Abstract
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. To find genes involved in FLD, we first examined the association of missense and nonsense variants with alanine aminotransferase 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. 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-3-phosphate 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. 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.
Highlights
BACKGROUND & AIMSFatty liver disease (FLD) is a growing epidemic that is expected to be the leading cause of end-stage liver disease within the decade
We identified 190 genetic variants independently associated with ALT at an exome-wide level, and further identified glycerol-3-phosphate acyltransferase (GPAM) rs2792751 and apolipoprotein E (APOE) rs429358 to be robustly associated with liver fat content and liver disease in the UK Biobank and validation cohorts
To identify novel genetic predictors associated with FLD, we first examined the association between 33,926 missense and nonsense common variants (MAF > 1%) and ALT in European participants from the UK Biobank cohort after excluding those with available measurement of liver fat content by proton density fat fraction (PDFF) (Supplementary Table 2)
Summary
BACKGROUND & AIMSFatty liver disease (FLD) is a growing epidemic that is expected to be the leading cause of end-stage liver disease within the decade. 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. 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. Several genetic variants contributing to FLD have been identified, there is still a missing hereditability
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