Evidence map›Paper›PMID 39192769›Full record

ArticleObesity (Silver Spring, Md.)2024

Identification and functional validation of rare coding variants in genes linked to monogenic obesity.

Çiğdem Köroğlu, Michael Traurig, Yunhua L Muller, Samantha E Day, Paolo Piaggi, Kim Wiedrich, Laura Vazquez, Robert L Hanson, Cristopher V Van Hout, Anna Alkelai and 3 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Obesity (Silver Spring, Md.), 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

13 authors.

Çiğdem KöroğluPhoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona, USA.ORCID https://orcid.org/0000-0002-6778-4773
Michael TraurigPhoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona, USA.
Yunhua L MullerPhoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona, USA.
Samantha E DayPhoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona, USA.ORCID https://orcid.org/0000-0002-9818-0972
Paolo PiaggiPhoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona, USA.ORCID https://orcid.org/0000-0003-2774-9161
Kim WiedrichPhoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona, USA.
Laura VazquezPhoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona, USA.
Robert L HansonPhoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona, USA.
Cristopher V Van HoutInternational Laboratory for Human Genome Research, National Autonomous University of Mexico, Campus Juriquilla, Queretaro, Mexico.ORCID https://orcid.org/0000-0001-9689-5344
Anna AlkelaiRegeneron Genetics Center, Tarrytown, New York, USA.
Alan R ShuldinerRegeneron Genetics Center, Tarrytown, New York, USA.
Clifton BogardusPhoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona, USA.
Leslie J BaierPhoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona, USA.

Funding

Whole Genome and Whole Exome Sequencing to Identify Genes for Type 2 Diabetes and ObesityZIADK075058 · NIDDK · NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES · PI BAIER, LESLIE J · 2011 to 2025
$20.0M
Genetic Epidemiology of Diabetes and ObesityZIADK069028 · NIDDK · NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES · PI HANSON, ROBERT · 2009 to 2025
$7.5M
Intramural NIH HHS ZIA DK075058Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of HealthRegeneron Genetics Center
6 · The paper itself

Abstract

objectiveRare cases of monogenic obesity, which may respond to specific therapeutics, can remain undetected in populations in which polygenic obesity is prevalent. This study examined rare DNA variation in established monogenic obesity genes within a community using whole-exome sequence data from 6803 longitudinally studied individuals.

methodsExome data across 15 monogenic obesity genes were analyzed for nonsynonymous variants observed in any child with a maximum BMI z score > 2 (N = 279) but not observed in a child with a maximum BMI z score ≤ 0 (n = 1542) or that occurred in adults in the top 5th percentile of BMI (n = 263) but not in adults below the median BMI (n = 2629). Variants were then functionally analyzed using luciferase assays.

resultsThe comparisons between cases of obesity and controls identified eight missense variants in six genes: DYRK1B, KSR2, MC4R, NTRK2, PCSK1, and SIM1. Among these, MC4R p.A303P and p.R165G were previously shown to impair MC4R function. Functional analyses of the remaining six variants suggest that KSR2 p.I402F and p.T193I and NTRK2 p.S249Y alter protein function.

conclusionsIn addition to MC4R, rare missense variants in KSR2 and NTRK2 may potentially explain the severe obesity observed for the carriers.

Indexed as

ObesityAdolescentAdultBasic Helix-Loop-Helix ProteinsBody Mass IndexChildExomeExome SequencingFemaleGenetic Predisposition to DiseaseHumansLongitudinal StudiesMaleMutation, MissenseProprotein Convertase 1Protein Serine-Threonine KinasesBasic Helix-Loop-Helix ProteinsMC4R protein, humanPCSK1 protein, humanProprotein Convertase 1Protein Serine-Threonine KinasesReceptor, Melanocortin, Type 4Repressor ProteinsSIM1 protein, human

Identifiers

PMID39192769
PMCPMC11361714

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.