Table 2. Previously published NAFLD risk variants with genome-wide significant association with clinical NAFLD phenotypes across all ancestries in the Million Veteran Program NAFLD analytic cohort.
| NAFLD Phenotype: ALT-Threshold (n = 192,616 Total: 60,542 cases, 132,074 controls) | NAFLD Phenotype: ALT-Metabolic (n = 191,038 Total: 58,964 cases, 132,074 controls | ||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Model 1 (Base) | Model 2 (Base + Alcohol)) | Model 3 (Base+Alcohol+Metab) | Model 1 (Base) | Model 2 (Base + Alcohol) | |||||||||||
| Previously published NAFLD risk variants | |||||||||||||||
| Gene | rsID | Chr | Pos (Mb) | EA | EAF | OR (95% CI) | P | OR (95% CI) | P | OR (95% CI) | P | OR (95% CI) | P | OR (95% CI) | P |
| LYPLAL1 | rs12137855 | 1 | 219.4 | C | 0.80 | 1.00 (0.98–1.02) | 0.9 | 1.00 (0.98–1.02) | 0.92 | 1.00 (0.98–1.02) | 0.83 | 1.00 (0.98–1.02) | 0.87 | 1.00 (0.98–1.02) | 0.89 |
| LYPLAL1* | rs3001032 | 1 | 219.7 | T | 0.69 | 1.04 (1.02–1.06) | 4.7E-07 | 1.04 (1.02–1.05) | 9.9E-07 | 1.04 (1.03–1.06) | 1.4E-07 | 1.04 (1.02–1.05) | 1.2E-06 | 1.04 (1.02–1.05) | 2.6E-06 |
| GCKR | rs780094 | 2 | 27.7 | T | 0.40 | 1.02 (1.00–1.03) | 0.02 | 1.02 (1.00–1.03) | 0.04 | 1.01 (0.99–1.03) | 0.20 | 1.02 (1.00–1.03) | 0.02 | 1.01 (1.00–1.03) | 0.06 |
| HSD17B13 | rs72613567 | 4 | 88.2 | T | 0.73 | 1.09 (1.07–1.11) | 2.7E-22 | 1.09 (1.07–1.11) | 2.2E-22 | 1.10 (1.08–1.12) | 3.0E-26 | 1.09 (1.07–1.11) | 8.1E-22 | 1.09 (1.07–1.11) | 1.0E-21 |
| PPP1R3B | rs4240624 | 8 | 9.2 | G | 0.09 | 1.12 (1.09–1.14) | 1.2E-22 | 1.12 (1.09–1.14) | 6.6E-22 | 1.12 (1.10–1.15) | 3.3E-22 | 1.12 (1.09–1.14) | 2.5E-22 | 1.12 (1.09–1.14) | 2.4E-21 |
| TM6SF2 | rs2228603 | 19 | 19.3 | T | 0.08 | 1.19 (1.15–1.22) | 4.3E-30 | 1.19 (1.16–1.23) | 7.1E-31 | 1.24 (1.20–1.27) | 5.0E-40 | 1.19 (1.15–1.22) | 3.9E-30 | 1.19 (1.16–1.23) | 1.3E-30 |
| TM6SF2 | rs58542926 | 19 | 19.4 | T | 0.07 | 1.23 (1.19–1.26) | 3.2E-46 | 1.23 (1.20–1.27) | 1.2E-47 | 1.29 (1.26–1.33) | 1.1E-63 | 1.23 (1.19–1.26) | 7.2E-46 | 1.23 (1.20–1.27) | 2.5E-47 |
| PNPLA3 | rs738409 | 22 | 44.3 | G | 0.23 | 1.31 (1.29–1.33) | 2.2E-210 | 1.31 (1.29–1.33) | 2.4E-210 | 1.35 (1.33–1.38) | 4.1E-232 | 1.31 (1.29–1.33) | 3.2E-211 | 1.31 (1.29–1.34) | 3.0E-210 |
*Newly defined LYPLAL1 variant associated with NAFLD in the Million Veteran Program based on the regional association plot (S1 Fig).
Abbreviations: rsID: dbSNP identifier (build 151), Chr: chromosome,Pos (Mb): megabase position on human genome reference hg19, EA: effect allele, EAF: effect allele frequency among Europeans (Million Veteran Program), OR: odds ratio of risk in cases compared to controls per effect allele (additive model), CI: confidence interval. LYPLAL1: Lysophospholipase-like Protein 1, GCKR: glucokinase regulatory protein, HSD17B13: Hydroxysteroid 17-Beta Dehydrogenase 13, PPP1R3B: protein phosphatase 1, TM6SF2: Transmembrane 6 Superfamily Member 2, PNPLA3: patatin-like phospholipase domain-containing protein 3. Model 1: adjusted for age, gender, and 10 principal components (PCs). Model 2: covariates in Model 1 + alcohol consumption at enrollment measured by the Alcohol Use Disorder Identification Test (AUDIT-C). Model 3: covariates in Model 2 + metabolic risk factors (Type II diabetes/prediabetes, hypertension, dyslipidemia and BMI ≥ 30 kg/m2). P-values below 0.006 (adjusted for multiple comparisons) are shown in bold font.