Abstract
The male-to-female (M:F) ratio for autism spectrum disorders (ASD), typically about 4:1, appears to decrease with increasing paternal age, but this relationship has not been systematically tested. With 393 ASD cases from families with two or more ASD cases, we categorized paternal age into five age groups (<30, 30–34, 35–39, 40–44, 45+) and found that the M:F ratio was significantly decreased with increasing paternal age groups and remained so after also adjusting for maternal age. No significant relationship between maternal age group and the M:F ratio was observed. This study suggests that the M:F ratio is reduced with increasing paternal age consistent with de novo genetic or genomic anomalies arising more frequently as men age and then conceive children.
References
Brooks, W. H. (2005). Autoimmune disorders result from loss of epigenetic control following chromosome damage. Medical Hypotheses, 64, 590–598. doi:10.1016/j.mehy.2004.08.005.
Cantor, R. M., Kono, N., Duvall, J. A., varez-Retuerto, A., Stone, J. L., Alarcon, M., et al. (2005). Replication of autism linkage: Fine-mapping peak at 17q21. American Journal of Human Genetics, 76, 1050–1056. doi:10.1086/430278.
Cantor, R. M., Yoon, J. L., Furr, J., & Lajonchere, C. M. (2007). Paternal age and autism are associated in a family-based sample. Molecular Psychiatry, 12, 419–421. doi:10.1038/sj.mp.4001966.
Croen, L. A., Najjar, D. V., Fireman, B., & Grether, J. K. (2007). Maternal and paternal age and risk of autism spectrum disorders. Archives of Pediatrics and Adolescent Medicine, 161, 334–340. doi:10.1001/archpedi.161.4.334.
Crow, J. F. (1997). The high spontaneous mutation rate: Is it a health risk? Proceedings of the National Academy of Sciences of the United States of America, 94, 8380–8386. doi:10.1073/pnas.94.16.8380.
Fombonne, E. (2003). Epidemiological surveys of autism and other pervasive developmental disorders: An update. Journal of Autism and Developmental Disorders, 33, 365–382. doi:10.1023/A:1025054610557.
Glasson, E. J., Bower, C., Petterson, B., de, K. N., Chaney, G., & Hallmayer, J. F. (2004). Perinatal factors and the development of autism: A population study. Archives of General Psychiatry, 61, 618–627. doi:10.1001/archpsyc.61.6.618.
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. doi:10.1093/hmg/7.3.571.
Lauritsen, M. B., Pedersen, C. B., & Mortensen, P. B. (2005). Effects of familial risk factors and place of birth on the risk of autism: A nationwide register-based study. Journal of Child Psychology and Psychiatry and Allied Disciplines, 46, 963–971. doi:10.1111/j.1469-7610.2004.00391.x.
Lord, C., Risi, S., Lambrecht, L., Cook, E. H., Jr, Leventhal, B. L., DiLavore, P. C., et al. (2000). The autism diagnostic observation schedule-generic: A standard measure of social and communication deficits associated with the spectrum of autism. Journal of Autism and Developmental Disorders, 30, 205–223. doi:10.1023/A:1005592401947.
Lord, C., Rutter, M., & Le Couteur, 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. doi:10.1007/BF02172145.
Ma, D. Q., Cuccaro, M. L., Jaworski, J. M., Haynes, C. S., Stephan, D. A., Parod, J., et al. (2007). Dissecting the locus heterogeneity of autism: Significant linkage to chromosome 12q14. Molecular Psychiatry, 12, 376–384. doi:10.1038/sj.mp.4001927.
Miles, J. H., Takahashi, T. N., Bagby, S., Sahota, P. K., Vaslow, D. F., Wang, C. H., et al. (2005). Essential versus complex autism: Definition of fundamental prognostic subtypes. American Journal of Medical Genetics. Part A, 135, 171–180. doi:10.1002/ajmg.a.30590.
Miller, M. C. (2006). Older father, autistic child. The Harvard Mental Health Letter, 23, 8.
Puleo, C. M., Reichenberg, A., Smith, C. J., Kryzak, L. A., & Silverman, J. M. (2008). Do autism-related personality traits explain higher paternal age in autism? Molecular Psychiatry, 13, 243–244. doi:10.1038/sj.mp.4002102.
