Dataset Information

Whole-Exome Sequencing Study of Extreme Phenotypes of NAFLD.

ABSTRACT: Nonalcoholic fatty liver disease (NAFLD) is a heterogeneous disease with highly variable outcomes. Patients with simple steatosis typically experience a benign course, whereas those with more advanced liver injury, nonalcoholic steatohepatitis (NASH), and advanced stage fibrosis suffer increased risk for complications such as cirrhosis, hepatic decompensation, and liver cancer. Genetic variants in patatin-like phospholipase domain-containing 3 (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2) and clinical factors including diabetes, obesity, and older age increase a patient's risk for NASH, advanced fibrosis, and worse outcomes. Despite substantial investigation and identification of some common variants associated with NAFLD and advanced fibrosis, the genetics and functional mechanisms remain poorly understood. This study aimed to identify genetic variants by whole-exome sequencing of NAFLD phenotypes to provide novel insights into mechanisms behind NAFLD pathogenesis and variability. We sequenced 82 patients with liver biopsy-confirmed NAFLD and 4455 population controls. NAFLD patients were divided into extreme phenotypes based on liver fibrosis stage and clinical risk factors to investigate rare variants that might predispose to or protect from advanced NAFLD fibrosis. We compared NAFLD extremes to each other and individually to population controls, exploring genetic variation at both the single-variant and gene-based level. We replicated known associations with PNPLA3 and TM6SF2 and advanced fibrosis, despite sample-size limitations. We also observed enrichment of variation in distinct genes for progressor or protective NAFLD phenotypes, although these genes did not reach statistical significance. Conclusion: We report the first whole-exome sequencing study of genetic variation in liver biopsy-confirmed NAFLD susceptibility and severity, using a small cohort of extreme NAFLD phenotypes and a large cohort of population controls.

SUBMITTER: Kleinstein SE

PROVIDER: S-EPMC6128233 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Whole-Exome Sequencing Study of Extreme Phenotypes of NAFLD.

Kleinstein Sarah E SE Rein Matthew M Abdelmalek Manal F MF Guy Cynthia D CD Goldstein David B DB Mae Diehl Anna A Moylan Cynthia A CA

Hepatology communications 20180905 9

Nonalcoholic fatty liver disease (NAFLD) is a heterogeneous disease with highly variable outcomes. Patients with simple steatosis typically experience a benign course, whereas those with more advanced liver injury, nonalcoholic steatohepatitis (NASH), and advanced stage fibrosis suffer increased risk for complications such as cirrhosis, hepatic decompensation, and liver cancer. Genetic variants in patatin-like phospholipase domain-containing 3 (<i>PNPLA3</i>) and transmembrane 6 superfamily memb ...[more]

PMID: 30202817

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Project description:PurposeDemographic, environmental, and genetic risk factors for age-related macular degeneration (AMD) have been identified; however, a substantial portion of the variance in AMD disease risk and heritability remains unexplained. To identify AMD risk variants and generate hypotheses for future studies, we performed whole exome sequencing for 75 individuals whose phenotype was not well predicted by their genotype at known risk loci. We hypothesized that these phenotypically extreme individuals were more likely to carry rare risk or protective variants with large effect sizes.MethodsA genetic risk score was calculated in a case-control set of 864 individuals (467 AMD cases, 397 controls) based on 19 common (≥1% minor allele frequency, MAF) single nucleotide variants previously associated with the risk of advanced AMD in a large meta-analysis of advanced cases and controls. We then selected for sequencing 39 cases with bilateral choroidal neovascularization with the lowest genetic risk scores to detect risk variants and 36 unaffected controls with the highest genetic risk score to detect protective variants. After minimizing the influence of 19 common genetic risk loci on case-control status, we targeted single variants of large effect and the aggregate effect of weaker variants within genes and pathways. Single variant tests were conducted on all variants, while gene-based and pathway analyses were conducted on three subsets of data: 1) rare (≤1% MAF in the European population) stop, splice, or damaging missense variants, 2) all rare variants, and 3) all variants. All analyses controlled for the effects of age and sex.ResultsNo variant, gene, or pathway outside regions known to be associated with risk for advanced AMD reached genome-wide significance. However, we identified several variants with substantial differences in allele frequency between cases and controls with strong additive effects on affection status after controlling for age and sex. Protective effects trending toward significance were detected at two loci identified in single-variant analyses: an intronic variant in FBLN7 (the gene encoding fibulin 7) and at three variants near pyridoxal (pyridoxine, vitamin B6) kinase (PDXK). Aggregate rare-variant analyses suggested evidence for association at ASRGL1, a gene previously linked to photoreceptor cell death, and at BSDC1. In known AMD loci we also identified 29 novel or rare damaging missense or stop/splice variants in our sample of cases and controls.ConclusionsIdentified variants and genes may highlight regions important in the pathogenesis of AMD and are key targets for replication.

Dataset Information

Whole-Exome Sequencing Study of Extreme Phenotypes of NAFLD.

Publications

Whole-Exome Sequencing Study of Extreme Phenotypes of NAFLD.

Similar Datasets

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