Population‐based meta‐analysis and gene‐set enrichment identifies FXR/RXR pathway as common to fatty liver disease and serum lipids

Figures

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  FIGURE 1. Study design of the two‐stage pathway analysis. FXR, farnesoid X receptor; GSEA, gene‐set enrichment analysis; GWAS, genome‐wide association study; HDL, high‐density lipoprotein; LDL, low‐density lipoprotein; MAGENTA, meta‐analysis gene‐set enrichment of variant associations; NAFLD, nonalcoholic fatty liver disease; RXR, retinoid X receptor; SNP, single‐nucleotide polymorphism; TG, triglycerides.

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  FIGURE 2. Summary of gene‐wise associations with liver attenuation. Each point corresponds to a single gene, with a gene‐wise p‐value on each axis (log scale) in either the African or European subgroups of Genetics of Liver Disease (GOLD). Filled circles represent credible genes, which are labeled with gene names. The bars represent the MAGENTA enrichment cutoff. ABCC2 (MRP2), ATP binding cassette subfamily C member 2 (multidrug resistance‐associated protein 2); ABCG5 (ABCG5), ATP‐binding cassette (ABC) transporter G5; ABCG8 (ABCG8), ATP‐binding cassette (ABC) transporter G8; APOB (APOB), apolipoprotein B; FABP6 (ILBP), fatty acid binding protein 6 (ileal lipid‐binding protein); FETUB (FETUB), fetuin B; FOXO1 (FOXO1A), forkhead box O1; MTTP (MTP), microsomal triglyceride transfer protein; NR0B2 (SHP), nuclear receptor subfamily 0 group B member 2 (small heterodimer partner); NR1H4 (FXR), nuclear receptor subfamily 1 group H member 4; PPARA (PPAR), peroxisome proliferator activated receptor alpha; SLC4A2 (AE2), solute carrier family 4 member 2 (anion exchange protein 2).

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  FIGURE 3. Summary of physiological role of credible genes. This graphic summarizes the well characterized role of each gene/protein (see text for additional detail). An intestinal enterocyte is shown in beige on the left with the lumen at the top of the figure; hepatocytes in blue are shown on the right. In both cells, cytosolic and nuclear proteins are shown in purple symbols, while membrane‐associated proteins are shown in brown symbols. TG, triglycerides.

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  FIGURE 4. UK Biobank laboratory associations for non‐synonymous variants in credible genes. Each row corresponds to a gene and non‐synonymous variant (or a pair of variants in the case of high linkage disequilibrium (r 2 > 0.5); one haplotype includes amino acid substitutions in both ABCG5 and ABCG8. The additional columns provide an inverse‐normal‐transformed effect size (expressed as upward red [increased percentage of a SD] and downward blue [decreased percentage of a SD] arrows) for individual traits. All of the effect sizes are oriented toward the low‐density lipoprotein (LDL)–increasing allele (see Table S7 for additional details). ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate aminotransferase; DBili, direct bilirubin; GGT, gamma‐glutamyltransferase; DBili, Direct bilirubin HDL, high‐density lipoprotein; LDL low‐density lipoprotein; TG, triglyceride.