Prenatal exposure to maternal depressed mood and the MTHFR C677T variant affect SLC6A4 methylation in infants at birth.
BACKGROUND
Prenatal and early postnatal exposure to maternal depression may "program" childhood behavior via epigenetic processes such as DNA methylation. Methylenetetrahydro-folate reductase (MTHFR) is an important enzyme in the generation of methyl groups for DNA methylation. The common MTHFR C677T variant is associated with depression in men and non-pregnant women, and with global changes in DNA methylation. This study investigated the effect of maternal MTHFR C677T genotype on antenatal maternal mood, and their impact on the gene-specific methylation in pregnant women and their newborn infants. The methylation status of SLC6A4, which encodes the transmembrane serotonin transporter, and BDNF, which encodes brain derived neurotrophic factor, were assessed because of their potential role in behaviour.


RESULTS
Depressed mood was assessed by the Edinburgh Postnatal Depression Scale (EPDS) and the Hamilton Rating Scale for Depression (HAM-D) in women (n = 82, all taking folate) during the 2(nd) and 3(rd) trimesters of pregnancy. The methylation status of SLC6A4 and BDNF were assessed in 3rd trimester maternal peripheral leukocytes and in umbilical cord leukocytes collected from their infants at birth. Women with the MTHFR 677TT genotype had greater 2(nd) trimester depressed mood (p<0.05). Increased 2(nd) trimester maternal depressed mood (EPDS scores) was associated with decreased maternal and infant SLC6A4 promoter methylation (p<0.05), but had no effect on BDNF promoter methylation.


CONCLUSIONS
These findings show that the MTHFR C677T variant is associated with greater depressed mood during pregnancy. We further showed that prenatal exposure to maternal depressed mood affects gene-specific DNA methylation patterns. These findings support the concept that alterations in epigenetic processes may contribute to developmental programming of behaviour by maternal depression.
Devlin
Angela M
AM
Department of Pediatrics, Child & Family Research Institute, University of British Columbia, Vancouver, Canada. angela.devlin@ubc.ca
Brain
Ursula
U
Austin
Jehannine
J
Oberlander
Tim F
TF
D000328:Adult; D001483:Base Sequence; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics; D019175:DNA Methylation; D003863:Depression; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D018811:Maternal Exposure; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D009035:Mothers; D036801:Parturition; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D011401:Promoter Regions, Genetic / Q000235:genetics; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*
D019208:Brain-Derived Neurotrophic Factor; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D042965:Methylenetetrahydrofolate Reductase (NADPH2)
Circulation. 1996 Jan 1;93(1):7-9
8616944
Am J Med Genet B Neuropsychiatr Genet. 2008 Jul 5;147B(5):543-9
17987668
Behav Brain Res. 1996;73(1-2):19-29
8788472
Science. 2003 Jul 18;301(5631):386-9
12869766
Proc Natl Acad Sci U S A. 2002 Apr 16;99(8):5606-11
11929966
J Neurochem. 1996 Jun;66(6):2621-4
8632190
PLoS One. 2008 May 07;3(5):e2085
18461137
N Engl J Med. 2003 Nov 20;349(21):2042-54
14627790
J Neurosci. 2008 Oct 15;28(42):10576-86
18923034
Int J Cancer. 2009 May 1;124(9):1999-2005
19123462
Am J Epidemiol. 2007 Jan 1;165(1):1-13
17074966
J Neurosci. 2008 Jan 2;28(1):199-207
18171937
Science. 2004 Oct 29;306(5697):879-81
15514160
Arch Gen Psychiatry. 2005 May;62(5):529-35
15867106
Early Hum Dev. 2008 Oct;84(10):689-97
18639992
Nat Neurosci. 2009 Mar;12(3):342-8
19234457
Epigenetics. 2008 Mar-Apr;3(2):97-106
18536531
Mol Psychiatry. 2007 Jun;12(6):522-43
17160067
J Med Genet. 2004 Jun;41(6):454-8
15173232
Am J Med Genet B Neuropsychiatr Genet. 2007 Jan 5;144B(1):101-5
16958039
Biol Psychiatry. 2009 May 1;65(9):760-9
19150054
Am J Hum Genet. 2008 Mar;82(3):696-711
18319075
Science. 1996 Nov 29;274(5292):1527-31
8929413
Arch Gen Psychiatry. 2008 Nov;65(11):1286-94
18981340
Anal Biochem. 2004 Oct 1;333(1):119-27
15351288
Br J Psychiatry. 2002 Jun;180:502-8
12042228
Mol Psychiatry. 2008 Jan;13(1):65-73
17519929
Biol Psychiatry. 2006 May 1;59(9):812-5
16442082
Biol Psychiatry. 1998 Aug 1;44(3):179-92
9693390
Arch Gen Psychiatry. 2006 Aug;63(8):898-906
16894066
Nat Rev Neurosci. 2003 Dec;4(12):1002-12
14618156
Mol Psychiatry. 2006 Apr;11(4):352-60
16402130
J Neurol Neurosurg Psychiatry. 1960 Feb;23:56-62
14399272
Nat Genet. 2003 Mar;33 Suppl:245-54
12610534
Nat Neurosci. 2004 Aug;7(8):847-54
15220929
Br J Psychiatry. 1987 Jun;150:782-6
3651732
Brain Res Mol Brain Res. 1999 May 7;68(1-2):141-8
10320791
Mol Psychiatry. 2008 Aug;13(8):772-85
17938638
Arch Pediatr Adolesc Med. 2010 May;164(5):444-51
20439795
Neurobiol Aging. 2006 Dec;27(12):1834-7
16343697
Nat Genet. 1995 May;10(1):111-3
7647779
Arch Gen Psychiatry. 2003 Jun;60(6):618-26
12796225
Am J Clin Nutr. 2006 Mar;83(3):708-13
16522921