Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma.
Chambers JC., Zhang W., Sehmi J., Li X., Wass MN., Van der Harst P., Holm H., Sanna S., Kavousi M., Baumeister SE., Coin LJ., Deng G., Gieger C., Heard-Costa NL., Hottenga J-J., Kühnel B., Kumar V., Lagou V., Liang L., Luan J., Vidal PM., Mateo Leach I., O'Reilly PF., Peden JF., Rahmioglu N., Soininen P., Speliotes EK., Yuan X., Thorleifsson G., Alizadeh BZ., Atwood LD., Borecki IB., Brown MJ., Charoen P., Cucca F., Das D., de Geus EJC., Dixon AL., Döring A., Ehret G., Eyjolfsson GI., Farrall M., Forouhi NG., Friedrich N., Goessling W., Gudbjartsson DF., Harris TB., Hartikainen A-L., Heath S., Hirschfield GM., Hofman A., Homuth G., Hyppönen E., Janssen HLA., Johnson T., Kangas AJ., Kema IP., Kühn JP., Lai S., Lathrop M., Lerch MM., Li Y., Liang TJ., Lin J-P., Loos RJF., Martin NG., Moffatt MF., Montgomery GW., Munroe PB., Musunuru K., Nakamura Y., O'Donnell CJ., Olafsson I., Penninx BW., Pouta A., Prins BP., Prokopenko I., Puls R., Ruokonen A., Savolainen MJ., Schlessinger D., Schouten JNL., Seedorf U., Sen-Chowdhry S., Siminovitch KA., Smit JH., Spector TD., Tan W., Teslovich TM., Tukiainen T., Uitterlinden AG., Van der Klauw MM., Vasan RS., Wallace C., Wallaschofski H., Wichmann H-E., Willemsen G., Würtz P., Xu C., Yerges-Armstrong LM., Alcohol Genome-wide Association (AlcGen) Consortium None., Diabetes Genetics Replication and Meta-analyses (DIAGRAM+) Study None., Genetic Investigation of Anthropometric Traits (GIANT) Consortium None., Global Lipids Genetics Consortium None., Genetics of Liver Disease (GOLD) Consortium None., International Consortium for Blood Pressure (ICBP-GWAS) None., Meta-analyses of Glucose and Insulin-Related Traits Consortium (MAGIC) None., Abecasis GR., Ahmadi KR., Boomsma DI., Caulfield M., Cookson WO., van Duijn CM., Froguel P., Matsuda K., McCarthy MI., Meisinger C., Mooser V., Pietiläinen KH., Schumann G., Snieder H., Sternberg MJE., Stolk RP., Thomas HC., Thorsteinsdottir U., Uda M., Waeber G., Wareham NJ., Waterworth DM., Watkins H., Whitfield JB., Witteman JCM., Wolffenbuttel BHR., Fox CS., Ala-Korpela M., Stefansson K., Vollenweider P., Völzke H., Schadt EE., Scott J., Järvelin M-R., Elliott P., Kooner JS.
Concentrations of liver enzymes in plasma are widely used as indicators of liver disease. We carried out a genome-wide association study in 61,089 individuals, identifying 42 loci associated with concentrations of liver enzymes in plasma, of which 32 are new associations (P = 10(-8) to P = 10(-190)). We used functional genomic approaches including metabonomic profiling and gene expression analyses to identify probable candidate genes at these regions. We identified 69 candidate genes, including genes involved in biliary transport (ATP8B1 and ABCB11), glucose, carbohydrate and lipid metabolism (FADS1, FADS2, GCKR, JMJD1C, HNF1A, MLXIPL, PNPLA3, PPP1R3B, SLC2A2 and TRIB1), glycoprotein biosynthesis and cell surface glycobiology (ABO, ASGR1, FUT2, GPLD1 and ST3GAL4), inflammation and immunity (CD276, CDH6, GCKR, HNF1A, HPR, ITGA1, RORA and STAT4) and glutathione metabolism (GSTT1, GSTT2 and GGT), as well as several genes of uncertain or unknown function (including ABHD12, EFHD1, EFNA1, EPHA2, MICAL3 and ZNF827). Our results provide new insight into genetic mechanisms and pathways influencing markers of liver function.