Biology subjects

Dehghan, A.

Publications and source records attributed to Dehghan, A..

7 recordsLinked to original sources

bioRxiv2023

Evidence for Involvement of WDPCP Gene in Alcohol Consumption, Lipid Metabolism, and Liver Cirrhosis

Alcohol consumption continues to cause a significant health burden globally. The advent of genome-wide association studies has unraveled many genetic loci associated with alcohol consumption. However, the biological effect of these loci and the pathways involved in alcohol consumption and its health consequences such as alcohol liver disease (ALD) remain to be elucidated. We combined human studies with model organisms Drosophila melanogaster and Caenorhabditis elegans to shed light on the molecular mechanisms underlying alcohol consumption and the health outcomes caused by alcohol intake. Using genetics and metabolite data within the Airwave study, a sample of police forces in the UK, we performed several analyses to identify changes in circulating metabolites that are triggered by alcohol consumption. We selected a set of genes annotated to genetic variants that are (1) known to be implicated in alcohol consumption, (2) are linked to liver function, and (3) are associated with expression (cis-eQTL) of their annotated genes. We used mutations and/or RNA interference (RNAi) to suppress the expression of these genes in C. elegans and Drosophila. We examined the effect of this suppression on ethanol consumption and on the sedative effects of ethanol. We also investigated the alcohol-induced changes in triacylglycerol (TGA) levels in Drosophila and tested differences in locomotion of C. elegans after acute exposure to ethanol. In human population, we found an enrichment of the alcohol-associated metabolites within the linoleic acid (LNA) and alpha linolenic acid (ALA) metabolism pathway. We further showed the effect of ACTR1B and MAPT on locomotion in C. elegans after exposure to ethanol. We demonstrated that three genes namely WDPCP, TENM2 and GPN1 modify TAG levels in Drosophila. Finally, we showed that gene expression of WDPCP in human population is linked to liver fibrosis and liver cirrhosis. Our results underline the impact of alcohol consumption on metabolism of lipids and pinpoints WDPCP as a gene with potential impact on fat accumulation upon exposure to ethanol suggesting a possible pathway to ALD.

genetics↗

bioRxiv2020

Epigenome-wide association meta-analysis of DNA methylation with coffee and tea consumption

Coffee and tea are extensively consumed beverages worldwide. Observational studies have shown contradictory findings for the association between consumption of these beverages and different health outcomes. Epigenetics is suggested as a mechanism mediating the effects of dietary and lifestyle factors on disease onset. We conducted epigenome-wide association studies (EWAS) on coffee and tea consumptions in 15,789 participants of European and African-American ancestries from 15 cohorts. EWAS meta-analysis revealed 11 CpG sites significantly associated with coffee consumption (P-value <1.1x10-7), nine of them annotated to the genes AHRR, F2RL3, FLJ43663, HDAC4, GFI1 and PHGDH, and two CpGs suggestively associated with tea consumption (P-value<5.0x10-6). Among these, cg14476101 was significantly associated with expression of its annotated gene PHGDH and risk of fatty liver disease. Knockdown of PHGDH expression in liver cells showed a correlation with expression levels of lipid-associated genes, suggesting a role of PHGDH in hepatic-lipid metabolism. Collectively, this study indicates that coffee consumption is associated with differential DNA methylation levels at multiple CpGs, and that coffee-associated epigenetic variations may explain the mechanism of action of coffee consumption in conferring disease risk.

genomics↗

bioRxiv2020

Genetic loci associated with prevalent and incident myocardial infarction and coronary heart disease in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium

