title: A functional polymorphism in the reduced folate carrier gene and DNA hypomethylation in mothers of children with autism.
abstract: 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.
authors.affiliation: Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA. jamesjill@uams.edu
authors.forename: S Jill
authors.initials: SJ
authors.lastname: James
authors.forename: Stepan
authors.initials: S
authors.lastname: Melnyk
authors.forename: Stefanie
authors.initials: S
authors.lastname: Jernigan
authors.forename: Oleksandra
authors.initials: O
authors.lastname: Pavliv
authors.forename: Timothy
authors.initials: T
authors.lastname: Trusty
authors.forename: Sara
authors.initials: S
authors.lastname: Lehman
authors.forename: Lisa
authors.initials: L
authors.lastname: Seidel
authors.forename: David W
authors.initials: DW
authors.lastname: Gaylor
authors.forename: Mario A
authors.initials: MA
authors.lastname: Cleves
mesh_terms: D000328:Adult; D000483:Alleles; D001321:Autistic Disorder / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation / Q000235:genetics*; D057890:Epigenomics; D005260:Female; D005492:Folic Acid / Q000378:metabolism; D005787:Gene Frequency; D006801:Humans; D008297:Male; D009035:Mothers; D011110:Polymorphism, Genetic / Q000235:genetics*; D058978:Reduced Folate Carrier Protein / Q000235:genetics*; D055815:Young Adult
chemical_list: D058978:Reduced Folate Carrier Protein; D005492:Folic Acid
references.citation: Am J Med Genet. 1999 Aug 20;88(4):311-23
references.pmid: 10402496
references.citation: Clin Sci (Lond). 1995 Jan;88(1):73-9
references.pmid: 7705005
references.citation: Pediatrics. 2008 Jun;121(6):1225-9
references.pmid: 18519493
references.citation: J Nutr. 2002 Aug;132(8 Suppl):2361S-2366S
references.pmid: 12163693
references.citation: Am J Epidemiol. 1998 Nov 1;148(9):893-901
references.pmid: 9801020
references.citation: Arch Pediatr Adolesc Med. 2007 Apr;161(4):356-61
references.pmid: 17404132
references.citation: QJM. 2001 Mar;94(3):159-66
references.pmid: 11259691
references.citation: J Autism Dev Disord. 2008 Nov;38(10):1976
references.pmid: 19011973
references.citation: J Nutr. 1999 Sep;129(9):1656-61
references.pmid: 10460200
references.citation: Am J Clin Nutr. 2005 Jun;81(6):1436-41
references.pmid: 15941899
references.citation: Br J Nutr. 2000 Jun;83(6):593-6
references.pmid: 10911766
references.citation: Clin Chim Acta. 2008 Dec;398(1-2):134-9
references.pmid: 18823966
references.citation: Biol Psychiatry. 1998 Jul 15;44(2):141-3
references.pmid: 9646897
references.citation: Birth Defects Res A Clin Mol Teratol. 2006 Jul;76(7):544-52
references.pmid: 16933307
references.citation: Mech Dev. 2001 May;103(1-2):35-47
references.pmid: 11335110
references.citation: Nature. 2009 May 28;459(7246):569-73
references.pmid: 19404257
references.citation: Hum Mol Genet. 2005 Feb 15;14(4):483-92
references.pmid: 15615769
references.citation: Psychiatr Genet. 2007 Jun;17(3):177-81
references.pmid: 17417062
references.citation: Electrophoresis. 2001 Aug;22(14):2838-43
references.pmid: 11565778
references.citation: Am J Hum Genet. 1998 Apr;62(4):969-78
references.pmid: 9529360
references.citation: Am J Clin Nutr. 1999 Oct;70(4):495-501
references.pmid: 10500018
references.citation: Beijing Da Xue Xue Bao Yi Xue Ban. 2005 Aug 18;37(4):341-5
references.pmid: 16086047
references.citation: Neurology. 1999 Mar 10;52(4):750-6
references.pmid: 10078722
references.citation: Arch Pediatr Adolesc Med. 2009 Jun;163(6):542-6
references.pmid: 19487610
references.citation: Birth Defects Res A Clin Mol Teratol. 2009 Apr;85(4):274-84
references.pmid: 19180567
references.citation: Mol Genet Metab. 2006 Apr;87(4):364-9
references.pmid: 16343969
references.citation: Am J Hum Genet. 1993 Mar;52(3):506-16
references.pmid: 8447318
references.citation: Atherosclerosis. 2001 Aug;157(2):451-6
references.pmid: 11472746
references.citation: J Nutr Biochem. 1999 Aug;10(8):490-7
references.pmid: 15539328
references.citation: Am J Clin Nutr. 2009 Feb;89(2):673S-7S
references.pmid: 19116320
references.citation: FASEB J. 2006 Jan;20(1):43-9
references.pmid: 16394266
references.citation: Nature. 2007 May 24;447(7143):425-32
references.pmid: 17522676
references.citation: Nutr Rev. 2008 May;66(5):250-5
references.pmid: 18454811
references.citation: Proc Nutr Soc. 2006 May;65(2):204-15
