scholarly journals Genome-Wide Association Study of Non-Alcoholic Fatty Liver Disease Identifies Association with Apolipoprotein E

2021 ◽  
Author(s):  
Cameron J Fairfield ◽  
Thomas M Drake ◽  
Riinu Pius ◽  
Andrew D Bretherick ◽  
Archie Campbell ◽  
...  
Keyword(s):  
Fatty Liver Disease ◽  
Alcohol Intake ◽  
Meta Analysis ◽  
Case Control ◽  
Genome Wide Association ◽  
Sensitivity Analyses ◽  
Alcoholic Fatty Liver ◽  
Genome Wide ◽  
Consistent Direction ◽  
Alcoholic Fatty Liver Disease

Background & Aims Genome-wide association studies (GWAS) have identified several risk loci for non-alcoholic fatty liver disease (NAFLD). Previous studies have largely relied on small sample sizes and have assessed quantitative traits. We performed a case-control GWAS in the UK Biobank using recorded diagnosis of NAFLD based on diagnostic codes recommended in recent consensus guidelines. Approach & Results We performed a GWAS of 4,761 cases of NAFLD and 373,227 healthy controls without evidence of NAFLD. Sensitivity analyses were performed excluding other co-existing hepatic pathology, adjusting for BMI and adjusting for alcohol intake. 9,723,654 variants were assessed by logistic regression adjusted for age, sex, genetic principal components and genotyping batch. We performed a GWA meta-analysis using available summary association statistics from two previously published case-control GWAS of NAFLD. Six risk loci were identified (P<5*10-8) of which one is novel in GWAS (rs429358 in APOE) and five are known (PNPLA3, TM6SF2, GCKR, MARC1 and TRIB1). Rs429358 (P=2.17*10-11) is a missense variant within the APOE gene determining ϵ4 vs ϵ2/ϵ3 alleles. All loci retained significance in sensitivity analyses without co-existent hepatic pathology and after adjustment for BMI. PNPLA3 and TM6SF2 remained significant after adjustment for alcohol (alcohol intake was known in only 158,388 individuals) with others demonstrating consistent direction and magnitude of effect. All 6 loci were significant on meta-analysis including APOE P=3.42*10-13 with consistent direction and magnitude of effect in all 6 loci in all three studies. The ϵ4 allele of APOE offered protection against NAFLD (odds ratio for heterozygotes 0.84 [95%CI 0.78-0.90] and homozygotes 0.64 [0.50-0.79]). Conclusions This GWAS demonstrates that the ϵ4 allele of APOE is strongly associated with protection against NAFLD.

scholarly journals Genome-Wide Meta-Analysis and Mendelian Randomization Identify Early Biomarkers of Non-Alcoholic Fatty Liver Disease

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A315-A315
Author(s):  
Emilie Gobeil ◽  
Erik Abner ◽  
Nooshin Ghodsian ◽  
Nele Taba ◽  
Alexis St-Amand ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver Disease ◽  
Mendelian Randomization ◽  
Meta Analysis ◽  
Blood Metabolites ◽  
Blood Proteins ◽  
Alcoholic Fatty Liver ◽  
Early Biomarkers ◽  
Genome Wide ◽  
Alcoholic Fatty Liver Disease

Abstract Background: The diagnosis of non-alcoholic fatty liver disease (NAFLD) is often challenging. Blood-based biomarkers which are causally influenced by NAFLD and that are not modulated by secondary non-causal pathways, are promising candidates for the identification of patients with NAFLD. Objectives: To identify blood metabolites and blood proteins that are causally impacted by the presence of NAFLD using Mendelian randomization (MR). Methods: We created a NAFLD genetic instrument through the identification of independent single-nucleotide polymorphisms associated with NAFLD in a meta-analysis of genome-wide association studies (GWAS) (6715 cases and 682,748 controls). Using inverse-variance weighted MR, we investigated the impact of NAFLD on 123 blood metabolites (in 24,925 participants from 10 European cohorts) and 3283 blood proteins (in 3301 participants from the INTERVAL cohort). Results: Our genetic instrument for genetically predicted NAFLD included 12 SNPs at the MTARC1, GCKR, LPL, TRIB1, LMO3, FTO, TM6SF2, APOE and PNPLA3 loci. After correction for false-discovery rate, we found a positive effect of NAFLD on blood tyrosine levels and on blood levels of eight proteins (encoded by the IDUA, ADH4, HMGCS1, GSTA1, ASL, POR, FBP1 and CTSZ genes). These association were robust to outliers and we found to evidence of horizontal pleiotropy. Conclusions: We report the existence of a potentially causal impact of the presence of NAFLD on tyrosine metabolism as well as on eight circulating proteins, which could potentially represent early biomarkers of NAFLD.

