Genome-wide association study of carotid intima-media thickness (cIMT) in sub-Saharan African populations: An AWI-Gen study

Simple item page
dc.contributor.authorBoua, Palwende Romuald
dc.date.accessioned2021-01-28T17:35:44Z
dc.date.available2021-01-28T17:35:44Z
dc.date.issued2020
dc.descriptionA thesis submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of PhD in Human Genetics, January 2020en_ZA
dc.description.abstractIt is estimated that by 2020 cardiovascular diseases (CVDs) will be the leading cause of death. The demographic and health transition in sub-Saharan Africa (SSA) has shifted the major causes of mortality from communicable and nutritional diseases to non-communicable diseases (NCDs). Atherosclerosis is a complex, progressive disorder affecting large and medium-sized arteries, preceding the development of CVDs such as ischemic heart disease, stroke, heart failure, peripheral arterial disease and rheumatic heart disease. Despite the epidemiological complexity of CVDs in SSA, the genetic susceptibility of the populations has remained understudied. Genome-wide association studies (GWAS) have revolutionized the field of complex disease genetics over the past decade, and provided insights into the genetic architecture of disease susceptibility and to advances in clinical care and personalized medicine. The evolutionary roots and genetic diversity of the continent represent an opportunity to shed new light on the genetic architecture of complex traits such as atherosclerosis. This thesis used the AWI-Gen (Africa Wits-INDEPTH Partnership for Genomic Studies) data to investigate whether genetic variation in SSA populations is associated with carotid intimamedia thickness (cIMT) (a marker for atherosclerosis) in middle-aged adults (40-60 years of age) and to examine interactions with key environmental factors. First, cIMT distributions in four SSA countries were characterised (Chapter 2). West African populations had higher cIMT compared to East and South Africa, despite having a lower prevalence of CVDs risk factors. West Africans also had higher cIMT compared to Asians and Europeans, but were concordant with data in African Americans, a trend not observed for East and South Africans. Our study is the first to report age-specific reference intervals of cIMT in SSA from a population-based study. Second, genetic susceptibility to atherosclerosis in SSA was investigated by performing a GWAS on 7894 unrelated middle-aged adults (3963 women, 3931 men) from the AWI-Gen study (with participants from East, South and West Africa), with adjustment for age, sex and 8 principal components (PCs) (Chapter 3). cIMT was measured by ultrasound and genotyping was performed on the H3Africa SNP Array (~2.3M SNPs). After imputation, we tested for association using BOLT-LMM. We identified two new African-specific genome-wide significant cIMT-associated loci (SIRPA (p=4.7E-08) and FBXL17 (p=2.5E-08)). Sex-stratification analysis revealed two male-specific loci (SNX29 (p=6.3E-9) and MAP3K7 (p=5.3E-8)), and two female-specific loci (ARNT2 (p=2.4E-09) and PROK1 (p=1.0E-08)). We also successfully replicated known cIMT-associated loci and identified novel African-specific variant and gene associations. Finally, we investigated gene-smoking interaction on cIMT in men from West Africa (Chapter 4). In Nanoro we identified new variants for the gene-smoking interactions for cIMT within the previously described RCBTB1 region (p-value=3.08E-08), and identified a new region at BCHE (p=2.20E-08). In the combined sample, variants were identified in the regulatory region and in a region of open chromatin of TBC1D8 (p-value=5.90E-09). Our study highlighted sex differences in atherosclerosis risk, and the role of gene-environment interaction. There was transferability of signals from studies of non-African populations, providing opportunities for fine-mapping and reducing credible SNP sets using African data. Greater inclusion of African populations in medical genomics is important for accelerating discoveries and identifying new genetic associations with traits for variants absent from other populations. Gene-environment interaction studies provide an opportunity for prevention and a precision public health approach.en_ZA
dc.description.librarianCK2021en_ZA
dc.facultyFaculty of Health Sciencesen_ZA
dc.identifier.urihttps://hdl.handle.net/10539/30414
dc.language.isoenen_ZA
dc.phd.titlePhDen_ZA
dc.titleGenome-wide association study of carotid intima-media thickness (cIMT) in sub-Saharan African populations: An AWI-Gen studyen_ZA
dc.typeThesisen_ZA
Files
Original bundle
Now showing 1 - 1 of 1
No Thumbnail Available
Name:
PhD_Thesis_Boua_Submission_16Jan2020_NoTtrack.pdf
Size:
10.34 MB
Format:
Adobe Portable Document Format
Description:
Download
License bundle
Now showing 1 - 1 of 1
No Thumbnail Available
Name:
license.txt
Size:
1.71 KB
Format:
Item-specific license agreed upon to submission
Description:
Download
Collections
ETD Collection