references.pmid: 16672082
references.citation: Am J Clin Nutr. 2000 May;71(5 Suppl):1295S-303S
references.pmid: 10799405
references.citation: Am J Med Genet A. 2003 Sep 1;121A(3):219-24
references.pmid: 12923861
references.citation: Clin Chem Lab Med. 2007;45(4):471-6
references.pmid: 17439323
references.citation: Am J Med Genet A. 2004 Nov 15;131(1):1-10
references.pmid: 15389703
references.citation: Curr Opin Allergy Clin Immunol. 2009 Oct;9(5):417-26
references.pmid: 19652594
references.citation: Am J Clin Nutr. 2005 Jan;81(1):147-53
references.pmid: 15640474
references.citation: Am J Med Genet. 1999 May 21;84(2):151-7
references.pmid: 10323741
references.citation: Scand J Clin Lab Invest. 1999 Apr;59(2):139-46
references.pmid: 10353328
references.citation: Life Sci. 2005 Oct 14;77(22):2735-42
references.pmid: 15964598
references.citation: Am J Hum Genet. 2000 Oct;67(4):986-90
references.pmid: 10958762
references.citation: Life Sci. 2006 Aug 1;79(10):957-66
references.pmid: 16750224
references.citation: Dialogues Clin Neurosci. 2009;11(1):35-43
references.pmid: 19432386
references.citation: Pharmacol Rev. 2002 Dec;54(4):599-618
references.pmid: 12429870
references.citation: Int J Dev Neurosci. 2008 Aug;26(5):423-34
references.pmid: 18423945
references.citation: Teratog Carcinog Mutagen. 1998;18(2):49-61
references.pmid: 9704382
references.citation: Mol Genet Metab. 2000 Aug;70(4):310-5
references.pmid: 10993718
references.citation: Proc Natl Acad Sci U S A. 2007 Aug 7;104(32):13056-61
references.pmid: 17670942
references.citation: Hum Mol Genet. 2001 Mar 1;10(5):433-43
references.pmid: 11181567
references.citation: J Nutr. 2001 Nov;131(11):2811-8
references.pmid: 11694601
references.citation: Autoimmun Rev. 2007 Aug;6(7):503-9
references.pmid: 17643940
references.citation: Hum Mol Genet. 2006 Oct 15;15 Spec No 2:R138-50
references.pmid: 16987877
references.citation: J Biol Chem. 2009 Jan 23;284(4):1982-9
references.pmid: 19001366
references.citation: Am J Clin Nutr. 2009 May;89(5):1488S-1493S
references.pmid: 19261726
references.citation: Arch Gen Psychiatry. 2007 Aug;64(8):980-1
references.pmid: 17679645
references.citation: Epigenetics. 2006 Oct-Dec;1(4):e1-11
references.pmid: 17486179
references.citation: Clin Chem. 2000 Feb;46(2):265-72
references.pmid: 10657384
references.citation: J Nutr. 1999 May;129(5):919-22
references.pmid: 10222379
references.citation: Genet Epidemiol. 1997;14(4):337-47
references.pmid: 9271708
references.citation: Pediatr Neurol. 2006 Nov;35(5):303-7
references.pmid: 17074598
references.citation: J Nutr. 1998 Jul;128(7):1204-12
references.pmid: 9649607
references.citation: Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2005 Jun;22(3):284-7
references.pmid: 15952116
references.citation: Am J Obstet Gynecol. 1999 Mar;180(3 Pt 1):660-4
references.pmid: 10076144
references.citation: PLoS Med. 2009 May 5;6(5):e1000061
references.pmid: 19434228
references.citation: Birth Defects Res A Clin Mol Teratol. 2008 Oct;82(10):676-83
references.pmid: 18937356
references.citation: Anal Chem. 2002 Sep 1;74(17):4526-31
references.pmid: 12236365
references.citation: Br J Nutr. 2006 Sep;96(3):415-7
references.pmid: 16925844
references.citation: Hum Mol Genet. 2008 Jul 1;17(13):2047-57
references.pmid: 18385101
references.citation: Am J Hum Genet. 2002 Nov;71(5):1222-6
references.pmid: 12375236
references.citation: Trends Neurosci. 2003 Mar;26(3):137-46
references.pmid: 12591216
references.citation: J Nutr. 2002 Aug;132(8 Suppl):2333S-2335S
references.pmid: 12163687
references.citation: Eur J Clin Nutr. 2006 Mar;60(3):364-71
references.pmid: 16340954
references.citation: Bioessays. 2003 May;25(5):464-77
references.pmid: 12717817
references.citation: Int J Epidemiol. 2009 Jun;38(3):715-23
references.pmid: 19336437
references.citation: Harv Rev Psychiatry. 2005 Jul-Aug;13(4):197-205
references.pmid: 16126606
references.citation: Am J Obstet Gynecol. 2008 Sep;199(3):276.e1-8
references.pmid: 18771981
references.citation: J Evol Biol. 2006 Jul;19(4):1007-32
references.pmid: 16780503
references.citation: Am J Med Genet B Neuropsychiatr Genet. 2006 Dec 5;141B(8):947-56
references.pmid: 16917939
references.citation: Curr Psychiatry Rep. 2009 Apr;11(2):137-42
references.pmid: 19302767
references.citation: J Biol Chem. 2000 Sep 22;275(38):29318-23
references.pmid: 10884384