Abstract:
Epidemiological research has shown that psychiatric and substance use disorders are
multimorbid conditions that are characterized by significant and complex genetic etiology. While
genome-wide association studies (GWAS) have identified thousands of single-nucleotide
polymorphisms (SNPs) associated with psychiatric and substance use disorders, the mechanisms
by which these SNPs contribute to the observed multimorbidities remain largely unknown. This
is because more than 90% of these SNPs reside in the non-coding regions of the genome, which
makes interpretation of their functional impacts challenging. To address this challenge, I integrated
different distinct levels of biological information (i.e. SNPs, gene expression, spatial genome
organization and protein-protein interactions) to identify tissue-specific regulatory impacts of
psychiatric and alcohol dependence-associated SNPs on biological pathways. This enabled me to
determine potential regulatory mechanisms that can explain the underlying multimorbidity among
these phenotypes. First, I have analysed 2,893 GWAS SNPs associated with attention-deficit
hyperactivity disorder (ADHD), anxiety, bipolar disorder (BD), unipolar depression (UD),
schizophrenia and cognitive functioning to identify the genes and biological pathways they control.
The analysis revealed 33 genes and 62 pathways that were commonly affected by tissue-specific
regulatory interactions associated with all six phenotypes. Next, I have identified the tissue-specific
regulatory landscape of alcohol dependence (AD). Of the AD regulatory interactions I identified,
42% were associated with genes encoding alcohol dehydrogenase (ADH) and aldehyde
dehydrogenase (ALDH) enzymes, and they were mostly linked to adipose and gastrointestinal
tissues. Further analyses of the global patterns of ADH and ALDH regulatory interactions
revealed ADH associations with AD-related traits and ALDH associations with psychiatric
disorders and cognition. Finally, I have identified the cortex-specific regulatory impacts of 344
SNPs associated with autism spectrum disorder, and showed that these SNPs were also linked to
other psychiatric disorders (e.g. schizophrenia, ADHD, BD). Subsequent protein-protein
interaction analysis revealed that these SNPs impact on immune pathways, fatty acid metabolism,
ribosome biogenesis, aminoacyl-tRNA biosynthesis and spliceosomes in the fetal cortex. By
contrast in the adult cortex, they largely affect immune pathways. Collectively, these results
highlight potential regulatory mechanisms and key pathways underlying the development of
psychiatric and substance use disorders, and their observed multi/co-morbidities. This integrative
approach, in combination with clinical studies, will contribute to personalized mechanistic
understandings of these complex disorders.