Table 2.
Eight common genetic variants associated with increased liver fat indices
| Lead variant | Chr. | Position (hg19) | Nearest gene | Consequence | Effect allele | Other allele | Effect allele freq. | Effect on liver fat, beta (95% CI) p value | Effect on liver fat, % (95% CI) p value | Effect on hepatic steatosis, OR (95% CI) p value |
|---|---|---|---|---|---|---|---|---|---|---|
| Newly associated variants | ||||||||||
| rs2642438 | 1 | 220970028 | MTARC1 | missense (p.T165A) | G | A | 0.70 | 0.05 (0.04–0.07) p = 2 × 10−9 | 0.22 (0.14–0.29) p = 3 × 10−9 | 1.17 (1.11–1.22) p = 6 × 10−11 |
| rs1229984 | 4 | 100239319 | ADH1B | missense (p.H48R) | C | T | 0.98 | 0.16 (0.11–0.21) p = 7 × 10−10 | 0.51 (0.29–0.72) p = 3 × 10−6 | 1.37 (1.18–1.59) p = 3 × 10−5 |
| rs112875651 | 8 | 126506694 | TRIB1 | intergenic | G | A | 0.61 | 0.05 (0.03–0.07) p = 4 × 10−10 | 0.19 (0.13–0.26) p = 2 × 10−8 | 1.10 (1.06–1.15) p = 9 × 10−6 |
| rs2250802 | 10 | 113921354 | GPAM | intronic | G | A | 0.27 | 0.05 (0.04–0.07) p = 1 × 10−9 | 0.24 (0.17–0.31) p = 1 × 10−10 | 1.13 (1.08–1.18) p = 1 × 10−7 |
| rs56252442 | 19 | 18229208 | MAST3 | intronic | T | G | 0.25 | 0.05 (0.03–0.07) p = 3 × 10−8 | 0.18 (0.1–0.25) p = 3 × 10−6 | 1.09 (1.04–1.14) p = 3 × 10−4 |
| Previously associated variants | ||||||||||
| rs58542926 | 19 | 19379549 | TM6SF2 | missense (p.E167K) | T | C | 0.07 | 0.29 (0.26–0.32) p = 3 × 10−85 | 1.37 (1.25–1.49) p = 1 × 10−104 | 1.90 (1.78–2.04) p = 1 × 10−75 |
| rs429358 | 19 | 45411941 | APOE | missense (p.R130C) | T | C | 0.85 | 0.12 (0.10–0.14) p = 2 × 10−29 | 0.51 (0.42–0.60) p = 2 × 10−28 | 1.40 (1.32–1.49) p = 2 × 10−26 |
| rs738409a | 22 | 44324727 | PNPLA3 | missense (p.I148M) | G | C | 0.21 | 0.19 (0.18–0.21) p = 6 × 10−95 | 0.88 (0.81–0.96) p = 1 × 10−106 | 1.59 (1.52–1.66) p = 7 × 10−83 |
A common variant genome-wide association study (GWAS) was performed to measure associations of 9.8 million common (alternate allele frequency > 1%) genetic variants with liver fat, quantified from MRI data using machine learning, in 32,974 individuals from the UK Biobank. Rows show the variant with the smallest p value (lead variant) at each of 8 loci associated with liver fat below the genome-wide significance threshold p value of 5 × 10−8 assessed using inverse normal transformed liver fat. “Newly associated” indicates variants not reported previously to be associated with liver fat at genome-wide significance. “Previously associated” indicates previously reported variants.13,14,29 The first 8 columns show information on each lead variant, including position, frequency, and consequence. “Effect on liver fat, beta” shows the effect of each variant on inverse normal transformed liver fat in SD units, assessed using a linear mixed model. For clinical interpretability, “Effect on liver fat, %” shows the effect of each variant in units of absolute liver fat percentage points, and “Effect on hepatic steatosis, OR” shows the effect of each variant on the risk of hepatic steatosis (liver fat > 5.5%)17 in odds ratio units, assessed using linear and logistic regression, respectively, in the same 32,974 individuals.
ars738409, the known causal variant in the PNPLA3 gene region,29 is in near-perfect linkage disequilibrium (inherited together, R2 = 0.999) with the lead variant in our study, rs738408. Chr., chromosome; freq., frequency; OR, odds ratio. See also Tables S3–S9.