Investigating cis- and trans-acting elements involved in regulating fetal hemoglobin gene expression using high throughput genetic data

Sickle cell anemia is caused by a single mutation in the β-hemoglobin gene, HBB. The disease originated in Africa and affects millions of people worldwide. Sickle hemoglobin tetramers polymerize upon deoxygenation and lead to hemolysis and vaso-occlusion. Patients with high fetal hemoglobin (HbF) can have milder disease. The only FDA-approved drug is hydroxyurea that increases HbF. HbF modulates the disease by preventing the polymerization of sickle hemoglobin and reduces the pain episodes, anemia, and organ damage associated with the disease. There are five common haplotypes associated with the HbS gene and that are very loosely associated with disease severity and HbF. Understanding the genetic bases of HbF regulation is a key factor to identify potential drug targets to induce HbF for therapeutic purposes. To fully understand the mechanism behind HbF regulation, developing a fast and accurate computational method for sickle cell haplotype classification is useful for examining the variability of HbF among sickle cell patients. Moreover, investigating the cis and trans-acting regulators of HbF gene expression to pinpoint the mechanism through which they regulate HbF is essential to develop a successful treatment. The availability of high-throughput genetic data provides an excellent opportunity to study HbF regulation in sickle cell patients and normal people comprehensively. The work reported in this thesis describes a fast and accurate method for sickle cell HBB haplotype classification. I also examine the differential effect of cis and trans-acting HbF hemoglobin regulators on -globin gene expression using the GTEx database and identify BCL2L1 as a new potential trans-regulator of HbF

A proteome-wide genetic investigation identifies several SARS-CoV-2-exploited host targets of clinical relevance

BACKGROUND: The virus SARS-CoV-2 can exploit biological vulnerabilities (e.g. host proteins) in susceptible hosts that predispose to the development of severe COVID-19. METHODS: To identify host proteins that may contribute to the risk of severe COVID-19, we undertook proteome-wide genetic colocalisation tests, and polygenic (pan) and cis-Mendelian randomisation analyses leveraging publicly available protein and COVID-19 datasets. RESULTS: Our analytic approach identified several known targets (e.g. ABO, OAS1), but also nominated new proteins such as soluble Fas (colocalisation probability >0.9, p=1 × 10(-4)), implicating Fas-mediated apoptosis as a potential target for COVID-19 risk. The polygenic (pan) and cis-Mendelian randomisation analyses showed consistent associations of genetically predicted ABO protein with several COVID-19 phenotypes. The ABO signal is highly pleiotropic, and a look-up of proteins associated with the ABO signal revealed that the strongest association was with soluble CD209. We demonstrated experimentally that CD209 directly interacts with the spike protein of SARS-CoV-2, suggesting a mechanism that could explain the ABO association with COVID-19. CONCLUSIONS: Our work provides a prioritised list of host targets potentially exploited by SARS-CoV-2 and is a precursor for further research on CD209 and FAS as therapeutically tractable targets for COVID-19. FUNDING: MAK, JSc, JH, AB, DO, MC, EMM, MG, ID were funded by Open Targets. J.Z. and T.R.G were funded by the UK Medical Research Council Integrative Epidemiology Unit (MC_UU_00011/4). JSh and GJW were funded by the Wellcome Trust Grant 206194. This research was funded in part by the Wellcome Trust [Grant 206194]. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission

New insights into the genetic etiology of Alzheimer’s disease and related dementias

Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

New insights into the genetic etiology of Alzheimer’s disease and related dementias

Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele