Genome-wide Studies Reveal Genetic Risk Factors for Hepatic Fat Content

Lifelines Cohort Study, Yanni Li, Eline H van den Berg, Alexander Kurilshikov, Dasha V Zhernakova, Ranko Gacesa, Shixian Hu, Esteban A Lopera-Maya, Alexandra Zhernakova, Vincent E de Meijer, Serena Sanna, Robin P F Dullaart, Hans Blokzijl, Eleonora A M Festen, Jingyuan Fu*, Rinse K Weersma*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Genetic susceptibility to metabolic associated fatty liver disease (MAFLD) is complex and poorly characterized. Accurate characterization of the genetic background of hepatic fat content would provide insights into disease etiology and causality of risk factors. We performed genome-wide association study (GWAS) on two noninvasive definitions of hepatic fat content: magnetic resonance imaging proton density fat fraction (MRI-PDFF) in 16,050 participants and fatty liver index (FLI) in 388,701 participants from the United Kingdom (UK) Biobank (UKBB). Heritability, genetic overlap, and similarity between hepatic fat content phenotypes were analyzed, and replicated in 10,398 participants from the University Medical Center Groningen (UMCG) Genetics Lifelines Initiative (UGLI). Meta-analysis of GWASs of MRI-PDFF in UKBB revealed five statistically significant loci, including two novel genomic loci harboring CREB3L1 (rs72910057-T, P = 5.40E-09) and GCM1 (rs1491489378-T, P = 3.16E-09), respectively, as well as three previously reported loci: PNPLA3, TM6SF2, and APOE. GWAS of FLI in UKBB identified 196 genome-wide significant loci, of which 49 were replicated in UGLI, with top signals in ZPR1 (P = 3.35E-13) and FTO (P = 2.11E-09). Statistically significant genetic correlation (rg) between MRI-PDFF (UKBB) and FLI (UGLI) GWAS results was found (rg = 0.5276, P = 1.45E-03). Novel MRI-PDFF genetic signals (CREB3L1 and GCM1) were replicated in the FLI GWAS. We identified two novel genes for MRI-PDFF and 49 replicable loci for FLI. Despite a difference in hepatic fat content assessment between MRI-PDFF and FLI, a substantial similar genetic architecture was found. FLI is identified as an easy and reliable approach to study hepatic fat content at the population level.

Original languageEnglish
Article numberqzae031
Number of pages12
JournalGenomics, Proteomics & Bioinformatics
Volume22
Issue number2
DOIs
Publication statusPublished - 3-Jul-2024

Keywords

  • Humans
  • Genome-Wide Association Study
  • Female
  • Male
  • Risk Factors
  • Genetic Predisposition to Disease/genetics
  • Liver/diagnostic imaging
  • Middle Aged
  • Polymorphism, Single Nucleotide/genetics
  • Magnetic Resonance Imaging
  • Non-alcoholic Fatty Liver Disease/genetics
  • Adult
  • Aged
  • Fatty Liver/genetics

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