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. 2024 Jul 3;22(2):qzae031.
doi: 10.1093/gpbjnl/qzae031.

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

Yanni Li  1   2   3 , Eline H van den Berg  1 , Alexander Kurilshikov  2 , Dasha V Zhernakova  2   4 , Ranko Gacesa  1   2 , Shixian Hu  1   2   5 , Esteban A Lopera-Maya  2 , Alexandra Zhernakova  2 ; Lifelines Cohort Study; Vincent E de Meijer  6 , Serena Sanna  2 , Robin P F Dullaart  7 , Hans Blokzijl  1 , Eleonora A M Festen  1 , Jingyuan Fu  2   8 , Rinse K Weersma  1
Collaborators, Affiliations

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

Yanni Li et al. Genomics Proteomics Bioinformatics. .

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.

Keywords: Fatty liver index; Genome-wide association study; Hepatic fat content; MAFLD; Magnetic resonance imaging proton density fat fraction.

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Conflict of interest statement

Rinse K. Weersma has received unrestricted research grants from Takeda, Johnson & Johnson, Ferring, and Tramedico as well as speaker fees from AbbVie, MSD, and Boston Scientific, and has acted as a consultant for Takeda Pharmaceuticals. All the other authors have declared no competing interests.

Figures

Figure 1
Figure 1
Flowchart describing the study design FLI, fatty liver index; GWAS, genome-wide association study; MRI-PDFF, magnetic resonance imaging proton density fat fraction; UGLI, UMCG Genetics Lifelines Initiative; UKBB, UK Biobank; UMCG, University Medical Center Groningen; MAFLD, metabolic associated fatty liver disease; MR, Mendelian randomization; EPoS, Elucidating Pathways of Steatohepatitis.
Figure 2
Figure 2
Manhattan plot showing meta-analysis results of MRI-PDFF GWASs in UKBB Two-sided P values were calculated by meta-analysis of GWASs of two MRI-PDFF imaging subsets, using inverse rank-sum transformation of continuous MRI-PDFF by PLINK (v2.0). Horizontal red line defines nominal genome-wide significance threshold (P = 5 × 10−8).
Figure 3
Figure 3
Manhattan plot showing FLI GWAS results in UKBB Manhattan plot shows the 196 associated risk loci of FLI GWAS results from UKBB. Horizontal red line indicates the threshold of association P value < 5 × 10−9.
Figure 4
Figure 4
Genetic correlation with LD regression of MRI-PDFF and FLI traits from UKBB and UGLI LD score regression in genetic correlation mode was used to estimate genetic similarity of two MAFLD phenotypes (MRI-PDFF and FLI) between MRI-PDFF (UKBB) and FLI (UKBB + UGLI). LD, linkage disequilibrium; MRI, magnetic resonance imaging.
See this image and copyright information in PMC

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