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The genetic architecture of NAFLD among inbred strains of mice.

Hui ST, Parks BW, Org E, Norheim F, Che N, Pan C, Castellani LW, Charugundla S, Dirks DL, Psychogios N, Neuhaus I, Gerszten RE, Kirchgessner T, Gargalovic PS, Lusis AJ - Elife (2015)

Bottom Line: Genome-wide association studies revealed three loci associated with hepatic TG accumulation.We hypothesize that Gde1 expression increases TG production by contributing to the production of glycerol-3-phosphate.Our multi-level data, including transcript levels, metabolite levels, and gut microbiota composition, provide a framework for understanding genetic and environmental interactions underlying hepatic steatosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States.

ABSTRACT
To identify genetic and environmental factors contributing to the pathogenesis of non-alcoholic fatty liver disease, we examined liver steatosis and related clinical and molecular traits in more than 100 unique inbred mouse strains, which were fed a diet rich in fat and carbohydrates. A >30-fold variation in hepatic TG accumulation was observed among the strains. Genome-wide association studies revealed three loci associated with hepatic TG accumulation. Utilizing transcriptomic data from the liver and adipose tissue, we identified several high-confidence candidate genes for hepatic steatosis, including Gde1, a glycerophosphodiester phosphodiesterase not previously implicated in triglyceride metabolism. We confirmed the role of Gde1 by in vivo hepatic over-expression and shRNA knockdown studies. We hypothesize that Gde1 expression increases TG production by contributing to the production of glycerol-3-phosphate. Our multi-level data, including transcript levels, metabolite levels, and gut microbiota composition, provide a framework for understanding genetic and environmental interactions underlying hepatic steatosis.

No MeSH data available.


Related in: MedlinePlus

Association mapping of hepatic TG.(A) Manhattan plot showing the significance (−log of p) of all SNPs and hepatic TG. Genome-wide significance cut-off at 1% false discovery rate (FDR) is shown by the red line and cut-off at 5% FDR is shown in green. (B) Locus plot for genome-wide significant locus on chromosome 7 with approximate linkage disequilibrium block and candidate genes.DOI:http://dx.doi.org/10.7554/eLife.05607.012
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fig5: Association mapping of hepatic TG.(A) Manhattan plot showing the significance (−log of p) of all SNPs and hepatic TG. Genome-wide significance cut-off at 1% false discovery rate (FDR) is shown by the red line and cut-off at 5% FDR is shown in green. (B) Locus plot for genome-wide significant locus on chromosome 7 with approximate linkage disequilibrium block and candidate genes.DOI:http://dx.doi.org/10.7554/eLife.05607.012

Mentions: To identify genetic loci associated with hepatic steatosis, we performed GWAS analysis on the hepatic TG contents with ∼200,000 high-quality SNPs spaced throughout the genome. The genome-wide significant threshold was set at 1.31 × 10−5, which corresponds to a 1% false discovery rate (FDR). We identified one genome-wide significant peak associated with hepatic TG content on chromosome 7 (Figure 5A). This peak does not overlap with any loci identified for obesity and insulin resistance in the same cohort of mice (Parks et al., 2013, 2015). In addition, the peak locus on chromosome 7 still reached genome-wide significance when association mapping was conditioned using adiposity (% fat) or insulin resistance (HOMA-IR) as covariates (Figure 6), indicating that the effect of the chromosome 7 locus on hepatic steatosis is independent of obesity and diabetes. The peak SNP (rs32519715, p = 1.15 × 10−6) falls in a LD block containing 17 genes (Figure 5B and Table 6). Three suggestive peaks, on chromosomes 3 (rs3708683; p = 5.47 × 10−5), 9 (rs36804270; p = 1.30 × 10−5), and 11 (rs13481015; p = 1.72 × 10−5) passed the genome-wide significant threshold of 5% FDR (p = 1.34 × 10−4). The peak on chromosome 9 also coincides with a genome-wide significant locus for insulin resistance (data not shown) and contains 13 genes within the LD block, whereas the peaks on chromosomes 3 and 11 contain 12 and 15 genes, respectively, within the associated LD blocks (Table 7).10.7554/eLife.05607.012Figure 5.Association mapping of hepatic TG.


