Influence of genetic variation on social behaviors and frontal cortex differences in generalized anxiety disorder
Chesna, Elizabeth Ann
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Certain behaviors have a major impact on the criminal justice system and medical field. The research presented here focuses on antisocial behaviors and generalized anxiety disorder (GAD). Antisocial behaviors such as aggression, criminal behavior, and drug abuse contribute to violent crime. In developed countries, the majority of violent crime is committed by a reduced group of antisocial recidivistic offenders. Currently, the United States has the largest incarceration rate in the world. Identification of genetic variants that influence these behaviors is crucial for the prevention of crime, reduction in recidivism, and the understanding of the etiology of criminal behavior in general. In the first part of this study, a custom primer panel for massively parallel sequencing (MPS) was designed to include 48 single nucleotide polymorphisms (SNPs) potentially associated with social behaviors. Traditional methods, such as single base extension (SBE), are limited in multiplexing capability and time consuming. MPS is more cost effective and allows for a large number of SNPs to be analyzed simultaneously. A preliminary sample set of 100 Caucasian male students were used to assess the validity and concordance of this custom MPS panel. Eight SNPs were genotyped using both SBE and MPS techniques, with all successful profiles being 100% concordant. Participants also completed a survey assessing multiple behaviors and psychological traits. While no significant associations were found in this preliminary sample pool, some trends were observed in behavioral traits. The findings of this study suggest that this panel can be used to simultaneously assess a large number of behavioral and psychological markers. To further explore these results, genetic variants observed in the preliminary control population were compared to a set of high risk individuals. Therefore, in the second part of this study, 19 markers associated with dopamine (DA) turnover and oxytocin (OXT) were compared between an inmate (N=100) and control (N=100) population. Two SNPs (rs909525 and rs1799836) associated with monoamine oxidase had significantly different major allele frequencies between control and inmate populations (p=0.00002 and p=0.00004 respectively). Moreover, haplotype analysis revealed strong linkage disequilibrium in markers associated with monoamine oxidase A (MAOA), catechol-O-methyl transferase (COMT), and OXT. Two haplotypes associated with MAOA had differences in frequency between controls and inmates. Haplotype GAT was observed more often in inmates than controls (p=0.0012) and GGT was not observed in the inmate population (p=0.000004). Multifactor dimensionality reduction was used to test for gene-gene interaction. Epistasis between markers was not found; however, strong redundancies between rs4680 and rs11476, and rs1799836 and rs740603 were observed. These results provide evidence that marker variation occurs between inmate and control samples and this variation may contribute to behaviors associated with delinquency. Anxiety disorders also have a major impact on society, as they are the most common type of psychiatric disorder. Among these, generalized anxiety disorder (GAD) is one of the most prevelant. GAD involves persistent anxiety and may worsen over time if left untreated. As a result, an individual’s daily life is impaired. Furthermore, there is an economic burden on society and the healthcare system. Imaging techniques, including functional magnetic resonance imaging (fMRI), have allowed for better understanding of structural and functional changes involved in GAD. In the third part of this study, fMRI was used to assess thickness and surface area differences in GAD patients. Moreover, eleven bilateral frontal regions defined in the Desikan-Kiliany Atlas were compared. A total of 300 participants were included in this study within three groups: GAD patients (N=100), psychiatric controls (N=100), and healthy controls (N=100). Groups were matched for demographic characteristics and other psychiatric conditions. No significant differences were observed for surface area in the left or right hemisphere; however, significant differences were found for thickness in both hemispheres. In the left hemisphere, lower thickness was observed in GAD patients verses healthy controls (p=0.0001) for the pars triangularis and superior frontal region (p=0.0000). Also, significantly lower thickness was observed in psychiatric controls compared to healthy controls (p=0.0000) for the superior frontal region. In the right hemisphere, lower thickness was observed in GAD patients versus healthy controls (p=0.0006) for the caudal middle frontal region and superior frontal region in GAD (p=0.0000). These findings provide evidence that these structures may be involved in GAD. Furthermore, they also suggest GAD may be due to damage from chronic stress as it suppresses neurogenesis, dendritic growth, and synaptic strength.