How life events get under the skin: Implications for suicide - PowerPoint PPT Presentation

How life events get “under the skin”: Implications for suicide prevention Gustavo Turecki MD PhD William Dawson Chair Douglas Hospital Research Centre McGill University

Turecki et al Trends in Neurosciences 2012

CSA, CPA and Suicide Attempts Suicide attempts at age 16-18 according to CSA and CPA types None Contact Penetration None Regular Severe 25 CSA CPA 20 15 10 5 0 Fergusson et al. Child Abuse & Neglect, 2008

Suicide and Childhood Adversity Suicide completers 45 % 41.4 40 35 29.3 30 25 20 15 10 6.8 5 0 Any abuse Suicides Psychiatric controls Community Controls Ostovar et al, 2009

Abuser identity and suicide risk Brezo et al, British J Psychiatry 2008

HOW CAN EVENTS OCCURRING DURING CHILDHOOD INCREASE LIFETIME SUICIDE RISK?

The effect of age and experience on children’s ability to discriminate 2 non-English contrasts Werker & Tees, 2005

Sensitive periods in musical training Difference in anterior corpus callosum volume according to age of musical training Penhune, 2011

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

Ecker, Nature 2012

Gene Gene ene 1 RNA polymerase II Gene ene 2 chr chromosome omosome DNA Transcription Factors

DNA CYTOSINE METHYLATION C mC SAM-CH3 SAM H 3 C DNMT

Environmental influences Environmental influences modify epigenetic marks around our genes and modify their expression CH 3 CH 3 CH 3 Promoter CH 3 CH 3 CH 3 Promoter

The GR Gene: complex promoter in rats and humans NGFIA transcription factor binding site GR promoter determine in which tissue GR is expressed. Exon 1-7 (in rat) and 1F (in human) are specific to the hippocampus. Exon 1-7 and its homologue 1-F posses binding sites for the transcription factor NGFIA. 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)

HPA Axis

HPA and suicide risk Risk = 26.8% Risk = 2.9% 1990-2008 – primary health settings N = 78 inpatients N = 786,868 oral glucocorticoid treatment courses DST = 1mg DST N = 372,696 patients Coryell & Schlesser, AJP 2001 Fardet et al, AJP 2012

MGSS Brain Bank – Ongoing brain bank collection • Suicides and sudden-death controls without medical intervention – Psychological autopsies • Semi-structured interviews with an average of two informants per case • Clinical vignette • Assessment by a blind panel for best-consensus DSM IV diagnoses • Validation with medical records www.douglasrecherche.qc.ca/suicide

GR expression is decreased in the hippocampus of abused suicide completers McGowan et al, Nature Neurosci 2009

Site-specific hypermethylation in hGR1F promoter in abused suicide completers NGFI- A transcription factor’s binding site McGowan et al, Nature Neuroscience 2009

Human NR3C1 First Exon V ariants c d 1 , 3 , 9, 10, 4, 5 e 1 1 , a 1 f 12 , 13 2 g 6, 7 14 Direction of Findings b c 1 8 1 15 Studies: Footnotes: Maternal gestational stress 1. Hompes et al. 2013 a. CpG 12 & 13with fear of delivery all trimesters 2. Hogg et al. 2013 b. CpG 6 with fear of delivery Gestational and birth-related complications 3. Oberlander et al. 2008 c. site- and parameter-specific: site) ↓ with fear of changes T1 & 2; 4. Radtke et al. 20 1 1 CpG 38/39 (near NGFI- A History of childhood adversity CpG 36 ↑ with fear of integrity T1 & 2; 5. Mulligan et al. 2012 CpG 36 ↑ with fear of delivery T3 6. Filiberto et al. 20 1 1 7. Bromer et al. 2012 d. CpG 1-3, NGFI- A site Psychiatric diagnosis 8. El Hajj et al. 2013 e. CpG 1 & 3 only (NGFI- A site is CpG 3 & 4) 9. McGowan et al. 2009 f. CpG 35 (NGFI- A site is CpG 37 & 38) 10. Perroud et al. 20 1 1 g. CpG 1 and 5 1 1. T yrka et al. 2012 12. Melas et al. 2013 13. Perroud et al. 2013 14. Dammann et al. 20 1 1 15. Labonte et al. 2012

Hippocampus GR Normal development Exposure to early – life adversity Normal levels of GR in the hippocampus Low levels of GR in the hippocampus Stress Amygdala Stress activates HPA axis Stress activates HPA axis Hypothalamus CRH Secretion of cortisol Secretion of cortisol AVP Anterior Pituitary Binding of cortisol to GR Binding of cortisol to in the hippocampus GR in the hippocampus ACTH (poor binding) Lack of inhibition of the Inhibition of the HPA axis HPA axis (negative feed back) Adrenal cortex Overactive HPA axis Cortisol

Comparative methylation patterns associated with early environment across species Suderman et al, PNAS 2012

