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Hepatology
Original research
PNPLA3 fatty liver allele was fixed in Neanderthals and segregates neutrally in humans
  1. Andreas Geier1,
  2. Jonas Trost1,
  3. Ke Wang2,3,
  4. Clemens Schmid2,4,
  5. Marcin Krawczyk5,6,
  6. Stephan Schiffels2
  1. 1Department of Medicine II, Division of Hepatology, University Hospital Wurzburg, Würzburg, Germany
  2. 2Department Archaeogenetics, Max-Planck-Institute for Evolutionary Anthropology, Leipzig, Germany
  3. 3School of Life Sciences, Fudan University, Shanghai, China
  4. 4International Max Planck Research School for the Science of Human History, Max Planck Institute for Geoanthropology, Jena, Germany
  5. 5Department of Medicine II, Saarland University Hospital and Saarland University Faculty of Medicine, Homburg, Germany
  6. 6Laboratory of Metabolic Liver Diseases, Center for Preclinical Research, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
  1. Correspondence to Professor Andreas Geier, Division of Hepatology, Department of Medicine II, University Hospital Wuerzburg, 97080 Wuerzburg, Germany; geier_a2{at}ukw.de; Dr Stephan Schiffels, Department Archaeogenetics, Max-Planck-Institute for Evolutionary Anthropology, 04301 Leipzig, Germany; stephan_schiffels{at}eva.mpg.de

Abstract

Objective Fat deposition is modulated by environmental factors and genetic predisposition. Genome-wide association studies identified PNPLA3 p.I148M (rs738409) as a common variant that increases risk of developing liver steatosis. When and how this variant evolved in humans has not been studied to date.

Design Here we analyse ancient DNA to track the history of this allele throughout human history. In total, 6444 published ancient (modern humans, Neanderthal, Denisovan) and 3943 published present day genomes were used for analysis after extracting genotype calls for PNPLA3 p.I148M. To quantify changes through time, logistic and, by grouping individuals according to geography and age, linear regression analyses were performed.

Results We find that archaic human individuals (Neanderthal, Denisovan) exclusively carried a fixed PNPLA3 risk allele, whereas allele frequencies in modern human populations range from very low in Africa to >50% in Mesoamerica. Over the last 15 000 years, distributions of ancestral and derived alleles roughly match the present day distribution. Logistic regression analyses did not yield signals of natural selection during the last 10 000 years.

Conclusion Archaic human individuals exclusively carried a fixed PNPLA3 allele associated with fatty liver, whereas allele frequencies in modern human populations are variable even in the oldest samples. Our observation might underscore the advantage of fat storage in cold climate and particularly for Neanderthal under ice age conditions. The absent signals of natural selection during modern human history does not support the thrifty gene hypothesis in case of PNPLA3 p.I148M.

  • fatty liver
  • genetics
  • lipid metabolism
  • nutrition

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information. All data and code for analysis are provided in a github repository: https://github.com/stschiff/PNPLA3_AADR_analysis. Raw data is from the Allen Ancient DNA Resource version 50. A reference list of all 172 publications that report primary data is available as online supplemental text file 1.

https://doi.org/10.1136/gutjnl-2023-331594

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    Data availability statement

    All data relevant to the study are included in the article or uploaded as supplementary information. All data and code for analysis are provided in a github repository: https://github.com/stschiff/PNPLA3_AADR_analysis. Raw data is from the Allen Ancient DNA Resource version 50. A reference list of all 172 publications that report primary data is available as online supplemental text file 1.

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    Footnotes

    • MK and SS are joint senior authors.

    • Contributors AG, MK and SS conceived and designed the study. JT, KW, CS and SS performed bioinformatic data preparation. JT performed analysis and prepared figures. AG, MK and SS wrote the paper with input from all coauthors. AG and SS act as the guarantors of the study.

    • Funding This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement number 851511).

    • Competing interests None declared.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.