22To better understand molecular pathways underlying liver health and disease, we performed 23 genome-wide association studies (GWAS) on circulating levels of alanine aminotransferase (ALT) 24 and aspartate aminotransferase (AST) across 408,300 subjects from four ethnic groups in the UK 25 Biobank, focusing on variants associating with both enzymes. Of these variants, the strongest 26 effect is a rare (MAF in White British = 0.12%) missense variant in the gene encoding manganese 27 efflux transporter SLC30A10, Thr95Ile (rs188273166), associating with a 5.9% increase in ALT 28 and a 4.2% increase in AST. Carriers have higher prevalence of all-cause liver disease (OR = 1.70; 29 95% CI = 1.24 to 2.34) and higher prevalence of extrahepatic bile duct cancer (OR = 23.8; 95% 30 CI = 9.1 to 62.1) compared to non-carriers. Over 4% of the cases of extrahepatic 31 cholangiocarcinoma in the UK Biobank carry SLC30A10 Thr95Ile. Unlike variants in SLC30A10 32 known to cause the recessive syndrome hypermanganesemia with dystonia-1 (HMNDYT1), the 33 Thr95Ile variant has a detectable effect even in the heterozygous state. Also unlike HMNDYT1-34 causing variants, Thr95Ile results in a protein that is properly trafficked to the plasma membrane 35 when expressed in HeLa cells. These results suggest that coding variation in SLC30A10 impacts 36 liver health in more individuals than the small population of HMNDYT1 patients. 37 are sensitive biomarkers of liver injury; in particular, alanine aminotransferase (ALT) and aspartate 44 aminotransferase (AST) are released into the circulation during damage to hepatocyte 45 membranes 1,2 . One powerful approach for understanding the molecular basis of liver disease has 46 been to perform genome-wide association studies (GWAS) of levels of circulating liver enzymes 47 across large population samples 1,3-13 . Combined GWAS of ALT and AST have previously revealed 48 genetic associations providing potential therapeutic targets for liver disease such as PNPLA3 14 and 49HSD17B13 15 . To further study the genetics of hepatocellular damage, we performed GWAS on 50 circulating levels of ALT and AST in 408,300 subjects, meta-analyzed across four ethnic groups 51 in the UK Biobank. 52
Results
53
GWAS summary
54We performed a GWAS of ALT and AST in four sub-populations in the UK Biobank (Asian or 55 Asian British, Black or Black British, Chinese, and Black or Black British; sample sizes, number 56 of variants tested, and lGC values, Supplementary Table 1; genome-wide significant associations, 57 Supplementary Table 2; Manhattan and QQ plots for each enzyme and sub-population, 58 Supplementary Figures 1 and 2). After meta-analyzing across sub-populations to obtain a single 59 set of genome-wide p-values for each enzyme (Manhattan plots, Figure 1), we found 244 and 277 60 independent loci associating at p < 5 x 10 -8 with ALT and AST, respectively, defined by lead SNPs 61 separated by at least 500 kilobases and pairwise linkage disequilibrium (LD) r 2 less than 0.2. 62Enzyme levels were strongly associated w...
