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A multiancestry genome-wide association study of unexplained chronic ALT elevation as a proxy for nonalcoholic fatty liver disease with histological and radiological validation

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a growing cause of chronic liver disease. Using a proxy NAFLD definition of chronic elevation of alanine aminotransferase (cALT) levels without other liver diseases, we performed a multiancestry genome-wide association study (GWAS) in the Million Veteran Program (MVP) including 90,408 cALT cases and 128,187 controls. Seventy-seven loci exceeded genome-wide significance, including 25 without prior NAFLD or alanine aminotransferase associations, with one additional locus identified in European American-only and two in African American-only analyses (P < 5 × 10−8). External replication in histology-defined NAFLD cohorts (7,397 cases and 56,785 controls) or radiologic imaging cohorts (n = 44,289) replicated 17 single-nucleotide polymorphisms (SNPs) (P < 6.5 × 10−4), of which 9 were new (TRIB1, PPARG, MTTP, SERPINA1, FTO, IL1RN, COBLL1, APOH and IFI30). Pleiotropy analysis showed that 61 of 77 multiancestry and all 17 replicated SNPs were jointly associated with metabolic and/or inflammatory traits, revealing a complex model of genetic architecture. Our approach integrating cALT, histology and imaging reveals new insights into genetic liability to NAFLD.

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Fig. 1: Overview of analysis pipeline.
Fig. 2: Manhattan plot of GWAS of 90,408 cALT cases and 128,187 controls in multiancestry meta-analysis.
Fig. 3: Venn diagram depicting overlapping liver, metabolic and inflammatory traits among cALT-associated loci.
Fig. 4: Seven gene clusters with distinct biomarker association profiles.

Data availability

The full summary-level association data from the multiancestry, EA, AA, HISP and ASN analyses from this report are available through dbGAP under accession number phs001672.v7.p1 (Veterans Administration MVP Summary Results from Omics Studies). Source data are provided with this paper.

Code availability

Imputation was performed using MiniMac4 and EAGLE v2. Association analysis was performed using PLINK2a. Post-GWAS processing software includes LD Hub v1.9.3, METAL v2011-03-25, DEPICT v140721, LDSC v1.0, GREGOR v4.0, HiCUP v0.8, STRING v11 and Ensembl Variant Effect Predictor with assembly GRCh37.p13 as outlined in Methods. Clear code for analysis is available at the associated website of each software package. Additional analyses were performed in R-4.1, Bioconductor v3.140 and R packages corrcoverage, CHiCAGO and OmnipathR, for which code can be found in their associated vignettes.

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Acknowledgements

This research is based on data from the MVP, Office of Research and Development, Veterans Health Administration and was supported by award MVP000. This publication does not represent the views of the Department of Veterans Affairs, the US Food and Drug Administration or the US Government. This research was also supported by funding from the Department of Veterans Affairs awards I01- BX003362 (P.S.T. and K.-M.C.) and I01 BX003341 (H.R.K. co-principal investigator) and the VA Informatics and Computing Infrastructure VA HSR RES 130457 (S.L.D. and J.A.L.). B.F.V. acknowledges support for this work from the National Institutes of Health (NIH)/National Institute of Diabetes and Digestive and Kidney Diseases (grants DK101478 and DK126194) and a Linda Pechenik Montague Investigator award. K.-M.C., S.M.D., J.M.G., C.J.O., L.S.P. and P.S.T. are supported by the VA Cooperative Studies Program. S.M.D. is supported by the VA (IK2 CX001780). Funding support is also acknowledged for M.S. (K23 DK115897), R.M.C. (R01 AA026302), D.E.K. (T32 HL007734), A.D.W. (R01 DK122586, R01 AI123539), J.B.M. (R01 HL151855, UM1 DK078616), W.R.W. (R01 HL137984 P41 EB029460), S.F.A.G. (R01 HD056465), L.B. (R01 LM010685), A.V.K. (K08 HG010155, U01 HG011719) and L.S.P. (VA awards CSP #2008, I01 CX001899, I01 CX001737 and I01 BX005831; NIH awards R01 DK127083, R03 AI133172, R21 AI156161, UL1 TR002378 and P30 DK111024; and Cystic Fibrosis Foundation award PHILLI12A0). The Rader lab was supported by NIH grants HL134853 (N.J.H. and D.J.R.) and DK114291-01A1 (K.T.C., N.J.H. and D.J.R.). We thank all study participants for their contribution. Support for imaging studies was provided by the University of Pennsylvania’s Institute for Translational Medicine and Therapeutics (NIH NCATS UL1 TR001878), the Penn Center for Precision Medicine Accelerator Fund.

