Genetic variants that associate with cirrhosis have pleiotropic effects on human traits - PubMed (original) (raw)

. 2020 Feb;40(2):405-415.

doi: 10.1111/liv.14321. Epub 2020 Jan 1.

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Genetic variants that associate with cirrhosis have pleiotropic effects on human traits

Vincent L Chen et al. Liver Int. 2020 Feb.

Abstract

Background and aims: Cirrhosis is characterized by extensive fibrosis of the liver and is a major cause of liver-related mortality. Cirrhosis is partially heritable but genetic contributions to cirrhosis have not been systemically explored. Here, we carry out association analyses with cirrhosis in two large biobanks and determine the effects of cirrhosis associated variants on multiple human disease/traits.

Methods: We carried out a genome-wide association analysis of cirrhosis as a diagnosis in UK BioBank (UKBB; 1088 cases vs. 407 873 controls) and then tested top-associating loci for replication with cirrhosis in a hospital-based cohort from the Michigan Genomics Initiative (MGI; 875 cases of cirrhosis vs. 30 346 controls). For replicating variants or variants previously associated with cirrhosis that also affected cirrhosis in UKBB or MGI, we determined single nucleotide polymorphism effects on all other diagnoses in UKBB (PheWAS), common metabolic traits/diseases and serum/plasma metabolites.

Results: Unbiased genome-wide association study identified variants in/near PNPLA3 and HFE, and candidate variant analysis identified variants in/near TM6SF2, MBOAT7, SERPINA1, HSD17B13, STAT4 and IFNL4 that reproducibly affected cirrhosis. Most affected liver enzyme concentrations and/or aspartate transaminase-to-platelet ratio index. PheWAS, metabolic trait and serum/plasma metabolite association analyses revealed effects of these variants on lipid, inflammatory and other processes including new effects on many human diseases and traits.

Conclusions: We identified eight loci that reproducibly associate with population-based cirrhosis and define their diverse effects on human diseases and traits.

Keywords: SNP; fibrosis; genetics; phenotype.

© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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Conflict of interest statement

CONFLICTS OF INTEREST

Vincent Chen, Yanhua Chen, Xiaomeng Du, Samuel Handelman, Elizabeth Speliotes: no financial conflicts of interest to disclose.

Figures

FIGURE 1

FIGURE 1

Study design

FIGURE 2

FIGURE 2

Quantile-quantile and Manhattan plots for GWAS of cirrhosis in UK BioBank. A, Quantile-quantile plot. B, Manhattan plot. GWAS, genome-wide association study

FIGURE 3

FIGURE 3

Representative pleiotropic effects of cirrhosis-increasing alleles. (A and B) Heat plot of the effect of cirrhosis-increasing alleles on phenome-wide association study in UK BioBank. Diagnoses are shown in (A) and blood cell traits in (B). (C) Heat plot of the effect of cirrhosis-increasing alleles on metabolic traits from publicly available GWAS. (D) Heat plot of the effect of cirrhosis-increasing alleles on serum/plasma metabolites. ‘Cirrhosis’ refers to cirrhosis diagnosis in UK BioBank (Methods). *IFNL4 trended towards a significant association with cirrhosis in UK BioBank (Z = 1.73, P = .08). Full lists of PheWAS analyses and metabolite labels are shown in Tables S3-S5. ApoB, ApoB; CH2.DB.ratio, CH2 groups in fatty acids; CH2.in.FA, CH2 groups to double bonds ratio; DHA, 22:6 docosahexaenoic acid; FAw3, Omega-3 fatty acids; FAw6, Omega-6 fatty acids; Gp, Glycoprotein acetyls mainly a1-acid glycoprotein; GWAS, genome-wide association study; IDL. PL, Phospholipids in intermediate-density lipoprotein; L.LDL.PL, Phospholipids in large low-density lipoproteins; L.VLDL.PL, Phospholipids in large very low-density lipoproteins; LDL.D, LDL diameter; M.LDL.PL, Phospholipids in medium low-density lipoproteins; M.VLDL.PL, Phospholipids in medium very low-density lipoproteins; MUFA, Mono-unsaturated fatty acids; otPUFA, Other polyunsaturated fatty acids than 18:2; PC, Phosphatidylcholine and other cholines; S.HDL.TG, Triglycerides in small high-density lipoproteins; S.LDL.P, Concentration of small low-density lipoprotein particles; S.VLDL.PL, Phospholipids in small very low-density lipoproteins; Serum.TG, Serum total triglycerides; Tot.FA, Total fatty acids; TotPG, Total phosphoglycerides; XL.HDL.TG, Triglycerides in very large high-density lipoproteins; XL.VLDL.PL, Phospholipids in very large very low-density lipoproteins; XS.VLDL.PL, Phospholipids in very small very low-density lipoproteins; XXL. VLDL.P, Concentration of chylomicrons and extremely large very low-density lipoproteins particles

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