CONTRIBUTIONS OF RARE GENETIC VARIANTS TO BIOMARKERS AND DISEASES
| dc.contributor.advisor | Paré, Guillaume | |
| dc.contributor.author | Pathan, Nazia | |
| dc.contributor.department | Medical Sciences | en_US |
| dc.date.accessioned | 2024-10-04T18:16:29Z | |
| dc.date.available | 2024-10-04T18:16:29Z | |
| dc.date.issued | 2024-11 | |
| dc.description.abstract | Most human genetic variants are rare (minor allele frequency, MAF <1%). This thesis investigates the significance of rare coding variants (RV), first with a literature review of vascular dementia (VaD), and subsequently in 31 continuous and 18 binary traits, utilizing whole exome sequence from the UK Biobank (N=167,348 and N=173,688, respectively). This was enabled with the development of the rare variant heritability (RARity) estimator and RARity-β. Genetic determinants of VaD are explored through genome-wide association studies, polygenic risk scores, heritability estimates, and family studies. Complexity and heterogeneity of the disease are highlighted, emphasizing the need for large-scale collaborations and integromics approaches to enhance discoveries. RARity estimates RV heritability (ĥ2RV) without assuming a specific genetic architecture. It revealed a significant loss of heritability (79%) due to gene-level RV aggregation. For 27 traits, ĥ2RV exceeded 5%, with height showing the highest at 21.9%. VaD risk factors such as ApoA-I, BMI, blood pressure, LDL-cholesterol, and triglycerides had ĥ2RV of 4.6% to 9.9%. RARity showed RVs as the source of “missing heritability”, identified 11 new gene-phenotype associations using gene-level heritability estimates, and showed that current pathogenicity predictors do not adequately enrich for RVs contributing to trait variance, indicating a need for better predictive algorithms. RARity-β estimates overall (ĥ2RV-liab) and gene-level heritability of binary traits on a liability scale. Significant ĥ2RV-liab was found for hypothyroidism, asthma, hypercholesterolemia, and essential hypertension, identifying 77 genes with significant contributions to ĥ2RV-liab, including 70 new gene-trait relationships. The PEPB1 gene's role in atrial fibrillation and the TSHR gene's link to hypothyroidism and sciatica are discussed. Results suggest that genes contributing significantly to ĥ2RV-liab have functional consequences. Overall, this thesis provides novel methodologies and insights into the understanding of complex traits and diseases. | en_US |
| dc.description.degree | Doctor of Philosophy (Medical Science) | en_US |
| dc.description.degreetype | Thesis | en_US |
| dc.description.layabstract | This thesis explores the role of genetic mutations (found in less than 1% of the population) in vascular dementia (VaD) and 49 other traits using data from over 167,000 individuals in the UK. Two tools, RARity and RARity-β, were developed to measure how much the mutations cause traits, like height, circulating blood proteins, and diseases to vary among individuals. Review of existing research on VaD emphasizes the complexity of the disease, and highlights the need for large-scale, collaborative research efforts. RARity and RARity-β showed that mutations have significant influence on measurable traits and diseases, with height being the most affected. These tools enabled discovery of genes linked to traits and assessment of current predictive tools to decide which mutations are detrimental to health. Overall, the findings suggest that rare genetic mutations play a crucial role in human health and emphasizes the need for better predictive tools to identify detrimental mutations. | en_US |
| dc.identifier.uri | http://hdl.handle.net/11375/30354 | |
| dc.language.iso | en | en_US |
| dc.subject | genetics, genomics, epidemiology, rare variants, mutations, heritability, CVD, vascular dementia, biomarkers, diseases | en_US |
| dc.title | CONTRIBUTIONS OF RARE GENETIC VARIANTS TO BIOMARKERS AND DISEASES | en_US |
| dc.type | Thesis | en_US |