Interaction of Cannabis Use Genes and Implicated Genes in Schizophrenia and Bipolar Disorder in a Molecular Pathway Analysis Open Access

Patel, Sonam Nitin (2015)

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Cannabis is the most commonly used illicit drug worldwide. With debate surrounding cannabis legalization, it has become an integral area of research in mental health. Recreational use is commonly implicated as a risk factorfor schizophrenia and bipolar disorder, yet the vast majority of users will not develop either disorder in their lifetime. The potential causal role between cannabis and these disorders remains uncertain.Broadly, the purpose of this thesis is to examine the relationship between genetic sequence variation in these mental disorders and incannabis abuse, and more specifically, to discern molecular pathways involving relevant susceptibility genes and potential causal pathways. Genetic variants implicated in schizophrenia, bipolar disorder and cannabis use were compiled from the Psychiatric Genetics Consortium and the National Institutes of Health Database of Genetic Phenotypes. Single nucleotide polymorphisms (SNPs) were mapped to specific genes for each dataset. Several shared genes were discovered in comparisons between cannabis use and schizophrenia susceptibility variants and between cannabis use and bipolar disorder variants. To better understand the physiological relevance of these genes, I conducted a gene set enrichment and molecular pathway analysis for genes that showed overlap between cannabis and schizophrenia (44 genes),and between cannabis and bipolar disorder (42 genes). Predictive molecular network analyses attested to the biological role of susceptibility genes within networks underlying cannabis use, schizophrenia and bipolar disorder. In particular, the cannabis schizophrenia connection involved networks that included DLG2 and ubiquitin. Acknowledgement of this gene-environment interaction is a significant factor when determining impact of environmental risk factors on the disorders, including cannabis use.

Table of Contents

Introduction. 1

A Review of the Literature. 6

Methods. 18

Study Design and Population. 18

Schizophrenia. 20

Figure 1. 21

Bipolar Disorder. 21

Cannabis use. 22

Variant Isolation and Gene Annotation. 28

Schizophrenia Variant Isolation. 28

Bipolar Disorder Variant Isolation. 28

Cannabis Use Variant Isolation. 29

Assessment of Molecular Pathways. 29

Gene Annotation. 30

Additional Mapping of Genes. 30

Analytical Plan. 30

Table 1. 32

Table 2. 33

Table 3. 34

Table 4. 35

Table 5. 35

Table 6. 35

Figure 2. 36

Figure 3. 37

Figure 4. 38

Results Figures. 39

Table 7. 39

Table 8. 39

Figure 5. 40

Figure 6. 40

Table 9. 41

Table 10. 48

Figure 7. 60

Figure 8. 61

Figure 9. 62

Figure 10. 63

Figure 11. 64

Figure 12. 64

Figure 13. 65

Figure 14. 67

Figure 15. - Figure 16. 67

Figure 17. 69

Results. 70

Molecular Pathway Modeling. 72

Discussion. 74

Shared Genes. 74

Enrichment Analyses. 75

Predicted Molecular Networks. 76

Limitations. 79

Public Health Implications and Future Directions in Research. 83

References. 84

Supplementary Figures. 106

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