X., Novosedlik, N., Wang, A., Hudson, M. L., Cohen, I. L., Chudley, A. E., et al. (2009). The DLX1and DLX2 genes and susceptibility to autism spectrum disorders. European Journal of Human Genetics, 17, 228–235.

    Article  PubMed  Google Scholar 

  • Lord, C., Rutter, M., Goode, S., Heemsbergen, J., Jordan, H., Mawhood, L., et al. (1989). Autism diagnostic observation schedule: A standardized observation of communicative and social behavior. Journal of Autism and Developmental Disorders, 19, 185–212.

    Article  PubMed  Google Scholar 

  • Lord, C., Rutter, M., & Le, C. A. (1994). Autism diagnostic interview-revised: A revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. Journal of Autism and Developmental Disorders, 24, 659–685.

    Article  PubMed  Google Scholar 

  • Marshall, C. R., Noor, A., Vincent, J. B., Lionel, A. C., Feuk, L., Skaug, J., et al. (2008). Structural variation of chromosomes in autism spectrum disorder. American Journal of Human Genetics, 82, 477–488.

    Article  PubMed  Google Scholar 

  • Mohammad, N. S., Jain, J. M., Chintakindi, K. P., Singh, R. P., Naik, U., & Akella, R. R. (2009). Aberrations in folate metabolic pathway and altered susceptibility to autism. Psychiatric Genetics, 19, 171–176.

    Article  PubMed  Google Scholar 

  • Ott, J. (1999). Methods of analysis and resources available for genetic trait mapping. Journal of Heredity, 90, 68–70.

    Article  PubMed  Google Scholar 

  • Pasca, S. P., Nemes, B., Vlase, L., Gagyi, C. E., Dronca, E., Miu, A. C., et al. (2006). High levels of homocysteine and low serum paraoxonase 1 arylesterase activity in children with autism. Life Sciences, 78, 2244–2248.

    Article  PubMed  Google Scholar 

  • Qiao, Y., Riendeau, N., Koochek, M., Liu, X., Harvard, C., Hildebrand, M. J., et al. (2009). Phenomic determinants of genomic variation in autism spectrum disorders. Journal of Medical Genetics, 46, 680–688.

    Article  PubMed  Google Scholar 

  • Reik, W., & Walter, J. (2001). Genomic imprinting: Parental influence on the genome. Nature Reviews Genetics, 2, 21–32.

    Article  PubMed  Google Scholar 

  • Risch, N., Spiker, D., Lotspeich, L., Nouri, N., Hinds, D., Hallmayer, J., et al. (1999). A genomic screen of autism: Evidence for a multilocus etiology. American Journal of Human Genetics, 65, 493–507.

    Article  PubMed  Google Scholar 

  • Schanen, N. C. (2006). Epigenetics of autism spectrum disorders. Human Molecular Genetics, 15(Spec No 2), R138–R150.

    Article  PubMed  Google Scholar 

  • Sebat, J., Lakshmi, B., Malhotra, D., Troge, J., Lese-Martin, C., Walsh, T., et al. (2007). Strong association of de novo copy number mutations with autism. Science, 316, 445–449.

    Article  PubMed  Google Scholar 

  • Tabolacci, E., Pietrobono, R., Moscato, U., Oostra, B. A., Chiurazzi, P., & Neri, G. (2005). Differential epigenetic modifications in the FMR1 gene of the fragile X syndrome after reactivating pharmacological treatments. European Journal of Human Genetics, 13, 641–648.

    Article  PubMed  Google Scholar 

  • Ulvik, A., Ueland, P. M., Fredriksen, A., Meyer, K., Vollset, S. E., Hoff, G., et al. (2007). Functional inference of the methylenetetrahydrofolate reductase 677C > T and 1298A > C polymorphisms from a large-scale epidemiological study. Human Genetics, 121, 57–64.

    Article  PubMed  Google Scholar 

  • van der Put, N. M., Gabreels, F., Stevens, E. M., Smeitink, J. A., Trijbels, F. J., Eskes, T. K., et al. (1998). A second common mutation in the methylenetetrahydrofolate reductase gene: An additional risk factor for neural-tube defects? American Journal of Human Genetics, 62, 1044–1051.

    Article  PubMed  Google Scholar 

  • Webb, T., & Watkiss, E. (1996). A comparative study of X-inactivation in Rett syndrome probands and control subjects. Clinical Genetics, 49, 189–195.

    Article  PubMed  Google Scholar 

  • Wilson, A. S., Power, B. E., & Molloy, P. L. (2007). DNA hypomethylation and human diseases. Biochimica et Biophysica Acta, 1775, 138–162.

    PubMed  Google Scholar 

  • Yi, P., Pogribny, I., & James, S. J. (2002). Multiplex PCR for simultaneous detection of 677 C– > T and 1298 A– > C polymorphisms in methylenetetrahydrofolate reductase gene for population studies of cancer risk. Cancer Letters, 181, 209–213.

    Article  PubMed  Google Scholar 

  • Zhao, J. H. (2004). 2LD, GENECOUNTING and HAP: Computer programs for linkage disequilibrium analysis. Bioinformatics, 20, 1325–1326.

    Article  PubMed  Google Scholar 

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Acknowledgments

We extend our sincere appreciation to our research subjects and their extended family members for their enthusiastic support of this study and acknowledge the resources provided by the AGRE (Autism Genetics Resource Exchange) consortium and the participating AGRE families. AGRE is a program of Cure Autism Now and supported, in part, by grant MH64547 from the NIMH to Daniel H. Geschwind (PI). This work was supported by an OMHF grant (JJAH principal investigator) and a CIHR Interdisciplinary Health Research Team grant (RT-43820) to the Autism Spectrum Disorders Canadian-American Research Consortium (ASD-CARC: www.autismresearch.ca) (JJAH, principal investigator); MESL sincerely appreciates the support provided by a Michael Smith Foundation for Health Research Career Investigator (Scholar) Award (2005–2010); and we appreciate the support of the New York State Office for People with Developmental Disabilities (OPWDD).

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Correspondence to Jeanette J. A. Holden.

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Liu, X., Solehdin, F., Cohen, I.L. et al. Population- and Family-Based Studies Associate the MTHFR Gene with Idiopathic Autism in Simplex Families. J Autism Dev Disord 41, 938–944 (2011). https://doi.org/10.1007/s10803-010-1120-x

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