Variants in multiple genetic loci modify the risk of non‐alcoholic fatty liver disease (NAFLD) and cirrhosis but there are limited data on the quantitative impact of variant copies on liver fibrosis.

To investigate the effect of PNPLA3, TM6SF2, MBOAT7, GCKR and HSD17B13 genotype on liver fibrosis assessed by magnetic resonance elastography (MRE), a reproducible, accurate, continuous biomarker of liver fibrosis.

This is a cross‐sectional analysis derived from a well‐characterised cohort at risk for NAFLD who underwent genotyping and MRE assessment. Liver stiffness (LS) was estimated using MRE and advanced fibrosis was defined as liver stiffness ≥3.63 kilopascals (kPa). Univariable and multivariable linear and logistic regression analysis, were used to assess the association between genotype and MRE.

Two hundred sixty‐four patients (63% women) with a mean age 53 (±17) years, and 31% Hispanic ethnicity with genotyping and MRE were included. The odds of advanced fibrosis were 3.1 (95% CI: 1.1‐8.9, P = 0.04) for CG and 6.5 (95% CI: 2.2‐18.9, P < 0.01) for GG compared to CC PNPLA3 genotype. Each PNPLA3 risk variant copy was associated with 0.40 kPa (95% CI: 0.19‐0.61, P < 0.01) increase in LS on MRE in analysis adjusted for age, sex and BMI and there was significant genotype‐age interaction (P < 0.01). Conversely, the protective TA allele in HSD17B13 was associated with a −0.41 kPa (95% CI: −0.76 to −0.05, P = 0.03) decrease in liver stiffness on MRE multivariable analysis.

Knowledge of PNPLA3 and HSD17B13 genotype may assist in the non‐invasive risk stratification of NAFLD with closer monitoring recommended for those with high genetic risk.