How life events get under the skin : Implications for suicide prevention

Transcription

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

2 Turecki et al Trends in Neurosciences 2012

3 CSA, CPA and Suicide Attempts Suicide attempts at age according to CSA and CPA types None Contact Penetration None Regular Severe CSA CPA Fergusson et al. Child Abuse & Neglect, 2008

4 Suicide and Childhood Adversity Suicide completers % Any abuse Suicides Psychiatric controls Community Controls Ostovar et al, 2009

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

6 HOW CAN EVENTS OCCURRING DURING CHILDHOOD INCREASE LIFETIME SUICIDE RISK?

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

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

9 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

10 Ecker, Nature 2012

11 Gene 1 Gene 2 RNA polymerase II Gene chromosome DNA Transcription Factors

12 DNA CYTOSINE METHYLATION C mc SAM-CH3 DNMT SAM H 3 C

13 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

14 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

15 GR methylation, GR expression and cognitive function in rats Weaver et al., Nat:Neurosci 2004 Nerve growth factor-inducible protein A (NGFI-A)

16 HPA Axis

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

18 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

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

20 Site-specific hypermethylation in hgr1f promoter in abused suicide completers NGFI-A transcription factor s binding site McGowan et al, Nature Neuroscience 2009

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

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

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

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

25 N = 355 Differentially methylated sequences and chromosomal distribution Hypermethylated N = % Hypomethylated N = % P = 0.67 Hypermethylated Hypomethylated Chromosome

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

27 Most significantly enriched functional annotation clusters Protein dimerization Immune response Cell adhesion Cell/neuronal plasticity Gene-expression regulation Category Enrichment Score: 2,106 Count % P-value MF protein homodimerization activity 13 4,39 0,0054 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 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 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 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 BP positive reg. of nucleobase, nucleoside, nucleotide and nucleic acid metabolic process 17 5,74 0,0280 BP positive regulation of transcription, DNA-dependent 14 4,73 0,0299 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

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

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30 MAOA: The warrior gene

31 SSC-A Cell Count Fluorescence-assisted cell sorting 1500 A C D K B Neuronal Fraction (32.7%) E F 100K Non Neuronal Fraction (56.1%) FITC-A

32 % of Methylation % of Methylation % of Methylation % of Methylation % of Methylation in MAOA IGR Non Neuronal Fraction (+) Suicide CTRL Total % of Methylation in MAOA IGR Non Neuronal Fraction (+) Suicide CTRL CpGs 13 % of Methylation in MAOA IGR Neuronal Fraction (+) * * Suicide CTRL CpGs * Total % of Methylation in MAOA IGR Neuronal Fraction (+) * Suicide CTRL

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

34 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

35 Viral-Mediated Gene Transfer HSV HSV IGR Technical Validation Cannulation Transfection (GFP) Expression MAOA/MAOB lincrna Behavioral Assessment Depression/Anxiety Impulsivity Aggression

36 % Animal Attacking % Animal Attacks Pre Screening Agressive behavior Intra DG lincrna HSV Infection Peak lincrna expression PT1 PT2 PT3 PI0 PI1 PI2 PI3 PI4 PI5 PI6 PI7 PI8 Re Sreening Agressive behavior Sacrificing and collecting tissue 0 day1 day2 day3

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38 GRIP Prevalence Cohort longitudinal school cohort representative of the Quebec general popluation 1509 boys & 1509 girls multiple informants Wave I Childhood Ages: 6-12 Assessment frequency: yearly Informants: teachers & parents Variables : childhood personality, family socioeconomic circumstances Wave II Adolescence ages: Assessment frequency: once Informants: adolescents & parents Variables: psychiatric history & suicidality Wave III Adulthood ages: Assessment frequency: once Informants: young adults Variables: psychopathology, suicidality, social support, partner violence, childhood abuse, etc Wave IV Adulthood ages: mid-20s Informants: subjects DNA Attempt Hx Personality variants Psychopathology

39 Childhood Adversity and Risk of Suicide Attempts Childhood Adversity 2.11 ( ) P<0.001 Suicide Attempts Ages 6 12 years Age 21 years Wanner et al, Psych Medicine 2012

40 Life Trajectories Adjusted risk = 60% increase in likelihood of suicide attempts Brezo et al, Arch Pediatr Adolesc Med. 2008

41 Anxiousness mediates the effect of childhood adversity on suicide attempts differently according to the presence of disruptive disorders A Presence of externalizing disorders: Full mediation Childhood Adversity OR=11.52 c ( ) High Anxiousness OR=2.07 b ( ) Suicide Attempts Nagelkerke R 2 =.14 B Absence of externalizing disorders: Partial mediation Childhood Adversity OR=1.60 a ( ) High Anxiousness OR=2.07 b ( ) Suicide Attempts OR=2.43 c ( ) Nagelkerke R 2 =.14 a.01<p<.05, b.001<=p<=.01, c P<.001 Wanner et al, Psych Medicine 2012

42 Jollant et al, AJP 2005 Impaired decision making in SA: The Iowa Gambling Test

43 Delis-Kaplan Executive Function Test: TSST effect on Word Color Inhibition (Stroop Effect) and Trail Making Test Group*TSST = F(1,25)=5.51, p<.05 Group*TSST = F(1,25)=6.13, p<.05 McGirr et al, JPN 2010

44 6-month Axis I Prevalence rates in Suicides and Controls from Montreal Suicides Controls 0.2 N = Drug Dep Drug Abuse Alcohol Dep Alcohol Ab SCZ MD Bipolar Anxiety Dis Kim et al, Psych Med 2003

45 Summary Early life adversity CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 Genes involved in the regulation of behavior (i.e. GR) Stable gene function regulation ( mrna) Chronic substance use Poor decision making Behavioral and emotional trait regulation Anxiety Impulsivity Increased suicide risk Depressive psychopathology Suicidal ideation Impaired regulation of emotional and cognitive responses Faciliation of acts

46 Turecki et al Trends in Neurosciences 2012

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48 Acknowledgements MGSS Naguib Mechawar Volodymyr Yerko Benoit Labonté Gilles Maussion Jennie Yang Marie-Martine Beaulieu Gang Chen Carl Ernst McGill University Moshe Szyf Michael Meaney Michael Hallett Matt Suderman University of Montreal Richard Tremblay Frank Vitaro Brigitte Wanner Johns Hopkins Robert Casero University of Texas Howard Gershenfeld Cleveland Clinic Veronique Lefebvre Support: CIHR, NIMH, FRSQ, AFSP, NARSAD Thanks to the Families