Reichenberg, A., Gross, R., Weiser, M., Bresnahan, M., Silverman, J., Harlap, S., et al. (2006). Advancing paternal age and autism. Archives of General Psychiatry, 63, 1026–1032. doi:10.1001/archpsyc.63.9.1026.
Ruder, A. (1985). Paternal-age and birth-order effect on the human secondary sex ratio. American Journal of Human Genetics, 37, 362–372.
Schellenberg, G. D., Dawson, G., Sung, Y. J., Estes, A., Munson, J., Rosenthal, E. et al. (2006). Evidence for multiple loci from a genome scan of autism kindreds. Molecular Psychiatry, 11, 1049–60, 979.
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. doi:10.1126/science.1138659.
Silverman, J. M., Smith, C. J., Schmeidler, J., Hollander, E., Lawlor, B. A., Fitzgerald, M., et al. (2002). Symptom domains in autism and related conditions: Evidence for familiality. American Journal of Medical Genetics, 114, 64–73. doi:10.1002/ajmg.10048.
Skuse, D. H. (2000). Imprinting, the X-chromosome, and the male brain: Explaining sex differences in the liability to autism. Pediatric Research, 47, 9–16. doi:10.1203/00006450-200001000-00006.
Stone, J. L., Merriman, B., Cantor, R. M., Yonan, A. L., Gilliam, T. C., Geschwind, D. H., et al. (2004). Evidence for sex-specific risk alleles in autism spectrum disorder. American Journal of Human Genetics, 75, 1117–1123. doi:10.1086/426034.
Szatmari, P., Paterson, A. D., Zwaigenbaum, L., Roberts, W., Brian, J., Liu, X. Q., et al. (2007). Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nature Genetics, 39, 319–328. doi:10.1038/ng1985.
Tsuchiya, K. J., Matsumoto, K., Miyachi, T., Tsujii, M., Nakamura, K., Takagai, S., et al. (2008). Paternal age at birth and high-functioning autistic-spectrum disorder in offspring. The British Journal of Psychiatry, 193, 316–321. doi:10.1192/bjp.bp.107.045120.
Volkmar, F. R., Szatmari, P., & Sparrow, S. S. (1993). Sex differences in pervasive developmental disorders. Journal of Autism and Developmental Disorders, 23, 579–591. doi:10.1007/BF01046103.
Weiss, L. A., Shen, Y., Korn, J. M., Arking, D. E., Miller, D. T., Fossdal, R., et al. (2008). Association between microdeletion and microduplication at 16p11.2 and autism. The New England Journal of Medicine, 358, 667–675. doi:10.1056/NEJMoa075974.
Wyrobek, A. J., Eskenazi, B., Young, S., Arnheim, N., Tiemann-Boege, I., Jabs, E. W., et al. (2006). Advancing age has differential effects on DNA damage, chromatin integrity, gene mutations, and aneuploidies in sperm. Proceedings of the National Academy of Sciences of the United States of America, 103, 9601–9606. doi:10.1073/pnas.0506468103.
Zhao, X., Leotta, A., Kustanovich, V., Lajonchere, C., Geschwind, D. H., Law, K., et al. (2007). A unified genetic theory for sporadic and inherited autism. Proceedings of the National Academy of Sciences of the United States of America, 104, 12831–12836. doi:10.1073/pnas.0705803104.
Acknowledgments
This work was supported by grants from the Beatrice and Samuel A. Seaver Foundation, the National Institutes of Health through a studies to Advance Autism Research and Treatment grant (MH-066673) and Cure Autism Now. We gratefully acknowledge all the families who participated in this study and the resources provided by the Autism Genetic Resource Exchange (AGRE) Consortium. The Autism Genetic Resource Exchange is a program of Cure Autism Now and is supported, in part, by grant MH64547 from the National Institute of Mental Health to Daniel H. Geschwind (PI); the web site http://www.agre.org contains a list of consortium members. We appreciate the support and consultations from Ms. Janet Longo-Abinanti and the time and effort from all the families who participated in this study.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Anello, A., Reichenberg, A., Luo, X. et al. Brief Report: Parental Age and the Sex Ratio in Autism. J Autism Dev Disord 39, 1487–1492 (2009). https://doi.org/10.1007/s10803-009-0755-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10803-009-0755-y