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The Role of FKBP5 Genetics and Epigenetics in Mediating the Effects

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The Role of FKBP5 Genetics and Epigenetics in Mediating the Effects 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 I declare that this thesis has not been submitted as an exercise for a 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- atric illness and is characterized by loss of pleasure, depressed mood, sleep disturbances and anxiety. Recently, an inflammatory theory of MDD has emerged, which pos- 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 conflicting results. The gene coding for FKBP5, 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 and childhood adversity might interact to explain structural and func- tional brain abnormalities in MDD patients. For this, we conducted studies on a database collected across two sites comprising a total of 104 MDD patients and 97 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 if these changes were mirrored by structural modifications and tested whether these could be explained by the interaction between genetic risk and exposure to childhood trauma. Thirdly, we investigated epigenetic modifications of the FKBP5 gene in depressed patients and controls. Previous studies have hypothe- sised that chronic stress might functionally regulate FKBP5 by methy- lation of its regulatory sites. We tested whether this modification was 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, we have shown that in patients carrying the high-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 between patients and controls when rs1360780 and childhood adver- sity were not considered. Therefore we suggest that the presence of both genetic and environmental risk factors is able to produce lasting 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 of rs1360780. In addition to this, across our studies we have identi- fied the inferior frontal lobe as a region whose structure and function 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 that the gene coding for the glucocorticoid regulator FKBP5 protein is a convergence point for the interplay between genetic and environ- mental risk factors of MDD. The size of the effects we detected ranged 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 majordepressivedisorder 3 1.1 Epidemiology 3 1.2 Diagnosis 4 1.3 Etiology 4 1.3.1 The monoamine hypothesis 4 1.3.2 The inflammatory hypothesis 7 1.3.3 Childhood adversity and inflammation 9 1.4 Conclusions 10 2 genetics of major depression 13 2.1 Monoamines 14 2.1.1 Monoamine oxidase 14 2.1.2 Tryptophan hydroxilase 14 2.1.3 Serotonin transporter 15 2.1.4 Serotonin receptor 16 2.1.5 Noradrenaline 16 2.1.6 Dopamine 17 2.2 Brain-derived neurotrophic factor 17 2.3 FK506 binding protein 51 17 2.4 Conclusions 19 3 magnetic resonance imaging 21 3.1 General principles 21 3.2 Structural magnetic resonance 23 3.3 Functional magnetic resonance 24 3.4 Diffusion magnetic resonance 26 3.5 Conclusion 27 4 magnetic resonance imaging of depression 29 4.1 Structural magnetic resonance and depression 29 4.2 Functional magnetic resonance and depression 31 4.3 Diffusion magnetic resonance 34 4.4 Conclusions 36 5 magnetic resonance imaging of depression ge- netics 37 5.1 Monoamines 37 5.1.1 Monoamine oxidase 37 5.1.2 Tryptophan hydroxylase 38 5.1.3 Serotonin transporter 38 5.1.4 Serotonin receptor 40 5.1.5 Noradrenaline 40 5.1.6 Dopamine 40 5.2 Brain-derived neurotrophic factor 40 5.3 FK506 binding protein 51 41 5.4 Conclusions 41 6 hypothesis 43 ii materials and methods 7 participants 49 7.1 Recruitment 49 8 rating scales 53 8.1 Hamilton Depression Rating scale 53 8.2 Beck’s Depression Inventory 53 8.3 Pittsburgh Sleep Quality Index 54 8.4 Childhood Trauma Questionnaire 54 9 biological samples 57 9.1 PAXgene whole blood 57 9.2 FKBP5 polymorphism 57 9.3 FKBP5 epigenetics 58 10 magnetic resonance imaging 59 10.1 Acquisition 59 10.1.1 T1 MRI 59 10.1.2 Functional MRI 59 10.1.3 Functional MRI task 60 10.1.4 Behavioural task analysis 61 10.1.5 Diffusion magnetic resonance 61 10.2 Data processing 61 10.2.1 Structural MRI 62 10.2.2 Functional MRI 64 10.2.3 Psychophysiological interaction 67 10.2.4 Diffusion magnetic resonance 68 iii studies 11 fmriofemotionrecognition andregulation 73 11.1 Background 73 11.2 Materials and methods 76 11.2.1 Sample 76 11.2.2 Rating Instruments 76 11.2.3 fMRI analysis 76 11.2.4 Behavioural analysis 78 11.2.5 Effect of medication 79 11.3 Results 79 11.3.1 Demographics 79 11.3.2 Behavioural analysis 79 11.3.3 fMRI activation analysis 80 11.3.4 Psychophysiological interaction 85 11.3.5 Correlational analysis 96 11.3.6 Effect of medication 97 11.4 Discussion 97 11.5 Conclusion 100 12 fkbp5 snp and emotion processing areas 103 12.1 Background 103 12.2 Materials and methods 105 12.2.1 Sample 105 12.2.2 Rating Instruments 105 12.2.3 Genetic analysis 106 12.2.4 fMRI analysis 106 12.3 Results 108 12.3.1 Sample 108 12.3.2 Behavioural analysis 110 12.3.3 fMRI 112 12.3.4 DTI 117 12.3.5 Interaction modelling 119 12.4 Discussion 122 12.5 Conclusion 125 13 fkbp5 methylation and emotion processing ar- eas 127 13.1 Background 127 13.2 Materials and methods 129 13.2.1 Sample 129 13.2.2 Rating Instruments 130 13.2.3 Genetic analysis 130 13.2.4 Demographic and clinical measures 130 13.2.5 Predictors of FKBP5 methylation 130 13.2.6 Magnetic resonance imaging 131 13.3 Results 134 13.3.1 Demographics and behavioural 134 13.3.2 Behavioural analysis 137 13.3.3 Predictors of FKBP5 methylation 137 13.3.4 Effect of FKBP5 methylation on brain structure and function 139 13.4 Discussion 146 13.5 Conclusion 149 iv discussion 14 discussion 153 14.1 Sample characteristics 153 14.2 Behavioural findings 155 14.3 fMRI of emotional regulation in MDD 156 14.4 FBKBP5 in MDD 157 14.5 Future directions and clinical implications 159 14.6 Conclusion 161 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 LISTOFFIGURES Figure 1 Generation of the MR signal 24 Figure 2 Canonical hemodynamic response function 25 Figure 3 Fractional anisotropy and diffusivity 27 Figure 4 Emotional processing changes in depression 34 Figure 5 Fractional anisotropy changes in depression 36 Figure 6 Task overview 60 Figure 7 Segmentation example 63 Figure 8 Motion correction example 65 Figure 9 Generation of a PPI regressor 68 Figure 10 Main task effects and gPPI ROIs 86 Figure 11 gPPI group*trial type interaction 92 Figure 12 Between group gPPI results 94 Figure 13 gPPI 2-way interaction results 95 Figure 14 gPPI 3-way interaction results 96 Figure 15 Effect of group*rs1360780 interaction 112 Figure
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