Mendelian Randomization Analysis Dissects the Relationship between NAFLD, T2D, and Obesity and Provides Implications to Precision Medicine
Open accessPreprint — published as 10.1016/j.jhep.2020.03.006
Abstract
Background: Non-alcoholic fatty liver disease (NAFLD) is epidemiologically correlated with both type 2 diabetes (T2D) and obesity. However, the causal inter-relationships among the three diseases have not been completely investigated. Aim: We aim to explore the causal relationships among the three diseases. Design and methods: We performed a genome-wide association study (GWAS) on fatty liver disease in ∼400,000 UK BioBank samples. Using this data as well as the largest-to-date publicly available summary-level GWAS data, we performed a two-sample bidirectional Mendelian Randomization (MR) analysis. This analysis tested the causal inter-relationship between NAFLD, T2D, and obesity, as well as the association between genetically driven NAFLD (with two well-established SNPs at the PNPLA3 and TM6SF2 loci) and glycemic and lipidemic traits, respectively. Transgenic mice expressing the human PNPLA3 I148I (TghPNPLA3-I148I) and PNPLA3 I148M (TghPNPLA3-I148M) isoforms were used to further validate the causal effects. Results: We found that genetically instrumented hepatic steatosis significantly increased the risk for T2D (OR=1.3, 95% CI: [1.2, 1.4], p =8.3e-14) but not the intermediate glycemic phenotypes at the Bonferroni-adjusted level of significance ( p <0.002). There was a moderate, but significant causal association between genetically driven hepatic steatosis and decreased risk for BMI (β=- 0.027 SD, 95%CI: [−0.043, −0.01], p =1.3e-4), but an increased risk for WHRadjBMI (Waist-Hip Ratio adjusted for BMI) (β=0.039 SD, 95%CI: [0.023, 0.054], p =8.2e-7), as well as a decreased level for total cholesterol (β=-0.084 SD, 95%CI [−0.13, −0.036], p =6.8e-4), but not triglycerides (β=0.02 SD, 95%CI [−0.023, 0.062], p =0.36). The reverse MR analyses suggested that genetically driven T2D (OR=1.1, 95% CI: [1.0, 1.2], p =1.7e-3), BMI (OR=2.3, 95% CI: [2.0, 2.7], p =1.4e-25) and WHRadjBMI (OR=1.5, 95% CI: [1.3, 1.8], p =1.1e-6) causally increase the NAFLD risk. In the animal study, as compared to the TghPNPLA3-I148I controls, the TghPNPLA3-I148M mice developed higher fasting glucose level and reduced glucose clearance. Meanwhile, the TghPNPLA3-I148M mice demonstrated a reduced body weight, increased central to peripheral fat ratio, decreased circulating total cholesterol as compared to the TghPNPLA3-I148I controls. Conclusion: This large-scale bidirectional MR study suggests that lifelong, genetically driven NAFLD is a causal risk factor for T2D (hence potentially a “NAFLD-driven T2D” subtype) and central obesity (or “NAFLD-driven obesity” subtype), but protects against overall obesity; while genetically driven T2D, obesity, and central obesity also causally increase the risk of NAFLD, hence a “metabolic NAFLD”. This causal relationship revealed new insights into disease subtypes and provided novel hypotheses for precision treatment or prevention for the three diseases.
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Some pleiotropic relationships are expected, such as obesity variants affecting risk of hepatic steatosis and type 2 diabetes, or variants influencing multiple autoimmune conditions.
“Some of these relationships are expected, such as the impact of obesity variants on risk of hepatic steatosis and type 2 diabetes84 or variants that influence multiple autoimmune conditions85.”
From A brief history of human disease genetics (2020) · cites this paper as [84]
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- Authors
- Liu, Z., Zhang, Y., Graham, S., Pique-Regi, R., Dong, X. C., Chen, Y. E., Willer, C., & Liu, W.
- Affiliations
- Purdue University West Lafayette (US)
- Eugene Applebaum College of Pharmacy and Health Sciences (US)
- University of Michigan (US)
- Indiana University School of Medicine (US)
- Corresponding author
- Liu, Wanqing
- ORCID
- Venue
- Journal of Hepatology
- Publisher
- openRxiv
- Published
- 2019-06-07
- Volume
- 73
- Issue
- 2
- Pages
- 263-276
- ISSN
- 0168-8278 (ISSN-L)
- PMC
- PMC7371536
- OpenAlex
- W3011769929
- Cited by
- 250
- References
- 94
- Citations by year
- 2026: 18 · 2025: 27 · 2024: 44 · 2023: 62 · 2022: 51 · 2021: 28 · 2020: 20
- FWCI
- 32.95
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Journal of Hepatology (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- IUScholarWorks (Indiana University) (submittedVersion)
- Funders
- Wayne State University
- Indiana Clinical and Translational Sciences Institute (UL1TR002529)
- Georgia Clinical and Translational Science Alliance (UL1TR002529)
- National Institutes of Health (UL1TR002529)
- National Institute on Alcohol Abuse and Alcoholism (R21AA024550)
- National Heart, Lung, and Blood Institute (R01HL137214)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK106540, R01DK120689, R01DK121925, R56DK091592, R01DK091592, P30DK097512)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- non-alcoholic fatty liver disease, type 2 diabetes, obesity, abdominal obesity, causal relationship, PNPLA3, PNPLA3 I148M, glucagon secretion, pancreatitis, hepatic cholesterol synthesis, thermogenesis, brown adipose tissue, visceral fat, insulin resistance, bidirectional Mendelian randomization
- MeSH terms
- Acyltransferases, Animals, Diabetes Mellitus, Type 2, Europe, Humans, Lipase, Membrane Proteins, Mice, Transgenic, Causality, Founder Effect, Protein Isoforms, Mice, Phospholipases A2, Calcium-Independent, Genome-Wide Association Study, Obesity, Abdominal, Mendelian Randomization Analysis, Non-alcoholic Fatty Liver Disease
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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