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.
Bibliographical noteFunding Information:
Sciences Research Council; UK MRC; British Heart Foundation; Wellcome Trust; Swiss National Science Foundation; Academy of Finland; Finnish Cardiovascular Research Foundation; Swedish Research Council; Swedish Heart-Lung Foundation; Helmholtz Zentrum München; German Research Center for Environmental Health; German Federal Ministry of Education and Research; German National Genome Research Network; Netherlands Organization for Scientific Research; Dutch Ministries of Economic Affairs, of Education, Culture and Science, for Health, Welfare and Sports; Netherlands Organization for Health Research and Development; Economic Structure Enhancing Fund of the Dutch government; Dutch Kidney Foundation; Dutch Diabetes Research Foundation; Dutch Brain Foundation; Dutch Research Institute for Diseases in the Elderly; Netherlands Genomics Initiative; Canadian Institutes for Health Research; Ontario Research Fund; The Barts and the London Charity; University Medical Center Groningen; University of Groningen; University of Oulu, Biocenter Oulu; University Hospital Oulu; Biocentrum Helsinki; Erasmus Medical Center and Erasmus University, Rotterdam; Karolinska Institutet; Stockholm County Council; Municipality of Rotterdam; Federal State of Mecklenburg-West Pomerania; AstraZeneca; GlaxoSmithKline; Siemens Healthcare; Novo Nordisk Foundation; Yrjö Jahnsson Foundation; Biomedicum Helsinki Foundation; Gyllenberg Foundation; Knut and Alice Wallenberg Foundation; Torsten and Ragnar Söderberg Foundation; Robert Dawson Evans Endowment, Boston University School of Medicine; Instrumentarium Science Foundation; Jenny and Antti Wihuri Foundation and the Canadian Primary Biliary Cirrhosis Society. A full list of acknowledgments is provided in the Supplementary Note.
We thank the many colleagues who contributed to collection and phenotypic characterization of the clinical samples, as well as genotyping and analysis of data. We also thank the research participants who took part in these studies. Major support for the work came from European Commission (FP5, FP6 and FP7); European Science Foundation; European Science Council; US NIH; US National Institute of Mental Health; US NIDDK; Genetic Association Information Network; US National Institute on Aging; US National Human Genome Research Institute; US NHLBI; UK NIHR; NIHR Comprehensive Biomedical Research Centre Imperial College Healthcare NHS Trust; NIHR Comprehensive Biomedical Research Centre Guy’s and St. Thomas’ NHS Trust; UK Biotechnology and Biological