The genetic architecture of NAFLD among inbred strains of mice.

Hui ST, Parks BW, Org E, Norheim F, Che N, Pan C, Castellani LW, Charugundla S, Dirks DL, Psychogios N, Neuhaus I, Gerszten RE, Kirchgessner T, Gargalovic PS, Lusis AJ - Elife (2015)

Association mapping of hepatic TG.(A) Manhattan plot showing the significance (−log of p) of all SNPs and hepatic TG. Genome-wide significance cut-off at 1% false discovery rate (FDR) is shown by the red line and cut-off at 5% FDR is shown in green. (B) Locus plot for genome-wide significant locus on chromosome 7 with approximate linkage disequilibrium block and candidate genes.DOI:http://dx.doi.org/10.7554/eLife.05607.012
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4493743&req=5

fig5: Association mapping of hepatic TG.(A) Manhattan plot showing the significance (−log of p) of all SNPs and hepatic TG. Genome-wide significance cut-off at 1% false discovery rate (FDR) is shown by the red line and cut-off at 5% FDR is shown in green. (B) Locus plot for genome-wide significant locus on chromosome 7 with approximate linkage disequilibrium block and candidate genes.DOI:http://dx.doi.org/10.7554/eLife.05607.012
Mentions: To identify genetic loci associated with hepatic steatosis, we performed GWAS analysis on the hepatic TG contents with ∼200,000 high-quality SNPs spaced throughout the genome. The genome-wide significant threshold was set at 1.31 × 10−5, which corresponds to a 1% false discovery rate (FDR). We identified one genome-wide significant peak associated with hepatic TG content on chromosome 7 (Figure 5A). This peak does not overlap with any loci identified for obesity and insulin resistance in the same cohort of mice (Parks et al., 2013, 2015). In addition, the peak locus on chromosome 7 still reached genome-wide significance when association mapping was conditioned using adiposity (% fat) or insulin resistance (HOMA-IR) as covariates (Figure 6), indicating that the effect of the chromosome 7 locus on hepatic steatosis is independent of obesity and diabetes. The peak SNP (rs32519715, p = 1.15 × 10−6) falls in a LD block containing 17 genes (Figure 5B and Table 6). Three suggestive peaks, on chromosomes 3 (rs3708683; p = 5.47 × 10−5), 9 (rs36804270; p = 1.30 × 10−5), and 11 (rs13481015; p = 1.72 × 10−5) passed the genome-wide significant threshold of 5% FDR (p = 1.34 × 10−4). The peak on chromosome 9 also coincides with a genome-wide significant locus for insulin resistance (data not shown) and contains 13 genes within the LD block, whereas the peaks on chromosomes 3 and 11 contain 12 and 15 genes, respectively, within the associated LD blocks (Table 7).10.7554/eLife.05607.012Figure 5.Association mapping of hepatic TG.

Bottom Line: Genome-wide association studies revealed three loci associated with hepatic TG accumulation.We hypothesize that Gde1 expression increases TG production by contributing to the production of glycerol-3-phosphate.Our multi-level data, including transcript levels, metabolite levels, and gut microbiota composition, provide a framework for understanding genetic and environmental interactions underlying hepatic steatosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States.

ABSTRACT
To identify genetic and environmental factors contributing to the pathogenesis of non-alcoholic fatty liver disease, we examined liver steatosis and related clinical and molecular traits in more than 100 unique inbred mouse strains, which were fed a diet rich in fat and carbohydrates. A >30-fold variation in hepatic TG accumulation was observed among the strains. Genome-wide association studies revealed three loci associated with hepatic TG accumulation. Utilizing transcriptomic data from the liver and adipose tissue, we identified several high-confidence candidate genes for hepatic steatosis, including Gde1, a glycerophosphodiester phosphodiesterase not previously implicated in triglyceride metabolism. We confirmed the role of Gde1 by in vivo hepatic over-expression and shRNA knockdown studies. We hypothesize that Gde1 expression increases TG production by contributing to the production of glycerol-3-phosphate. Our multi-level data, including transcript levels, metabolite levels, and gut microbiota composition, provide a framework for understanding genetic and environmental interactions underlying hepatic steatosis.

No MeSH data available.


Related in: MedlinePlus