The role of FKBP5 genetics and epigenetics in mediating the effects of early life adversity on ...

275 Pages·2017·9.42 MB·English

Trinity College Dublin
SCHOOL OF MEDICINE
Thesis submitted for the degree of Doctor of Philosophy
The role of FKBP5 genetics and epigenetics in
mediating the effects of early life adversity on
emotional processing brain regions in major
depressive disorder
Candidate: PhD Supervisor:
Leonardo Tozzi, MD Prof. Thomas Frodl, MD
Academic Year 2017-2018

DECLARATION
Ideclarethatthisthesishasnotbeensubmittedasanexercisefora
degree at this or any other university and it is entirely my own work.
I agree to deposit this thesis in the University’s open access institu-
tional repository or allow the library to do so on my behalf, subject
to Irish Copyright Legislation and Trinity College Library conditions
of use and acknowledgement.
Stanford, February 26, 2018
Leonardo Tozzi

SUMMARY
Major depressive disorder (MDD) is the most widespread psychi-
atricillnessandischaracterizedbylossofpleasure, depressedmood,
sleep disturbances and anxiety.
Recently,aninflammatorytheoryofMDDhasemerged,whichpos-
tulates that chronic dysregulation of the stress hormone axis and in-
creased inflammation might be crucial in the pathogenesis of the dis-
order.
MDD shows genetic high-heritability. However, most association
analyses investigating polymorphisms in MDD have so far met with
5
conflicting results. The gene coding for FKBP , a glucocordicoid re-
ceptor regulator protein, could play a role in vulnerability to MDD,
especially in the presence of chronic environmental stressors such as
childhood maltreatment.
Magnetic resonance imaging (MRI) is a safe and non-invasive tech-
nique that allows the investigation of the brain in vivo by using pow-
erful magnetic fields. MDD patients show volume reduction, grey
matter loss and altered function in regions that are crucial for emo-
tional regulation.
The aim of our project was to investigate how genetics of FKBP5
andchildhoodadversitymightinteracttoexplainstructuralandfunc-
tional brain abnormalities in MDD patients. For this, we conducted
studies on a database collected across two sites comprising a total of
104 97
MDD patients and healthy controls.
First of all, we investigated which changes in activation and func-
tional coupling were associated with MDD during an MRI task in-
volving directing attention towards and away from the valence of
emotional stimuli.
Secondly, we investigated whether patients carrying the high-risk
allele of the rs1360780 FKBP5 functional single nucleotide polymor-
phism showed differential activation during our task conditions com-
pared to patients without genetic risk. We then sought to determine
ifthesechangesweremirroredbystructuralmodificationsandtested
whether these could be explained by the interaction between genetic
risk and exposure to childhood trauma.
Thirdly,weinvestigatedepigeneticmodificationsoftheFKBP5gene
in depressed patients and controls. Previous studies have hypothe-
sisedthatchronicstressmightfunctionallyregulateFKBP5bymethy-
lationofitsregulatorysites. Wetestedwhetherthismodificationwas
related to childhood adversity as well as to reduced grey matter and
altered function in emotional processing areas.
Our results have confirmed that MDD patients show differences in
activation in regions involved in emotional recognition. Functional
connectivity between some of these areas and between ones belong-
ing to the task-positive and default mode networks was also altered,
in particular in trials involving regulation of negative emotions and
recognition of positive ones.
Furthermore,wehaveshownthatinpatientscarryingthehigh-risk
allele of rs1360780, demethylation of the intron sites of the FKBP5
gene promoter was correlated with the amount of early life maltreat-
ment endured. There was no overall difference in methylation levels
1360780
between patients and controls when rs and childhood adver-
sity were not considered. Therefore we suggest that the presence of
bothgeneticandenvironmentalriskfactorsisabletoproducelasting
epigenetic changes in a gene that has a prominent role in glucocorti-
coid receptor regulation.
Childhood maltreatment also explained structural differences in
temporal lobe white matter between MDD carrying different alleles
1360780
of rs . In addition to this, across our studies we have identi-
fiedtheinferiorfrontallobeasaregionwhosestructureandfunction
are influenced by both FKBP5 allelic status and methylation. Cru-
cially, this area was less active during emotional recognition in MDD