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Contributions

M.V., S.R., K.-M.C., D.J.R., B.F.V. and P.S.T. were responsible for the concept and design. M.V., S.R., K.-M.C., D.J.R., B.F.V. and P.S.T. performed data acquisition, analysis or interpretation. M.V., S.R., K.-M.C. and B.F.V. drafted the manuscript. Critical revision of the manuscript for important intellectual content was carried out by M.V., K.M. Lorenz, K.M. Lee, M.S., D.E.K., X.Z., C.T., R.L.K., H.R.K., A.V., A.G., D.M.K., Y.V.S., J.E.H., D.R.M., P.D.R., L.S.P., S.M., S.L.D., J.S.L., T.L.A., S.P., K.C., T.L.E., S.M.D., P.W.W., J.M.G., C.J.O., P.S.T., J.B.M., J.A.L., B.F.V., K.-M.C., Q.M.A., R.D., H.J.C., A.K.D., L.A.L., J.B.N., A.E.L., M.B.J., N.V., A.B., S.R., X.G., J. He, Y.G., C.C., R.P.M., C.V.S., J.P., R.M.C., M.E.H., M.T.M., W.R.W., J. Huang, K.T.C., N.J.H., C.-T.L., M.T.L., J.Y., M.B., J.T., X.L., H.J.L., Y.-D.I.C., K.D.T., R.-K.C., R.M.K., S.V., J.B., K.R.R., B.A.N.-T., J.B.S., A.J.S., N.C., K.A.R., B.D.M., D.G., A.D.W., E.M., Y.S., N.M., A.V.K., S.F.A.G., C.D.B., D.S., L.B., J.I.R. and D.J.R. Finally, K.-M.C., D.J.R. and B.F.V. provided administrative, technical or material support. VA MVP: M.V., K.M. Lorenz, K.M. Lee, M.S., D.E.K., X.Z., C.T., R.L.K., H.R.K., A.V., A.G., D.M.K., Y.V.S., J.E.H., D.R.M., P.D.R., L.S.P., S.M., S.L.D., J.S.L., R.M.C., T.L.A., S.P., K.C., T.L.E., S.M.D., P.W.W., J.M.G., C.J.O., P.S.T., J.B.M., J.A.L., B.F.V. and K.-M.C. Geisinger-Regeneron DiscovEHR Collaboration/Regeneron Genetics Center: L.A.L., J.B.N., A.E.L., M.B.J., N.V. and A.B. EPoS Consortium: Q.M.A., R.D., H.J.C. and A.K.D.

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Correspondence to Benjamin F. Voight or Kyong-Mi Chang.

