Genetic, epigenetic and neuroimaging markers associated with conduct disorder and callous-unemotional traits in females

Farrow, Elizabeth ORCID: 0000-0003-0509-1637 (2022). Genetic, epigenetic and neuroimaging markers associated with conduct disorder and callous-unemotional traits in females. University of Birmingham. Ph.D.

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Abstract

The aim of this thesis was to better understand the pathways from (epi)genetic variation to brain structure and response in youth with CD and varying levels of CU traits. Epigenetic and genetic data from female youth from a mix-sex sample were integrated with structural and functional neuroimaging data to explore whether there was evidence for sex-specific associations between these variables. DNA methylation, grey matter volume (GMV), brain response to emotional faces and OXTR genotype were investigated using either linear regression analyses or structural equation modelling (SEM). In chapter 3, salivary DNA data from female youth were analysed and I identified a region on chromosome 1 (incorporating the SLC25A24 gene), which showed differential methylation according to the CD x CU interaction effect. Specifically, I observed an inverse pattern of correlation between CU traits and methylation in females with CD (positive) as compared to TD females (negative). Across the whole cohort, level of methylation of this region was also negatively associated with GMV in several brain regions including the superior frontal gyrus, dorsolateral prefrontal cortex, supramarginal gyrus, secondary visual cortex and ventral posterior cingulate cortex. Chapter 4 examined the association between this SLC25A24 gene methylation and brain response to emotional faces. A positive association between SLC25A24 methylation and brain response to faces (i.e., angry, fearful and neutral) was observed in regions across the whole brain. Across all faces, the significant regions were within the right hemisphere (ventral caudate, para-hippocampal region, superior temporal cortex and mid-temporal region). Response to angry or fearful, as compared to neutral, faces was also positively associated with SLC25A24 methylation in areas across both hemispheres, including the inferior frontal gyrus, angular gyrus, pre-central gyrus, occipital lobe, ventral posterior cingulate and dorsal anterior cingulate cortex (ACC). In chapter 5, I tested whether a structural equation model including OXTR genotype data, age, IQ, site, CU-trait score and brain response data from the amygdala (during emotional face processing) could explain a significant amount of the variance in CD symptoms in males-only, females-only and mixed-sex youth. Neither direct associations between OXTR genotype and variation in CD symptoms, nor indirect associations via other factors in the model explained a significant amount of overall CD symptom variation. In males only, there was an association between left amygdala response to angry faces and OXTR genotype (as represented by a composite risk score including data from 34 SNPs). Overall, the findings presented here demonstrate that both sex and level of CU traits are crucial factors to consider when investigating the biological mechanisms and neural correlates associated with CD.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):