1. Exome-Wide Association Study on Alanine Aminotransferase Identifies Sequence Variants in the GPAM and APOE Associated With Fatty Liver Disease
- Author
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François Pattou, Panu K. Luukkonen, Violeta Raverdy, Ville Männistö, Stefano Romeo, Daniele Prati, Salvatore Petta, Rosaria Maria Pipitone, Rocco Spagnuolo, Guido Baselli, Rosellina Margherita Mancina, Oveis Jamialahmadi, Grazia Pennisi, Federica Tavaglione, Luca Valenti, Francesco Malvestiti, Dorothée Thuillier, Jussi Pihlajamäki, Ester Ciociola, Hannele Yki-Järvinen, HUS Internal Medicine and Rehabilitation, Department of Medicine, Department of Biochemistry and Developmental Biology, Jamialahmadi O., Mancina R.M., Ciociola E., Tavaglione F., Luukkonen P.K., Baselli G., Malvestiti F., Thuillier D., Raverdy V., Mannisto V., Pipitone R.M., Pennisi G., Prati D., Spagnuolo R., Petta S., Pihlajamaki J., Pattou F., Yki-Jarvinen H., Valenti L., and Romeo S.
- Subjects
0301 basic medicine ,Genome-wide association study ,Liver disease ,0302 clinical medicine ,ENRICHMENT ANALYSIS ,Non-alcoholic Fatty Liver Disease ,Risk Factors ,Nonalcoholic fatty liver disease ,Exome ,CONFERS SUSCEPTIBILITY ,Genetics ,INSULIN-RESISTANCE ,medicine.diagnostic_test ,Fatty liver ,Gastroenterology ,Alanine Transaminase ,1-Acylglycerol-3-Phosphate O-Acyltransferase ,3. Good health ,GENOME ,Europe ,Phenotype ,Liver biopsy ,030211 gastroenterology & hepatology ,Nonalcoholic Fatty Liver Disease ,MAFLD ,Single-nucleotide polymorphism ,Biology ,Transaminase ,Risk Assessment ,03 medical and health sciences ,Apolipoproteins E ,NAFLD ,medicine ,Genetic predisposition ,Humans ,Genetic Predisposition to Disease ,HEPATIC STEATOSIS ,Genetic association ,MAFLD, Phenotype, Reproducibility of Results, Risk Assessment, Risk Factors, Transcriptome, Genetic Variation, Metabolic Associated Fatty Liver Disease, Nonalcoholic Fatty Liver Disease, Transaminase, 1-Acylglycerol-3-Phosphate O-Acyltransferase, Alanine Transaminase, Apolipoproteins E, Biomarkers, Europe, Exome, Gene Expression Profiling, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Non-alcoholic Fatty Liver Disease ,Hepatology ,MUTATIONS ,Gene Expression Profiling ,Genetic Variation ,Reproducibility of Results ,medicine.disease ,X-RECEPTOR ,GENE ,030104 developmental biology ,3121 General medicine, internal medicine and other clinical medicine ,Metabolic Associated Fatty Liver Disease ,RNA-SEQ DATA ,Transcriptome ,PATHOGENICITY ,Biomarkers ,Genome-Wide Association Study - Abstract
BACKGROUND & AIMS: Fatty liver disease (FLD) is a growing epidemic that is expected to be the leading cause of end-stage liver disease within the next decade. Both environmental and genetic factors contribute to the susceptibility of FLD. Several genetic variants contributing to FLD have been identified in exome-wide association studies. However, there is still a missing hereditability indicating that other genetic variants are yet to be discovered. METHODS: To find genes involved in FLD, we first examined the association of missense and nonsense variants with alanine amino transferase at an exome-wide level in 425,671 participants from the UK Biobank. We then validated genetic variants with liver fat content in 8930 participants in whom liver fat measurement was available, and replicated 2 genetic variants in 3 independent cohorts comprising 2621 individuals with available liver biopsy. RESULTS: We identified 190 genetic variants independently associated with alanine aminotransferase after correcting for multiple testing with Bonferroni method. The majority of these variants were not previously associated with this trait. Among those associated, there was a striking enrichment of genetic variants influencing lipid metabolism. We identified the variants rs2792751 in GPAM/GPAT1, the gene encoding glycerol-3phosphate acyltransferase, mitochondrial, and rs429358 in APOE, the gene encoding apolipoprotein E, as robustly associated with liver fat content and liver disease after adjusting for multiple testing. Both genes affect lipid metabolism in the liver. CONCLUSIONS: We identified 2 novel genetic variants in GPAM and APOE that are robustly associated with steatosis and liver damage. These findings may help to better elucidate the genetic susceptibility to FLD onset and progression.
- Published
- 2020