BackgroundGenome-wide association studies have identified multiple genomic loci associated with coronary artery disease, but most are common variants in non-coding regions that provide limited information on causal genes and etiology of the disease. To better understand etiological pathways that might lead to discovery of new treatments or prevention strategies, we focused our investigation on low-frequency and rare sequence variations primarily residing in coding regions of the genome while also exploring associations with common variants. Methods and ResultsUsing samples of individuals of European ancestry from ten cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, both cross-sectional and prospective analyses were conducted to examine associations between genetic variants and myocardial infarction (MI), coronary heart disease (CHD), and all-cause mortality following these events. Single variant and gene-based analyses were performed separately in each cohort and then meta-analyzed for each outcome. A low-frequency intronic variant (rs988583) in PLCL1 was significantly associated with prevalent MI (OR=1.80, 95% confidence interval: 1.43, 2.27; P=7.12 x 10-7). Three common variants, rs9349379 in PHACTR1, and rs1333048 and rs4977574 in the 9p21 region, were significantly associated with prevalent CHD. Four common variants (rs4977574, rs10757278, rs1333049, and rs1333048) within the 9p21 locus were significantly associated with incident MI. We conducted gene-based burden tests for genes with a cumulative minor allele count (cMAC) [≥] 5 and variants with minor allele frequency (MAF) < 5%. TMPRSS5 and LDLRAD1 were significantly associated with prevalent MI and CHD, respectively, and RC3H2 and ANGPTL4 were significantly associated with incident MI and CHD, respectively. No loci were significantly associated with all-cause mortality following a MI or CHD event. ConclusionThis study confirmed previously reported loci influencing heart disease risk, and one single variant and three genes associated with MI and CHD were newly identified and warrant future investigation.

genetics↗

bioRxiv2019

Genome-wide association study provides new insights into the genetic architecture and pathogenesis of heart failure

Heart failure (HF) is a leading cause of morbidity and mortality worldwide1. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained2-4. We report the largest GWAS meta-analysis of HF to-date, comprising 47,309 cases and 930,014 controls. We identify 12 independent variant associations with HF at 11 genomic loci, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function suggesting shared genetic aetiology. Expression quantitative trait analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homeostasis (BAG3), and cellular senescence (CDKN1A). Using Mendelian randomisation analysis we provide new evidence supporting previously equivocal causal roles for several HF risk factors identified in observational studies, and demonstrate CAD-independent effects for atrial fibrillation, body mass index, hypertension and triglycerides. These findings extend our knowledge of the genes and pathways underlying HF and may inform the development of new therapeutic approaches.

genetics↗

bioRxiv2018

What explains the effect of education on cardiovascular disease? Applying Mendelian randomization to identify the consequences of education inequality

Key PointsO_ST_ABSQuestionC_ST_ABSWhat is the role of body mass index, systolic blood pressure and smoking in mediating the effect of education on cardiovascular disease risk?\n\nFindingWe find consistent evidence that body mass index, systolic blood pressure and smoking mediate the effect of education, explaining up to 18%, 27% and 33% respectively. Including all three risk factors in a model together explains around 40% of the effect of education.\n\nMeaningIntervening on body mass index, systolic blood pressure and smoking would lead to reductions in cases of CVD attributable to lower levels of education. Over half of the effect of education on risk of cardiovascular disease is not mediated through these risk factors.\n\nImportanceLower levels of education are causally related to higher cardiovascular risk, but the extent to which this is driven by modifiable risk factors also associated with education is unknown.\n\nObjectiveTo investigate the role of body mass index, systolic blood pressure and smoking in explaining the effect of education on risk of cardiovascular disease outcomes.\n\nDesignMultivariable regression analysis of observational data and Mendelian randomization (MR) analysis of genetic data.\n\nSettingUK Biobank and international genome-wide association study consortia.\n\nParticipantsPredominantly individuals of European ancestry.\n\nMain outcomes and measuresThe effects of education (per 1-standard deviation increase, equivalent to 3.6 years) on coronary heart disease, cardiovascular disease (all subtypes), myocardial infarction and stroke risk (all measured in odds ratio, OR), and the degree to which this is mediated through body mass index, systolic blood pressure and smoking.\n\nResultsEach additional standard deviation of education associated with 13% lower risk of coronary heart disease (OR 0.87, 95% confidence interval [CI] 0.84 to 0.89) in observational analysis and 37% lower risk (OR 0.63, 95% CI 0.60 to 0.67) in Mendelian randomization analysis. As a proportion of the total risk reduction, body mass index mediated 15% (95% CI 13% to 17%) and 18% (95% CI 14% to 23%) in the observational and Mendelian randomization estimates, respectively. Corresponding estimates for systolic blood pressure were 11% (95% CI 9% to 13%) and 21% (95% CI 15% to 27%), and for smoking, 19% (15% to 22%) and 33% (95% CI 17% to 49%). All three risk factors combined mediated 42% (95% CI 36% to 48%) and 36% (95 % CI 16% to 63%) of the effect of education on coronary heart disease in observational and Mendelian randomization respectively. Similar results were obtained when investigating risk of stroke, myocardial infarction and all-cause cardiovascular disease.\n\nConclusions and relevanceBMI, SBP and smoking mediate a substantial proportion of the protective effect of education on risk of cardiovascular outcomes and intervening on these would lead to reductions in cases of CVD attributable to lower levels of education. However, more than half of the protective effect of education remains unexplained and requires further investigation.

