Sadeghi-Alavijeh, Omid; (2023) Elucidating the genetic architecture of cystic kidney disease using whole genome sequencing. Doctoral thesis (Ph.D), UCL (University College London).

Preview

Text phd_elucidating_genetics_cykd_omid_sadeghi_alavijeh_final_post_viva.pdf - Other Download (4MB) | Preview

Abstract

Cystic kidney disease (CyKD) is the commonest life-threatening monogenic disorder, causing great morbidity and mortality. Whilst there is believed to be a strongly monogenic architecture, an unbiased whole genome sequencing approach to understanding the underlying genetic architecture has never previously been attempted. In this thesis I used statistical genetics and bioinformatics methodology to investigate the genetic architecture of CyKD as well as two other rare disorders, urinary stone disease (USD) and extreme early onset hypertension (EEHTN), using whole genome sequencing data from the 100,000 Genomes Project. I used population-based tools to assess the rare and common variant associations in diverse ancestry matched cohorts seeking enrichment of single nucleotide/indel and structural variants on a genome-wide and per-gene basis. In all three disorders this improved our understanding of the underlying architecture. CyKD is shown to be strongly monogenic as expected but low-frequency and common variants are shown to play an important role in pathogenesis and causation of this disease, revealing a role for polygenic factors. The heritability of USD is shown to be heavily influenced by low-frequency variants in the sodium-phosphate transporter gene SLC34A3, which explains much of the missing heritability not detected by previous large-scale common variant association studies. This finding bridges the gap between the traditional thinking that USD is either monogenic or polygenic/environmental. Finally, EEHTN is shown to likely be an extreme manifestation of primary hypertension, with a strong polygenic basis. These results support the idea that with better sequencing and larger biobanks, an omnigenic model of disease will become more demonstrable for a broader range of phenotypes, consistent with genotype-phenotype heterogeneity, variable expressivity and incomplete penetrance observed in all three diseases. Finally, I demonstrate that population level approaches traditionally used to study common disease are applicable and useful in rare disease research.

Download activity - last month

Export as XMLCSVJSON

Download activity - last 12 months

Export as JSONXMLCSV

Downloads by country - last 12 months

Export as JSONXMLCSV

Archive Staff Only

View Item