epigenetics in personalized psychiatry · irritable bowel syndrome, chronic pain, chronic fatigue1...
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Epigeneticsin personalized psychiatry
Stephan Claes, Md, PhD
University Psychiatric Center KU Leuven
Epigeneticsin personalized psychiatry
1. Early life stress and mental health
2. Looking for epigenetic marks
3. Towards personalized psychiatry
Early life stress and psychopathology
Trauma is an important risk factor for a number of psychiatric disorders
• Anxiety and mood disrorders 1
• Substance abuse 2
• Personality disorders 3
• Psychosis 4
1. Heim C & Nemeroff CB. Biol Psychiatry, 46: 1509-22, 1999.2. Anda R et al. Eur Arch Psych Clin Neurosci 256: 174-86, 2006.3. Ball JS et al. Curr Psychiatry Rep 11: 63-8, 2009.4. Morgan C & Fisher H. Schizophr Bull 33:3-10, 2007
Early life stress and (funcctional) somatic disorders
• Risk factor for functional somatic disorders, such as irritable bowel syndrome, chronic pain, chronic fatigue1
• Risk factor for somatic disorders, such as diabetes, astma, autoimmune and cardiovascular disorders2, 3, 4
1. Van Houdenhove, B., & Luyten, P. (2009). In: Trauma and physical health. Understanding the effects of extreme stress and psychological harm. (pp. 37-64). London/New York: Routledge.
2. Batten, S. et al. Journal of Clinical Psychiatry, 65, 249-254, 2004.3. Dube, S. R. et al. Psychosomatic Medicine, 71, 243-250, 2005.4. Goodwin, R. D., & Stein, M. D. Psychological Medicine, 34, 509-520, 2004.
DOHaD hypothesis
Developmental Origins of Health and Disease
Barker and Osmond 1986, The Lancet
infant undernutrition
1920
coronary heart disease
1970
The Dutch famine
Consequences of famine during pregnancy are multiple, and time-dependent
Roseboom T, de Rooij S, Painter R. The Dutch famine and its long-term consequences for adult health. Early Hum Dev 82:485-91, 2006.
The Barker hypothesis: Developmental Origins of (Behavior,)
Health & Disease [DO(B)HaD]
Prenatal stress and mental health:early development
• Babies of mothers with many negative life events and/or with higher cortisol levels during pregnancy show increased crying, negative facial expressions and higher irritability at ages of 3 and 6 months (1, 2, 3)
• Babies of mothers with increased anxiety and/or higher cortisol levels during pregnancy show increased anxiety at the age of 6-9 years (4)
• Maternal anxiety during pregnancy accounts for 22% of the variability in ADHD symptoms at the age of 6-12 years (5, 6)
1. Würmser et al., 2006; 2. De weerth et al., 2003; 3. Davis et al., 2007;4. Davis & Sandman, 2012; 5. Grizenko et al., 2012; 6. Van den Bergh & Marcoen, 2014;
The consequences of ELS
• Rats taken away from the dam during 3 hours at day 2-14 postnatally (1)
• Throughout life:
• Increased anxiety
• Hyper-responsive HPA-as
• Cognitive dysfunctions
• Structural defects in de
hippocampus
(1) Huot RL et al. Brain Res. 2002 Sep 20;950(1-2):52-63
“Early life stress” and pathology
ELS
Psychiatric disorders
Somaticdisorders
Psychosomatic disorders
Modulation of the biological stress response
Epigeneticmodifications
Epigeneticmodifications
Epigeneticsin personalized psychiatry
1. Early life stress and mental health
2. Looking for epigenetic marks
3. Towards personalized psychiatry
C. Sandi; Nature Reviews Neuroscience, 2004
GR
GRGR
GRGR
GR
early life stress
DNA methylation
changes
dysregulated stress system
Cortisol
Crucial role of theglucocorticoidreceptor (GR)
ELS and GR methylation
Significant Associations of Childhood Adversity Variables and Percent Methylation at Predicted CpG Sites (1–4).The Parental Care scale of the Parental Bonding Instrument reflects parental warmth, affection, and involvement; lower scoresreflect greater parental coldness, rejection, and detachment. Maltreatment reflects the total score of Childhood Trauma Questionnaire. Parental loss is defined as loss of a parent before age 18, including death (N=12) and/or prolonged separation/desertion (N=14).
Tyrka AR et al. Childhood adversity and epigenetic modulation of the leukocyte glucocorticoid receptor: preliminaryfindings in healthy adults. PLoS One. 2012;7(1):e30148.
• 99 healthy adults• History of early trauma
(maltreatment, early parentalloss) was associated withincreased NR3C1 promoter methylation
• NR3C1 promoter methylationcoupled to blunted cortisol response to Dex/CRH test
8-15 w 16-27 w 28-37 w °
SCR
EEN
ING
MOTHER
GENERAL INFORMATION (health, substance use, …) + + +
PSYCHIATRIC – PSYCHOLOGICAL QUESTIONNAIRE
• Edinburgh Depression Scale (EDS) + + +
• Spielberger State and Trait Anxiety Inventory (STAI) + + +
• Pregnancy Related Anxiety Questionnaire (PRAQ) + + +
• Maternal and Fetal Attachment Scale (MFAS) + + +
BIO
L.
PAR
AM
.