Genome-wide study Immunoprecipitation (MeDIP)-chip N abused suicide: 27 N controls: 17 Weber et al, Nature Genet 2005

Differentially methylated sequences and chromosomal distribution N = 355 Hypomethylated N = 110 31% Hypermethylated N = 245 69% P = 0.67 Hypermethylated Hypomethylated Chromosome

Inverse correlation between whole-genome expression and promoter methylation r = - 0.14, p≤4.6x10 -247 Labonté et al, Archives of General Psychiatry, 2012

Most significantly enriched functional annotation clusters Category Enrichment Score: 2,106 Count % P-value MF protein homodimerization activity 13 4,39 0,0054 Protein dimerization MF protein dimerization activity 17 5,74 0,0093 MF identical protein binding 19 6,42 0,0095 Category Enrichment Score: 1,683 Count % PValue BP negative regulation of immune response 4 1,35 0,0062 BP negative regulation of immune system process 6 2,03 0,0085 Immune response BP negative regulation of response to stimulus 6 2,03 0,0180 BP regulation of immune effector process 4 1,35 0,1975 Category Enrichment Score: 1,625 Count % PValue BP cell-cell adhesion 11 3,72 0,0095 Cell adhesion BP cell adhesion 18 6,08 0,0373 BP biological adhesion 18 6,08 0,0378 Category Enrichment Score: 1,545 Count % PValue CCs cell soma 8 2,70 0,0091 CCs cell projection 18 6,08 0,0174 Cell/neuronal plasticity CCs neuron projection 11 3,72 0,0215 CCs dendrite 5 1,69 0,1926 Category Enrichment Score: 1,481 Count % PValue BP positive regulation of biosynthetic process 21 7,09 0,0044 BP positive reg. of macromolecule biosynthetic process 19 6,42 0,0106 MF transcription activator activity 14 4,73 0,0106 BP positive reg. of macromolecule metabolic process 23 7,77 0,0107 BP positive reg. of nitrogen compound metabolic process 18 6,08 0,0186 BP positive regulation of transcription 16 5,41 0,0248 MF transcription factor activity 24 8,11 0,0254 BP positive r. of transcription from RNA pol. II promoter 12 4,05 0,0258 positive reg. of nucleobase, nucleoside, nucleotide Gene-expression BP and nucleic acid metabolic process 17 5,74 0,0280 BP positive regulation of transcription, DNA-dependent 14 4,73 0,0299 regulation BP positive regulation of gene expression 16 5,41 0,0311 BP positive regulation of cellular biosynthetic process 18 6,08 0,0313 BP positive regulation of RNA metabolic process 14 4,73 0,0316 MF transcription regulator activity 33 11,15 0,0361 MF sequence-specific DNA binding 16 5,41 0,0466 BP regulation of transcription 49 16,55 0,0768 BP regulation of transcription from RNA pol. II promoter 17 5,74 0,0860 BP regulation of transcription, DNA-dependent 35 11,82 0,0863 BP transcription 40 13,51 0,0999 BP regulation of RNA metabolic process 35 11,82 0,1087 MF DNA binding 42 14,19 0,1861

MAO IGR Methylation levels MAOA DMRs 7150 bp after MAOA 3’ end 12300 bp after MAOB 3’ end

MAOA: The “warrior” gene

Fluorescence-assisted cell sorting 1500 A C D Cell Count 1000 500 10 4 10 5 10 2 10 3 0 E F B 200K Neuronal Fraction (32.7%) SSC-A Non Neuronal 100K Fraction (56.1%) 0 10 2 10 3 10 4 10 5 0 FITC-A

Total % of Methylation in MAOA % of Methylation in MAOA IGR IGR Non Neuronal Fraction (+) Non Neuronal Fraction (+) 100 75 Suicide CTRL % of Methylation % of Methylation 80 60 60 45 Suicide 40 30 CTRL 20 15 0 0 1 2 3 4 5 6 7 8 9 10 11 12- CpGs 13 Total % of Methylation in MAOA % of Methylation in MAOA IGR IGR Neuronal Fraction (+) Neuronal Fraction (+) 90 Suicide CTRL 100 * * % of Methylation % of Methylation * 80 75 * 60 Suicide 60 40 CTRL 45 20 0 30 1 2 3 4 5 6 7 8 9 10 11 12-13 CpGs

MAO findings Hypomethylation in Hypomethylation in the neuronal cell suicide completers fraction * 100% 8 kb 0% MAOA MAOB Low Exp. in Suicide High Exp. in Suicide * * Suicide CTRL Low levels of • lincRNA in MAOA/B intergenic region H3K27me3 • Repressed by epigenetic mechanisms in suicide • DNA methylation and chromatin states change in suicides * • Increased lincRNA expression • lincRNA regulates MAOA expression in the brain

LincRNA • RNAs longer than 200bp • No open reading frame • Poorly conserved evolutionarily • Highly expressed in the CNS • Play a role in neurogenesis Ulitsky & Bartel, Cell 2013