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Sökning: WFRF:(Morris Andrew P.) > Övrigt vetenskapligt/konstnärligt

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  • Chikowore, Tinashe, et al. (författare)
  • GWAS transethnic meta-analysis of BMI in similar to 700k individuals reveals novel gene-smoking interaction in African populations
  • 2020
  • Ingår i: Genetic Epidemiology. - : John Wiley & Sons. - 0741-0395 .- 1098-2272. ; 44:5, s. 475-476
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
    • Sixty two percent of the 1.12 billion obese people globally reside in low‐middle income countries, 77% of which are in Africa. There is paucity of data on gene‐lifestyle interactions associated with the increasing prevalence of obesity among Africans. We hypothesised that gene‐environment interacting (GEI) variants exhibit heterogenous effects on obesity in transethnic meta‐analysis of marginal SNP associations as a result of modification by an unknown exposure that varies across populations.Body mass index (BMI) genome‐wide association study (GWAS) summary statistics for 678,671 individuals representative of the major global ancestries were aggregated at 21,338,816 SNPs via fixed‐effects meta‐analysis. Lead SNPs attaining genome‐wide significance (P  < 5 × 10−8) were tested for heterogeneity in effects between GWAS. Lead SNPs with significant evidence of heterogeneity after Bonferroni correction were then selected for interaction analysis with selected lifestyle factors in an independent AWI‐Gen study of 10,500 African participants. Significant interaction findings were then replicated in 3,177 individuals of African ancestry in the UK Biobank.Of 881 lead SNPs, five had significant heterogenous effects on BMI (P  < 5.7 × 10−5). Rs471094, at the CDKAL1 locus had significant interaction with smoking status, which reduced the effect of the BMI raising allele in current smokers (Betaint = −0.949 kg/m2; P int = .002) compared with non‐smokers in AWI‐Gen. This finding was validated in the UK Biobank (Betaint = −1.471 kg/m2, P int = .020; meta‐analysis Betaint = −1.050 kg/m2, P int = .0002). Our results highlight the first gene‐lifestyle interaction on BMI in Africans and demonstrate the utility of transethnic meta‐analysis of GWAS for identifying GEI effects.
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3.
  • Klaric, Lucija, et al. (författare)
  • Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19.
  • 2021
  • Ingår i: medRxiv : the preprint server for health sciences. - : Cold Spring Harbor Laboratory. ; , s. 1-28
  • Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
    • Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quantitative trait loci (pQTL) data from the SCALLOP consortium, involving meta-analysis of up to 26,494 individuals, and COVID-19 genome-wide association data from the Host Genetics Initiative, we performed MR for 157 COVID-19 severity protein biomarkers. We identified significant MR results for five proteins: FAS, TNFRSF10A, CCL2, EPHB4 and LGALS9. Further evaluation of these candidates using sensitivity analyses and colocalization testing provided strong evidence to implicate the apoptosis-associated cytokine receptor FAS as a causal mediator of severe COVID-19. This effect was specific to severe disease. Using RNA-seq data from 4,778 individuals, we demonstrate that the pQTL at the FAS locus results from genetically influenced alternate splicing causing skipping of exon 6. We show that the risk allele for very severe COVID-19 increases the proportion of transcripts lacking exon 6, and thereby increases soluble FAS. Soluble FAS acts as a decoy receptor for FAS-ligand, inhibiting apoptosis induced through membrane-bound FAS. In summary, we demonstrate a novel genetic mechanism that contributes to risk of severe of COVID-19, highlighting a pathway that may be a promising therapeutic target.
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