Li, Wenqianglong; (2023) The Relationship Between Genetic Risk for Alcohol Use Disorders and Antisocial Personality Disorder, and other Complex Traits. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

INTRODUCTION: Alcohol use disorder (AUD) is a prevalent psychiatric disease, driven by both environmental and genetic factors. To deepen our understanding, this research aims to identify replicable novel loci, understand associations between AUD genetic risk variants and brain morphology, and explore shared genetic risk variants between AUD and comorbid psychiatric diseases such as antisocial personality disorder (ASPD). METHODOLOGY: We first improved the identification of AUD risk loci using AUD scores as a quantitative variable, while examining the influence of the regression model applying a quasi-Poisson distribution. This accounted for the skewed distribution of AUD criterion scores within genome-wide association studies (GWAS) populations towards more severe cases. To explore the potential risk genetic AUD and alcohol consumption (AC) pose on brain morphology, we utilised the largest available GWAS results of AUD and AC along with genetic and imaging data from the UK Biobank. We investigated the impact of AUD polygenic risk scores (AUD-PRS) and alcohol consumption polygenic risk scores (AC-PRS) on brain volumes in individuals consuming less than 14 alcohol units per week. Lastly, we conducted the largest meta-analytic GWAS of ASPD to date, considering individuals diagnosed with AUD to explore shared genetic risk variants. RESULTS: Our innovative GWAS data analysis approach revealed that the quantitative trait analysis adjusting for the criterion score distribution provided the greatest precision. Imaging genetics identified negative associations between AUD-PRS and brain/grey matter volumes in cortical and subcortical regions in individuals consuming less than 14 alcohol units per week. A significant chromosome 15 variant (rs9806493) association was found in the GWAS of ASPD in individuals diagnosed with AUD (Z score = -5.501, p = 3.77 x 10-8 ). The phenomewide analysis identified associations between SLCO3A1 and educational attainment, depression, alcohol dependence, and lifetime number of sexual partners. PRS analysis revealed positive correlations between ASPD and smoking, ADHD, depression traits, and post-traumatic stress disorder, but negative correlations with alcohol intake frequency, reproductive traits, and level of educational attainment. CONCLUSION: Our findings suggest that novel GWAS methods, adjusted for the distribution of quantitative traits, could enhance the identification of disease genetic risk variants. Alcohol consumption alone may not account for brain abnormalities resulting from alcohol's neurotoxic effects; AUD genetic risk factors could be predispositional. With AUD samples exhibiting ASPD symptoms, we provide evidence of an association of ASPD risk with SLCO3A1 and shed light on the genetic architecture and pleiotropic associations of ASPD.

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