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Understanding how environmental adversity increases suicide risk: epigenetic mechanisms. Gustavo Turecki MD PhD William Dawson Chair Douglas Hospital Research Centre McGill University. CSA, CPA and Suicide Attempts. Fergusson et al. Child Abuse & Neglect, 2008. Childhood abuse and SB.
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Understanding how environmental adversity increases suicide risk: epigenetic mechanisms Gustavo Turecki MD PhD William Dawson Chair Douglas Hospital Research Centre McGill University
CSA, CPA and Suicide Attempts Fergusson et al. Child Abuse & Neglect, 2008
Childhood abuse and SB Brezo et al, British J Psychiatry 2008
How can events occurring during childhood influence suicide risk later on in life?
Glucocorticoid Receptor (GR) regulation, quality of maternal care, and cognitive function in rats Regulation of hippocampal GR expression by maternal care…. … affects behavioral phenotype in adult rats. Francis et al., Science 1999; Caldji et al., PNAS 1998
Nerve growth factor-inducible protein A (NGFI-A) Meaney and Szyf, 2005
ACCCCTTAGGCCTAGGGAACTTCTTACCTACCTTGGCGCGCGCGCGCGCGCGCTTACCTTTTTAATATAACCCCTTAGGCCTAGGGAACTTCTTACCTACCTTGGCGCGCGCGCGCGCGCGCTTACCTTTTTAATATA CCTTGAAGAATGGATGGAACCGCGC
Serotonin transporter gene (5HTT) and sequence variability 5-HTT gene Promoter variants AAAGGRRRRGTTAGTAC – short (s) variant AAAGGRRRRRRRRRRRRRRRRRRRRGTTAGTAC – long (L) variant S variant L variant
Epigenetics: DNA Methylation Protein CH3 CH3 CH3 Protein Protein Environmental factors
Epigenetics:Chromatin modifications Active Inactive Tsankova et al, 2007
Volcano plots of four MZ twin versus co-twin WBC DNA methylation profile comparisons (black), with overlay of four matched twin DNA versus self comparisons (green) for each set of MZ twins Kaminsky et al, Nat Genet 2009
GR gene: 11 untranslated exon 1variants in Rats and Humans Turner and Muller, Mol. Endo. 2005
GR methylation, GR expression and cognitive function in rats Weaver et al., Nat:Neurosci 2004 Nerve growth factor-inducible protein A (NGFI-A)
GR regulation, early life trauma, and cognitive function in humans • Hippocampal GR in humans: • GR mRNA is downregulated in different psychiatric illnesses. Webster et al., Mol. Psych. 2002
Trier Social Stress Test and Suicide Risk McGirr et al, 2008
Could early childhood adversity be associated with increased GR promoter methylation in suicide?
Sample Suicides with documented evidence of severe childhood abuse/neglect (N=12) AOD =34.17 years PMI = 24.20 pH = 6.32 Suicides with out Hx of abuse/neglect (N=12) AOD = 33.8 PMI =39 pH=6.5 Sudden death controls without Hx of abuse/neglect ( N= 12) AOD = 35.75 years PMI = 23.45 pH = 6.44
GR expression in human hippocampus McGowan et al, Nature Neurosci 2009
Is the increased GR promoter methylation a general genomic effect?
Nearest Neighbour analysis of methylated CpG content McGowan et al, PlosOne 2008
In vitro analysis of GR1F promoter methylation 255 bp (solid underline) construct 125 bp ( broken underline) construct Circles: specific CpGdinucleotidesmethylated in each construct Boxes represent known or putative canonical and noncanonical NGFI-A binding sites with the shaded area: beginning of the exon McGowan et al, Nat Neuroscience 2009
Patch Methylation and ChIPAssays McGowan et al, Nat Neuroscience 2009
Early negative life stressors Mediators Moderators Biological and Genetic Examples: Suicide Makeup Example: Personality traits: high IIABs Gender Substance abuse Life events Major Depression Genetic makeup Social factors Turecki, JPN 2005
gustavo.turecki@mcgill.ca • www.douglasrecherche.qc.ca/suicide