Genome-wide association study identifies variants associated with histologic features of nonalcoholic Fatty liver disease

Abstract

Background & aims: Little data are available from genome-wide association studies (GWASs) of liver histology in patients with nonalcoholic fatty liver disease (NAFLD). We conducted a pilot GWAS in patients with NAFLD, characterized by histology, who were enrolled in the NASH Clinical Research Network (CRN) Database Study.

Methods: We studied clinical, laboratory, and histologic data from 236 non-Hispanic white women with NAFLD. We analyzed 324,623 single nucleotide polymorphisms (SNPs) from the 22 autosomal chromosomes. Multivariate-adjusted logistic regression analyses were conducted for binary outcomes, and linear regression analysis was applied for quantitative traits. A P value < 1 × 10(-6) was considered to be significant.

Results: In multivariate models adjusted for age, body mass index, diabetes, waist/hip ratios, and levels of glycated hemoglobin, the NAFLD activity score was associated with the SNP rs2645424 on chromosome 8 in farnesyl diphosphate farnesyl transferase 1 (FDFT1) (P = 6.8 × 10(-7)). The degree of fibrosis was associated with the SNP rs343062 on chromosome 7 (P = 2.7 × 10(-8)). SNPs associated with lobular inflammation included SNP rs1227756 on chromosome 10 in COL13A1 (P = 2.0 × 10(-7)), rs6591182 on chromosome 11 (P = 8.6 × 10(-7)), and rs887304 on chromosome 12 in EFCAB4B (P = 7.7 × 10(-7)). SNPs associated with serum levels of alanine aminotransferase included rs2499604 on chromosome 1 (P = 2.2 × 10(-6)), rs6487679 on chromosome 12 in PZP (P = 1.3 × 10(-6)), rs1421201 on chromosome 18 (P = 1.0 × 10(-5)), and rs2710833 on chromosome 4 (P = 6.3 × 10(-7)). No significant associations were observed between genotypes and steatosis, ballooning degeneration, portal inflammation, or other features of NAFLD.

Conclusions: A GWAS significantly associated genetic variants with features of hepatic histology in patients with NAFLD. These findings should be validated in larger and more diverse cohorts.

Figure 1

Figure 1a. Manhattan Plot NASH activity score (NAS) Figure 2a shows the Manhattan plot for NAS. X-axis is chromosome number, and Y-axis is −log₁₀(p-value) from GWAS. Each point represents a profiled SNP. Figure 1b. Manhattan plot for fibrosis Figure 2b shows the Manhattan plot for fibrosis. X-axis is chromosome number, and Y-axis is −log₁₀(p-value) from GWAS. Each point represents a profiled SNP. The arrow indicates the SNP with a p-value less than 1.0e-06. Figure 1c. Manhattan plot for lobular Figure 2c shows the Manhattan plot for lobular. X-axis is chromosome number, and Y-axis is −log₁₀(p-value) from the GWAS. Each point represents a profiled SNP. The arrow indicates the SNP with a p-value less than 1.0e-06.

Figure 1

Figure 1a. Manhattan Plot NASH activity score (NAS) Figure 2a shows the Manhattan plot for NAS. X-axis is chromosome number, and Y-axis is −log₁₀(p-value) from GWAS. Each point represents a profiled SNP. Figure 1b. Manhattan plot for fibrosis Figure 2b shows the Manhattan plot for fibrosis. X-axis is chromosome number, and Y-axis is −log₁₀(p-value) from GWAS. Each point represents a profiled SNP. The arrow indicates the SNP with a p-value less than 1.0e-06. Figure 1c. Manhattan plot for lobular Figure 2c shows the Manhattan plot for lobular. X-axis is chromosome number, and Y-axis is −log₁₀(p-value) from the GWAS. Each point represents a profiled SNP. The arrow indicates the SNP with a p-value less than 1.0e-06.

Figure 1

Figure 1a. Manhattan Plot NASH activity score (NAS) Figure 2a shows the Manhattan plot for NAS. X-axis is chromosome number, and Y-axis is −log₁₀(p-value) from GWAS. Each point represents a profiled SNP. Figure 1b. Manhattan plot for fibrosis Figure 2b shows the Manhattan plot for fibrosis. X-axis is chromosome number, and Y-axis is −log₁₀(p-value) from GWAS. Each point represents a profiled SNP. The arrow indicates the SNP with a p-value less than 1.0e-06. Figure 1c. Manhattan plot for lobular Figure 2c shows the Manhattan plot for lobular. X-axis is chromosome number, and Y-axis is −log₁₀(p-value) from the GWAS. Each point represents a profiled SNP. The arrow indicates the SNP with a p-value less than 1.0e-06.

Figure 2

Figure 2a. Regional plot for NASH activity score (NAS) Figure 3a shows −log₁₀(p-value) from association analysis for all SNPs in the region around the top SNP rs2645424 for NAS (50 kb on each side). X-axis shows position of the SNPs along chromosome 8; Y-axis in the left gives −log₁₀(p-value). P-values were obtained from association analysis when including age and BMI as covariates and assuming an additive genetic model. Y-axis in the right shows recombination rate (cM/Mb). r² shows measure of the LD between this SNP and target SNP. The genes (NEIL2, FDFT1, and CTSB) are located in the region as indicated at the bottom portion of the figure. Figure 2b. Regional plot for fibrosis Figure 3b shows −log₁₀(p-value) from association analysis for all SNPs in the region around the top SNP rs343064 for fibrosis (50 kb on each side). X-axis shows position of the SNPs along chromosome 7; Y-axis gives −log₁₀(p-value). P-values were obtained from association analysis which included age, BMI, diabetic status, waist-hip-ratio and HbA1c as covariates and assuming a recessive genetic model. Y-axis in the right shows recombination rate (cM/Mb). r² shows measure of the LD between this SNP and target SNP.

Figure 2

Figure 2a. Regional plot for NASH activity score (NAS) Figure 3a shows −log₁₀(p-value) from association analysis for all SNPs in the region around the top SNP rs2645424 for NAS (50 kb on each side). X-axis shows position of the SNPs along chromosome 8; Y-axis in the left gives −log₁₀(p-value). P-values were obtained from association analysis when including age and BMI as covariates and assuming an additive genetic model. Y-axis in the right shows recombination rate (cM/Mb). r² shows measure of the LD between this SNP and target SNP. The genes (NEIL2, FDFT1, and CTSB) are located in the region as indicated at the bottom portion of the figure. Figure 2b. Regional plot for fibrosis Figure 3b shows −log₁₀(p-value) from association analysis for all SNPs in the region around the top SNP rs343064 for fibrosis (50 kb on each side). X-axis shows position of the SNPs along chromosome 7; Y-axis gives −log₁₀(p-value). P-values were obtained from association analysis which included age, BMI, diabetic status, waist-hip-ratio and HbA1c as covariates and assuming a recessive genetic model. Y-axis in the right shows recombination rate (cM/Mb). r² shows measure of the LD between this SNP and target SNP.