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H.R.K. is a scientific advisory board member for Dicerna Pharmaceuticals, Sophrosyne Pharmaceuticals and Enthion Pharmaceuticals; a consultant for Sobrera Pharmaceuticals; the recipient of research funding and medication supplies for an investigator-initiated study from Alkermes; a member of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative, which during the past 3 years was supported by Alkermes, Amygdala Neurosciences, Arbor Pharmaceuticals, Dicerna, Ethypharm, Indivior, Lundbeck, Mitsubishi and Otsuka; and is named as an inventor on the Patent Cooperation Treaty patent application #15/878,640 entitled ‘Genotype-guided dosing of opioid agonists,’ filed 24 January 2018. D.G. is employed part-time by Novo Nordisk. A.V.K. is an employee and holds equity in Verve Therapeutics; has served as a scientific advisor to Amgen, Third Rock Ventures, Illumina, and Foresite Labs; received a sponsored research agreement from IBM Research; and is listed as a co-inventor on a patent application for use of imaging data in assessing body fat distribution and associated cardiometabolic risk. S.J.A. is President of Sanyal Bio; has stock options in Genfit, Galmed, Exhalenz, Durect, Tiziana, Algernon and Indalo; has served as a consultant to Intercept, Gilead, Bristol Myers Squibb, Novartis, Pfizer, Lilly, Novo Nordisk, AstraZeneca, Medimmune, Merck, Allergan, Albireo, Boehringer Ingelhiem, Celgene, NGM, Glympse, Conatus, Genentech, Tern, Takeda, Hemoshear, Immuron, Surrozen, Poxel, Path AI, Second Genome, Zydus, Chiasma, Surrozen, Poxel, Blade, Pliant, Liposcience, Cymabay, Salix, Ferring and Teva; and his institution has received grants from Intercept, Gilead, Novartis, Merck, AstraZeneca, Malinckrodt, Pfizer, Lilly, Salix and Bristol Myers Squibb. V.C.U. has ownership interests in Sanyal Bio. K.R.R. is on the NASH Advisory Board at Novo Nordisk and receives grant support from TARGET-NASH, Bristol Myers Squibb and Intercept Pharmaceuticals. J.B.N., A.E.L., M.B.J., N.V., A.B., M.E.H. and L.A.L. receive salary, stocks and/or stock options from Regeneron Pharmaceuticals. R.P.M. and C.C. are employees and shareholders of Gilead Sciences. Q.M.A. is coordinator of the EU IMI-2 LITMUS consortium, which is funded by the EU Horizon 2020 program and the European Federation of Pharmaceutical Industries and Associations. Q.M.A. reports research grant funding from Allergan/Tobira, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Glympse Bio, Intercept, Novartis Pharma and Pfizer; Consultancy for 89Bio, Abbvie/Allergan, Akero, Altimentiv, Altimmune, AstraZeneca, Axcella, Blade, BMS, BNN Cardio, Boehringer Ingelheim, Cirius, CymaBay, EcoR1, E3Bio, Eli Lilly & Company, Galmed, Genentech, Genfit, Gilead, Grunthal, HistoIndex, Indalo, Intercept Pharma, Inventiva, IQVIA, Janssen, Johnson & Johnson, Madrigal, MedImmune, Medpace, Merck, Metacrine, NGMBio, North Sea Therapeutics, Novartis, Novo Nordisk, PathAI, Pfizer, Poxel, ProSciento, Raptor Pharma, Roche, Servier, Shionogi, Terns, The Medicines Company and Viking Therapeutics; speaker fees from Abbott Laboratories, Allergan/Tobira, BMS, Clinical Care Options, Falk, Fishawack, Genfit, Gilead, Integritas Communications, Kenes and Medscape; and royalties from Elsevier. S.M.D. receives research support from RenalytixAI and personal consulting fees from Calico Labs outside the scope of the current research. S.L.D. reports grants from Alnylam Pharmaceuticals, Astellas Pharma, AstraZeneca Pharmaceuticals, Biodesix, Boehringer Ingelheim International, Celgene Corporation, Eli Lilly and Company, Genentech, Gilead Sciences, GlaxoSmithKline, Innocrin Pharmaceuticals, IQVIA, Janssen Pharmaceuticals, Kantar Health, MDxHealth, Merck & Co, Myriad Genetic Laboratories, Novartis International and Parexel International Corporation through the University of Utah or Western Institute for Veteran Research outside the submitted work. C.J.O. is an employee of Novartis Institute for Biomedical Research. S.F.A.G. is the Daniel B. Burke Endowed Chair for Diabetes Research. The remaining authors declare no competing interests.

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Supplementary Figures 1–14 and note.

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Supplementary Table 1

Supplementary Tables 1–33.

Source data

Source Data Fig. 4

The data are all the association of the lead SNPs with other traits, summarized into one file with directions.

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Vujkovic, M., Ramdas, S., Lorenz, K.M. et al. A multiancestry genome-wide association study of unexplained chronic ALT elevation as a proxy for nonalcoholic fatty liver disease with histological and radiological validation. Nat Genet 54, 761–771 (2022). https://doi.org/10.1038/s41588-022-01078-z

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