A functional polymorphism in the reduced folate carrier gene and DNA hypomethylation in mothers of children with autism

• Published in: American journal of medical genetics. Part B, Neuropsychiatric genetics Vol. 153B; no. 6; pp. 1209 - 1220
• Main Authors: James, S. Jill, Melnyk, Stepan, Jernigan, Stefanie, Pavliv, Oleksandra, Trusty, Timothy, Lehman, Sara, Seidel, Lisa, Gaylor, David W., Cleves, Mario A.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.09.2010; Wiley-Liss
• Subjects: Adenosine; Adult; Alleles; Autism; Autistic Disorder - genetics; Biological and medical sciences; Carbon; Case-Control Studies; Child; Child clinical studies; Child, Preschool; Children; Developmental disorders; Differentiation; DNA biosynthesis; DNA methylation; DNA Methylation - genetics; Embryogenesis; epigenetics; Epigenomics; Female; Fetuses; Folic acid; Folic Acid - metabolism; Gene expression; Gene Frequency; Gene polymorphism; General aspects. Genetic counseling; homocysteine; Humans; Infantile autism; Male; maternal; Medical genetics; Medical sciences; Metabolism; Microenvironments; Mothers; Organogenesis; polymorphism; Polymorphism, Genetic - genetics; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; reduced folate carrier; Reduced Folate Carrier Protein - genetics; Young Adult; Human; Nervous system diseases; Developmental disorder; Folate; Genetic disease; Autism; Genetic counseling; Gene; Mother; DNA; Epigenetics; DNA methylation; Genetics; Carrier; reduced folate carrier; Methylation; Neurological disorder; Child; Polymorphism; maternal
• ISSN: 1552-4841; 1552-485X; 1552-485X
• DOI: 10.1002/ajmg.b.31094

The biologic basis of autism is complex and is thought to involve multiple and variable gene–environment interactions. While the logical focus has been on the affected child, the impact of maternal genetics on intrauterine microenvironment during pivotal developmental windows could be substantial. Folate‐dependent one carbon metabolism is a highly polymorphic pathway that regulates the distribution of one‐carbon derivatives between DNA synthesis (proliferation) and DNA methylation (cell‐specific gene expression and differentiation). These pathways are essential to support the programmed shifts between proliferation and differentiation during embryogenesis and organogenesis. Maternal genetic variants that compromise intrauterine availability of folate derivatives could alter fetal cell trajectories and disrupt normal neurodevelopment. In this investigation, the frequency of common functional polymorphisms in the folate pathway was investigated in a large population‐based sample of autism case‐parent triads. In case–control analysis, a significant increase in the reduced folate carrier (RFC1) G allele frequency was found among case mothers, but not among fathers or affected children. Subsequent log linear analysis of the RFC1 A80G genotype within family trios revealed that the maternal G allele was associated with a significant increase in risk of autism whereas the inherited genotype of the child was not. Further, maternal DNA from the autism mothers was found to be significantly hypomethylated relative to reference control DNA. Metabolic profiling indicated that plasma homocysteine, adenosine, and S‐adenosylhomocyteine were significantly elevated among autism mothers consistent with reduced methylation capacity and DNA hypomethylation. Together, these results suggest that the maternal genetics/epigenetics may influence fetal predisposition to autism. © 2010 Wiley‐Liss, Inc.