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Cited by 227Genomics and Rare DiseasesPeroxisome Proliferator-Activated ReceptorsGenetic Associations and Epidemiology

Prospective functional classification of all possible missense variants in PPARG

Open access
UK Monogenic Diabetes Consortium, Majithia, Amit R, Myocardial Infarction Genetics Consortium, UK Congenital Lipodystrophy Consortium, Tsuda, Ben, Agostini, Maura, Gnanapradeepan, Keerthana, Rice, Robert +18 more·2016·Nature Genetics
DOI 10.1038/ng.3700PMC PMC5131844
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Abstract

Clinical exome sequencing routinely identifies missense variants in disease-related genes, but functional characterization is rarely undertaken, leading to diagnostic uncertainty. For example, mutations in PPARG cause Mendelian lipodystrophy and increase risk of type 2 diabetes (T2D). Although approximately 1 in 500 people harbor missense variants in PPARG, most are of unknown consequence. To prospectively characterize PPARγ variants, we used highly parallel oligonucleotide synthesis to construct a library encoding all 9,595 possible single-amino acid substitutions. We developed a pooled functional assay in human macrophages, experimentally evaluated all protein variants, and used the experimental data to train a variant classifier by supervised machine learning. When applied to 55 new missense variants identified in population-based and clinical sequencing, the classifier annotated 6 variants as pathogenic; these were subsequently validated by single-variant assays. Saturation mutagenesis and prospective experimental characterization can support immediate diagnostic interpretation of newly discovered missense variants in disease-related genes.

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  • PPARG was subjected to one of the earliest MAVEs applied to an endocrine disease gene.

    “PPARG was subjected to one of the earliest MAVEs applied to an endocrine disease gene (106).”

    From Massively parallel functional genomic assays in endocrinology: from promise to delivery (2026) · cites this paper as [106]

    The Abstract (page unavailable) describes a pooled assay that experimentally evaluated all 9,595 possible single-amino-acid substitutions in PPARG, a gene linked to lipodystrophy and type 2 diabetes. This supports identifying the study as a MAVE of an endocrine disease gene. Our copy does not establish that it was one of the earliest such studies. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • PPARγ has been subjected to a MAVE.

    “No receptors for such canonical hormones have yet been subjected to a MAVE; however, another important member of the nuclear hormone receptor family that is of endocrine relevance, namely PPARγ, has.”

    From Massively parallel functional genomic assays in endocrinology: from promise to delivery (2026) · cites this paper as [106]

  • MAVE data for PPARG were used to train a supervised machine learning classifier of PPARγ variant pathogenicity.

    “MAVE data were further utilised to train a supervised machine learning classifier of the pathogenicity of PPARγ variants.”

    From Massively parallel functional genomic assays in endocrinology: from promise to delivery (2026) · cites this paper as [106]

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Research works printed but not linked: 26

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Authors
UK Monogenic Diabetes Consortium, Majithia, A. R., Myocardial Infarction Genetics Consortium, UK Congenital Lipodystrophy Consortium, Tsuda, B., Agostini, M., Gnanapradeepan, K., Rice, R., Peloso, G., Patel, K. A., Zhang, X., Broekema, M. F., Patterson, N., Duby, M., Sharpe, T., Kalkhoven, E., Rosen, E. D., Barroso, I., Ellard, S., Kathiresan, S., O'Rahilly, S., Chatterjee, K., Florez, J. C., Mikkelsen, T., Savage, D. B., & Altshuler, D.
Affiliations
  • Broad Institute (US)
  • University of Cambridge (GB)
  • University of Exeter (GB)
  • University Medical Center Utrecht (NL)
  • Beth Israel Deaconess Medical Center (US)
  • National Health Service (GB)
Corresponding author
Majithia, Amit R
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2016-10-17
Volume
48
Issue
12
Pages
1570-1575
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/ng.3700
PMC
PMC5131844
OpenAlex
W2537556928
Cited by
227
References
4
Citations by year
2026: 9 · 2025: 16 · 2024: 24 · 2023: 20 · 2022: 25 · 2021: 24 · 2020: 22 · 2019: 30 · 2018: 33 · 2017: 21 · 2016: 3
FWCI
19.45
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Apollo (University of Cambridge) (acceptedVersion)
  • Pure Amsterdam UMC (submittedVersion, cc-by)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
  • Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
  • Royal Devon and Exeter Research Repository (Royal Devon and Exeter) (submittedVersion)
  • ResearchSpace (University of Auckland) (submittedVersion)
  • Apollo
Funders
  • Harvard Catalyst (1KL2 TR001100‐01)
  • Wellcome Trust (107064/Z/15/Z, 107064, 110082/Z/15/Z, 095564/Z/11/Z, 100574/Z/12/Z, 095564, 095515/Z/11/Z)
  • Broad Institute
  • National Institute for Health and Care Research (NF-SI-0513-10109, NF-SI-0514-10176, NF-SI-0507-10380, CL-2013-23-001)
  • Scheme for Promotion of Academic and Research Collaboration
  • National Institutes of Health (KL2TR001100)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK097768, K24DK110550, K08DK102877)
  • National Center for Advancing Translational Sciences
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords
PPARγ, missense mutations, saturation mutagenesis, variant pathogenicity prediction, human macrophages, type 2 diabetes, clinical exome sequencing, variant interpretation, supervised learning
MeSH terms
Diabetes Mellitus, Type 2, Female, Humans, Lipodystrophy, Macrophages, Male, Myocardial Infarction, Prospective Studies, Case-Control Studies, Amino Acid Substitution, Mutation, Missense, PPAR gamma

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