epidemiology↗

bioRxiv2018

Genetic variants related to antihypertensive targets inform drug efficacy and side effects

BackgroundDrug effects can be investigated through natural variation in the genes for their protein targets. We aimed to use this approach to explore the potential side effects and repurposing potential of antihypertensive drugs, which are amongst the most commonly used medications worldwide.\n\nMethodsWe identified genetic instruments for antihypertensive drug classes as variants in the gene for the corresponding target that associated with systolic blood pressure at genome-wide significance. To validate the instruments, we compared Mendelian randomisation (MR) estimates for drug effects on coronary heart disease (CHD) and stroke risk to randomised controlled trial (RCT) results. Phenome-wide association study (PheWAS) in the UK Biobank was performed to identify potential side effects and repurposing opportunities, with findings investigated in the Vanderbilt University Biobank (BioVU) and in observational analysis of the UK Biobank.\n\nFindingsWe identified suitable genetic instruments for beta-blockers (BBs) and calcium channel blockers (CCBs). MR estimates for their effect on CHD and stroke risk respectively were comparable to results from RCTs against placebo. PheWAS in the UK Biobank identified an association of the CCB genetic risk score (scaled to drug effect) with increased risk of diverticulosis (odds ratio [OR] 1.23, 95%CI 1.10-1.38), with a consistent estimate found in BioVU (OR 1.16, 95%CI 0.94-1.44). Association with diverticulosis was further supported in observational analysis of CCB use in the UK Biobank (OR 1.08, 95%CI 1.02-1.15).\n\nInterpretationWe identified valid genetic instruments for BBs and CCBs. Using genetic and observational approaches, we highlighted a previously unreported potential detrimental effect of CCBs on risk of diverticulosis. This work serves as a proof of concept that investigation of genetic variants can offer a complementary approach to exploring the efficacy and side effects of anti-hypertensive medications.\n\nFundingWellcome Trust.

genetics↗

bioRxiv2018

Systematic evaluation of the causal relationship between DNA methylation and C-reactive protein

Elevated C-reactive protein (CRP) levels are an indicator of chronic low-grade inflammation. Epigenetic modifications, including DNA methylation, have been linked to CRP, but systematic investigations into potential underlying causal relationships have not yet been performed.\n\nWe systematically performed two-sample Mendelian randomization and colocalization analysis between CRP and DNA methylation levels, using GWAS and EWAS summary statistics as well as individual level data available through the ARIES subset of the Avon Longitudinal Study of Parents and Children (ALSPAC; 1,616 participants).\n\nWe found no convincing examples for a causal association from CRP to DNA methylation. Testing for the reverse (a putative causal effect of DNA methylation on CRP), we found three CpG sites that had shared genetic effects with CRP levels after correcting for multiple testing (cg26470501 (offspring: beta=0.07 [0.03, 0.11]; mothers: beta=0.08 [0.04, 0.13]), cg27023597 (offspring: beta=0.18 [0.10, 0.25]; mothers: beta=0.20 [0.12, 0.28]) and cg12054453 (offspring: beta=0.09 [0.05, 0.13])) influenced CRP levels. For all three CpG sites, linked to the genes TMEM49, BCL3 and MIR21, increased methylation related to an increase in CRP levels. Two CpGs (cg27023597 and cg12054453) were influenced by SNPs in genomic regions that had not previously been implicated in CRP GWASs, implicating them as novel genetic associations.\n\nOverall, our findings suggest that CRP associations with DNA methylation are more likely to be driven by either confounding or causal influences of DNA methylation on CRP levels, rather than the reverse.

genetics↗