MOTHER
Saliva: Basal cortisol secretion (4x/day – 1 d.) + + +
CHILD
Cord blood sample +
“Prenatal and Early Life Stress (PELS) Study”: Tilburg, Londen, Leuven
Prenatal anxiety and GR methylation
aaccccgF12tagcccctttcgF13aagtgacacacttcacgF14caactcgF15gcccgF16gc
gF17gcgF18gcgF19gcgF20cgF21ggccactcacgF22cagctcagccgF23cgF24ggaggcgF25ccccgF2
6gc
tcttgtggcccgF27cccgF28ctgtcacccgF29caggggcactggcgF30gcgF31cttgccgF32
ccaaggggcagagcgF33agctcccgF34agtgggtctggagccgF35cgF36gagctgggc
gF37ggggcgF38ggaaggaggtagcgF39agaaaagaaactggagaaactcgF40gtggcc
F36.39: T2: Cort
F20.21: T1: Pregn. Anx. - T2: Pregn & Gen. Anx.
F12.13: T1 & T2: Pregn. Anx.
Hompes T, Izzi B, … , Claes S. Investigating the influence of maternal cortisol and emotional state during pregnancy on the DNA methylation status of the glucocorticoid receptor gene (NR3C1) promoter region in cord blood. J PsychiatrRes. 2013 Jul;47(7):880-91.
Figure 4. Results of meta-analyses of prenatal stress exposure influence on methylation of the CpG sites 35 to 39. From left to right, displayed variables consist of: study, sample size (n), a graphical representation of the computed correlations, correlation values between methylation and the assessed prenatal stress variable, their corresponding confidence intervals and the weightof each study in the meta-analysis as determined by a random effects model.
Published in: H Palma-Gudiel; A Córdova-Palomera; E Eixarch; M Deuschle; L Fañanás; Epigenetics 2015, 10, 893-902.DOI: 10.1080/15592294.2015.1088630Copyright © 2015 Taylor & Francis Group, LLC
From: Genome-wide Epigenetic Regulation by Early-Life Trauma
Arch Gen Psychiatry. 2012;69(7):722-731. doi:10.1001/archgenpsychiatry.2011.2287
Figure 1. Chromosomal location and expression. A, Chromosomal distribution of differentially methylated probes in
abused suicide completers (SAs). The first row represents the chromosomal location of probes with increased
methylation (hypermethylated) in the SAs and the second row indicates the chromosomal location of probes with
decreased methylation (hypomethylated) in the SAs. B, Inverse correlation between whole-genome expression and
promoter methylation differences between SAs and controls. The mean promoter methylation differences (Meth) and
gene expression (Expr) differences show that differential methylation is inversely correlated with differential gene
expression across the genome (Pearson r = −0.19, P ≤ 4.0E−6). Data were obtained by summarizing promoter
methylation and gene expression differences across regions of 1 megabase throughout the whole genome.
Not just GR…
high anxiety
n = 23
low anxiety
n = 22
Genome-wide data analysis
Differentially methylatedregions (DMR)
Candidate genePathways andnetworks
GABBR1?
rank
combp
refGene
name
Location (GRCh37/hg19
assembly)
Minimum
P-value
Number
of
probes
Stouffer-
Liptak-
Kechris P-
value
Šidák
corrected
CpG
island
1 TP53INP1 chr8:95962083-95962464 5.7E-07 6 6.36E-12 1.42E-06 yes
2 PRSS50 chr3:46759334-46759699 1.2E-06 8 3.097E-11 7.24E-06 yes
3 HOXC4 chr12:54446278-54446577 1.8E-06 6 4.24E-11 1.21E-05 no
4 PKP3 chr11:396685-397078 1.3E-05 3 7.065E-10 0.000153 yes
5 ZNF764 chr16:30572738-30573014 0.00015 5 1.136E-08 0.003506 yes
6 PPT2 chr6:32120954-32121421 4.5E-05 14 2.556E-08 0.00466 no
7 GABBR1 chr6:29595001-29595316 0.00015 7 2.70E-07 0.07059 yes
8 PITPNM3 chr17:6358362-6358600 0.00278 4 2.88E-07 0.09817 yes
9 ESRRG chr1:217306589-217306764 0.00734 3 1.01E-06 0.3886 no
10 HS3ST2 chr16:22959593-22959820 0.00383 2 0.0001211 1 yes
Candidate gene selection top gene in both methods located in a CpG island
GABBR1
Validation EpiTYPER
Vangeel EB, et al. Clin Epigenetics. 2017 Oct 3;9:107.
The infant stress system and GABBR1 methylation
2 months 4 months 12 months
* p < 0,05 ** p < 0,01
* ** **
Vangeel EB, et al. Clin Epigenetics. 2017 Oct 3;9:107.
GABBR1
Rat hippocampal GABBR1 expressiondecreased by 36% in prenatal stress
Receptor for GABAergicneurotransmission
Regulates early-life and chronic psychosocial stress
Depression-like phenotype
GABBR1 epigenetics in psychiatric research
Newborn stress response
?
Vangeel EB, et al. Clin Epigenetics. 2017 Oct 3;9:107.
• Why has nature developed such a mechanism?
• Are epigenetic changes heritable?
A lot of questions
27
Epigeneticsin personalized psychiatry
1. Early life stress and mental health
2. Looking for epigenetic marks
3. Towards personalized psychiatry
Weaver et al:
• rats (hippocampus)
• Better maternal care (LG/ABN) changes methylation patterns at the GR 1F promoter region in the pups
Epigenetic marks of prenatal stress: reversible?
Weaver IC. Nat Neurosci. 2004 Aug;7(8):847-54.
Pharmacological interventions?
• Mainly in cancer research
• DNA methyltransferase inhibitors, such as
• 5-azacytidine (azacitidine)
• 5-aza-2'-deoxycytidine (decitabine)