compared to controls and its activation was inversely correlated with
depression severity.
Taken together, findings across our three studies provide evidence
5
that the gene coding for the glucocorticoid regulator FKBP protein
is a convergence point for the interplay between genetic and environ-
mentalriskfactorsofMDD.Thesizeoftheeffectswedetectedranged
from small to moderate, suggesting that more and larger studies are
needed to disentangle them from other potential confounding con-
tributors to brain structure and function.
CONTENTS
List of Figures viii
List of Tables viii
i introduction
1 major depressive disorder 3
11 3
. Epidemiology
12 4
. Diagnosis
13 4
. Etiology
131 4
. . The monoamine hypothesis
132 7
. . The inflammatory hypothesis
133 9
. . Childhood adversity and inflammation
14 10
. Conclusions
2 genetics of major depression 13
21 14
. Monoamines
211 14
. . Monoamine oxidase
212 14
. . Tryptophan hydroxilase
213 15
. . Serotonin transporter
214 16
. . Serotonin receptor
215 16
. . Noradrenaline
216 17
. . Dopamine
22 17
. Brain-derived neurotrophic factor
23 506 51 17
. FK binding protein
24 19
. Conclusions
3 magnetic resonance imaging 21
31 21
. General principles
32 23
. Structural magnetic resonance
33 24
. Functional magnetic resonance
34 26
. Diffusion magnetic resonance
35 27
. Conclusion
4 magnetic resonance imaging of depression 29
41 29
. Structural magnetic resonance and depression
42 31
. Functional magnetic resonance and depression
43 34
. Diffusion magnetic resonance
44 36
. Conclusions
5 magnetic resonance imaging of depression ge
-
netics 37
51 37
. Monoamines
511 37
. . Monoamine oxidase
512 38
. . Tryptophan hydroxylase
513 38
. . Serotonin transporter
514 40
. . Serotonin receptor
515 40
. . Noradrenaline
516 40
. . Dopamine
52 40
. Brain-derived neurotrophic factor
53 506 51 41
. FK binding protein
54 41
. Conclusions
6 hypothesis 43
ii materials and methods
7 participants 49
71 49
. Recruitment
8 rating scales 53
81 53
. Hamilton Depression Rating scale
82 53
. Beck’s Depression Inventory
83 54
. Pittsburgh Sleep Quality Index
84 54
. Childhood Trauma Questionnaire
9 biological samples 57
91 57
. PAXgene whole blood
92 5 57
. FKBP polymorphism
93 5 58
. FKBP epigenetics
10 magnetic resonance imaging 59
101 59
. Acquisition
1011 1 59
. . T MRI
1012 59
. . Functional MRI
1013 60
. . Functional MRI task
1014 61
. . Behavioural task analysis
1015 61
. . Diffusion magnetic resonance
102 61
. Data processing
1021 62
. . Structural MRI
1022 64
. . Functional MRI
1023 67
. . Psychophysiological interaction
1024 68
. . Diffusion magnetic resonance
iii studies
11 fmri of emotion recognition and regulation 73
111 73
. Background
112 76
. Materials and methods
1121 76
. . Sample
1122 76
. . Rating Instruments
1123 76
. . fMRI analysis
1124 78
. . Behavioural analysis
1125 79
. . Effect of medication
113 79
. Results
1131 79
. . Demographics
1132 79
. . Behavioural analysis
1133 80
. . fMRI activation analysis
1134 85
. . Psychophysiological interaction
1135 96
. . Correlational analysis
1136 97
. . Effect of medication
114 97
. Discussion
115 100
. Conclusion
12 fkbp5 snp and emotion processing areas 103
121 103
. Background
122 105
. Materials and methods
1221 105
. . Sample
1222 105
. . Rating Instruments
1223 106
. . Genetic analysis
1224 106
. . fMRI analysis
123 108
. Results
1231 108
. . Sample
1232 110
. . Behavioural analysis
1233 112
. . fMRI
1234 117
. . DTI
1235 119
. . Interaction modelling
124 122
. Discussion
125 125
. Conclusion
13 fkbp5 methylation and emotion processing ar
-
eas 127
131 127
. Background
132 129
. Materials and methods
1321 129
. . Sample
1322 130
. . Rating Instruments
1323 130
. . Genetic analysis
1324 130
. . Demographic and clinical measures
1325 5 130
. . Predictors of FKBP methylation
1326 131
. . Magnetic resonance imaging
133 134
. Results
1331 134
. . Demographics and behavioural
1332 137
. . Behavioural analysis
1333 5 137
. . Predictors of FKBP methylation
1334 5
. . Effect of FKBP methylation on brain structure
139
and function
134 146
. Discussion
135 149
. Conclusion
iv discussion
14 discussion 153
141 153
. Sample characteristics
142 155
. Behavioural findings
143 156
. fMRI of emotional regulation in MDD
144 5 157
. FBKBP in MDD
145 159
. Future directions and clinical implications
146 161
. Conclusion
v appendix
a role of the applicant 165
b acknowledgments 167
c own publications 169
d study information consent and scales 171
,
e cami sequences details 197
f tcin sequences details 205
bibliography 211