Browsing by Subject "Genome-wide association study"

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    Chromosome 16q22 variants in a region associated with cardiovascular phenotypes correlate with ZFHX3 expression in a transcript-specific manner
    (BioMed Central, 2014-12-24) Martin, Ruairidh I R; Owens, W A; Cunnington, Michael S; Mayosi, Bongani M; Koref, Mauro S; Keavney, Bernard D
    Background: The ZFHX3 gene, located in Chromosome 16q22.3, codes for a transcription factor which is widely expressed in human tissues. Genome-wide studies have identified associations between variants within the gene and Kawasaki disease and atrial fibrillation. ZFHX3 has two main transcripts that utilise different transcription start sites. We examined the association between genetic variants in the 16q22.3 region and expression of ZFHX3 to identify variants that regulate gene expression. Results: We genotyped 65 single-nucleotide polymorphisms to tag genetic variation at the ZFHX3 locus in two cohorts, 451 British individuals recruited in the North East of England and 310 mixed-ancestry individuals recruited in South Africa. Allelic expression analysis revealed that the minor (A) allele of rs8060701, a variant in the first intron of ZFHX3, was associated with a 1.16-fold decrease in allelic expression of both transcripts together, (p = 4.87e-06). The minor (C) allele of a transcribed variant, rs10852515, in the second exon of ZFHX3 isoform A was independently associated with a 1.36-fold decrease in allelic expression of ZFHX3 A (p = 7.06e-31), but not overall ZFHX3 expression. However, analysis of total gene expression of ZFHX3 failed to detect an association with genotype at any variant. Differences in linkage disequilibrium between the two populations allowed fine-mapping of the locus to a 7 kb region overlapping exon 2 of ZFHX3 A. We did not find any association between ZFHX3 expression and any of the variants identified by genome wide association studies. Conclusions: ZFHX3 transcription is regulated in a transcript-specific fashion by independent cis-acting transcribed polymorphisms. Our results demonstrate the power of allelic expression analysis and trans-ethnic fine mapping to identify transcript-specific cis-acting regulatory elements.
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    Genome-wide association studies of severe P. falciparum malaria susceptibility: progress, pitfalls and prospects
    (2019-08-14) Damena, Delesa; Denis, Awany; Golassa, Lemu; Chimusa, Emile R
    Abstract Background P. falciparum malaria has been recognized as one of the prominent evolutionary selective forces of human genome that led to the emergence of multiple host protective alleles. A comprehensive understanding of the genetic bases of severe malaria susceptibility and resistance can potentially pave ways to the development of new therapeutics and vaccines. Genome-wide association studies (GWASs) have recently been implemented in malaria endemic areas and identified a number of novel association genetic variants. However, there are several open questions around heritability, epistatic interactions, genetic correlations and associated molecular pathways among others. Here, we assess the progress and pitfalls of severe malaria susceptibility GWASs and discuss the biology of the novel variants. Results We obtained all severe malaria susceptibility GWASs published thus far and accessed GWAS dataset of Gambian populations from European Phenome Genome Archive (EGA) through the MalariaGen consortium standard data access protocols. We noticed that, while some of the well-known variants including HbS and ABO blood group were replicated across endemic populations, only few novel variants were convincingly identified and their biological functions remain to be understood. We estimated SNP-heritability of severe malaria at 20.1% in Gambian populations and showed how advanced statistical genetic analytic methods can potentially be implemented in malaria susceptibility studies to provide useful functional insights. Conclusions The ultimate goal of malaria susceptibility study is to discover a novel causal biological pathway that provide protections against severe malaria; a fundamental step towards translational medicine such as development of vaccine and new therapeutics. Beyond singe locus analysis, the future direction of malaria susceptibility requires a paradigm shift from single -omics to multi-stage and multi-dimensional integrative functional studies that combines multiple data types from the human host, the parasite, the mosquitoes and the environment. The current biotechnological and statistical advances may eventually lead to the feasibility of systems biology studies and revolutionize malaria research.