scholarly journals Electronic Health Record-Based Genome-Wide Meta-Analysis and Mendelian Randomization Identify Metabolic and Phenotypic Consequences of Non-Alcoholic Fatty Liver Disease

2021 ◽  
Author(s):  
Nooshin Ghodsian ◽  
Erik Abner ◽  
Connor A. Emdin ◽  
Émilie Gobeil ◽  
Nele Taba ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver Disease ◽  
Mendelian Randomization ◽  
Meta Analysis ◽  
Genetic Correlations ◽  
Health Record ◽  
Susceptibility Loci ◽  
Alcoholic Fatty Liver ◽  
Genome Wide ◽  
Alcoholic Fatty Liver Disease

Abstract Non-alcoholic fatty liver disease (NAFLD) is a complex disease linked with several chronic diseases. We aimed at identifying genetic variants associated with NAFLD as well as blood biomarkers that may be causally impacted by NAFLD. We performed a genome-wide meta-analysis of four cohorts of electronic health record-documented NAFLD (8434 cases and 770,180 controls) and confirmed known susceptibility loci (GCKR, MAU2/TM6SF2, APOE, and PNPLA3). We also identified potentially new loci (LPL, FTO and TR1B1) and report an effect of lower LPL expression in adipose tissue on NAFLD susceptibility. Mendelian randomization analyses identified an effect of NAFLD on tyrosine metabolism and on blood levels of three proteins. Positive genetic correlations between NAFLD and cardiometabolic traits and negative genetic correlations with parental lifespan, socio-economic factors and ketone bodies were observed. Altogether, this analysis revealed novel susceptibility loci for NAFLD and early biomarkers of NAFLD that could be used to identify patients with NAFLD.

scholarly journals Electronic Health Record-Based Genome-Wide Meta-Analysis Identifies New Susceptibility Loci for Non-Alcoholic Fatty Liver Disease

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A501-A501
Author(s):  
Nooshin Ghodsian ◽  
Erik Abner ◽  
Émilie Gobeil ◽  
Nele Taba ◽  
Alexis St- Amand ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Human Disease ◽  
Fatty Liver Disease ◽  
Liver Diseases ◽  
Meta Analysis ◽  
Genetic Loci ◽  
Alcoholic Fatty Liver ◽  
Genome Wide ◽  
Alcoholic Fatty Liver Disease

Abstract Background: Non-alcoholic fatty liver disease (NAFLD) is the most prevalent form of liver disease. Observational studies documented associations of NAFLD with several chronic and infectious diseases but whether these associations underlie causal effects is unknown. The molecular mechanisms and genetic architecture of NAFLD are poorly understood. Our objectives were to identify genetic loci associated with NAFLD and determine whether the presence of NAFLD was causally associated with human diseases. Methods: We created a NAFLD genetic instrument through the identification of independent single-nucleotide polymorphisms (SNPs) associated with NAFLD in a meta-analysis of genome-wide association study (GWAS) (6715 cases and 682,748 controls). Using inverse-variance weighted Mendelian Randomization (MR), we investigated the impact of NAFLD on human disease-related phenotypes in the UK Biobank and FinnGen cohorts as well as in the COVID-19 host genetics initiative. Results: We first performed a GWAS meta-analysis of four cohorts and found variants significantly associated with NAFLD (p&lt;5.0E-8) at six genetic loci (MTARC1, GCKR, TRIB1, LMO3, SUGP1 [TM6SF2] and PNPLA3). Using a risk factor informed Bayesian approach (bGWAS), we identify variants at three additional loci (LPL, FTO, and APOE). To determine if the association between NAFLD and human diseases shows evidence of causality, we performed MR across the human disease-related phenome (&gt;800 diseases) using a genetic instrument for NAFLD. Results of these analyses suggest that NAFLD was not causally associated with diseases outside the spectrum of liver diseases. We also found no causal association between genetically predicted NAFLD and COVID-19-related outcomes. Conclusions: This study identified several new genetic loci associated with NAFLD. NAFLD was not causally associated with diseases outside those of the spectrum of liver diseases. This finding suggests that the resolution of NAFLD might not prevent other diseases previously associated with NAFLD.

scholarly journals Non‐alcoholic fatty liver disease in premenopausal women with polycystic ovary syndrome: A systematic review and meta‐analysis

JGH Open ◽  
2021 ◽  
Vol 5 (4) ◽  
pp. 434-445
Author(s):  
Mohamed Shengir ◽  
Tianyan Chen ◽  
Elena Guadagno ◽  
Agnihotram V Ramanakumar ◽  
Peter Ghali ◽  
...  
Keyword(s):  
Systematic Review ◽  
Liver Disease ◽  
Polycystic Ovary Syndrome ◽  
Fatty Liver Disease ◽  
Polycystic Ovary ◽  
Meta Analysis ◽  
Premenopausal Women ◽  
Ovary Syndrome ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease
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