Evidence map›Paper›PMID 33513366›Full record

ArticleCell metabolism2021

A regulatory variant at 3q21.1 confers an increased pleiotropic risk for hyperglycemia and altered bone mineral density.

Nasa Sinnott-Armstrong, Isabel S Sousa, Samantha Laber, Elizabeth Rendina-Ruedy, Simon E Nitter Dankel, Teresa Ferreira, Gunnar Mellgren, David Karasik, Manuel Rivas, Jonathan Pritchard and 10 more

Open access · hybridAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell metabolism, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers, 2 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
32citing papers in PubMed, 2 pooled it
3.7field-weighted citation impact, top 6% of its field
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

32 citing papers in PubMed, 2 syntheses or guidelines pooled it, 52 citations in OpenAlex.

  1. Pooled it
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  5. Edge-rich Cu-NTheranostics · 2026
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  15. A commoneLife · 2024
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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

20 authors at 12 institutions in 5 countries.

Nasa Sinnott-ArmstrongMetabolism Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Cell Circuits and Epigenomics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Genetics, Stanford University, Stanford 94305 CA, USA.
Isabel S SousaMetabolism Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Else Kröner-Fresenius-Center for Nutritional Medicine, School of Life Sciences, Technical University of Munich, Freising 85354, Germany.
Samantha LaberMetabolism Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Cell Circuits and Epigenomics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Big Data Institute, University of Oxford, Oxford, UK.
Elizabeth Rendina-RuedyCenter for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, ME 04074, USA.
Simon E Nitter DankelUniversity of Bergen, Bergen 5020, Norway; Mohn Nutrition Research Laboratory, Department of Clinical Science, University of Bergen, 5020 Bergen, Norway; Hormone Laboratory, Department of Medical Biochemistry and Pharmacology, Haukeland University Hospital, 5021 Bergen, Norway.
Teresa FerreiraBig Data Institute, University of Oxford, Oxford, UK.
Gunnar MellgrenUniversity of Bergen, Bergen 5020, Norway; Mohn Nutrition Research Laboratory, Department of Clinical Science, University of Bergen, 5020 Bergen, Norway; Hormone Laboratory, Department of Medical Biochemistry and Pharmacology, Haukeland University Hospital, 5021 Bergen, Norway.
David KarasikInstitute for Aging Research, Hebrew SeniorLife and Harvard Medical School, Boston, MA 02131, USA; Faculty of Medicine of the Galilee, Bar-Ilan University, Safed, Israel.
Manuel RivasDepartment of Biomedical Data Science, Stanford University, Stanford, CA 94305, USA.
Jonathan PritchardDepartment of Genetics, Stanford University, Stanford 94305 CA, USA; Department of Biology, Stanford University, Stanford, CA 94305, USA.
Anyonya R GunturCenter for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, ME 04074, USA.
Roger D CoxMedical Research Council Harwell, Oxfordshire, UK.
Cecilia M LindgrenProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Big Data Institute, University of Oxford, Oxford, UK.
Hans HaunerElse Kröner-Fresenius-Center for Nutritional Medicine, School of Life Sciences, Technical University of Munich, Freising 85354, Germany; Institute of Nutritional Medicine, School of Medicine, Technical University of Munich, Freising 85354, Germany; Clinical Cooperation Group "Nutrigenomics and Type 2 Diabetes" of the German Center of Diabetes Research, Helmholtz Center Munich, Munich 85764, Germany.
Richard SallariMetabolism Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Clifford J RosenCenter for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, ME 04074, USA.
Yi-Hsiang HsuInstitute for Aging Research, Hebrew SeniorLife and Harvard Medical School, Boston, MA 02131, USA; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02131, USA.
Eric S LanderMetabolism Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Cell Circuits and Epigenomics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Biology, MIT, Cambridge, MA 02142, USA; Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
Douglas P KielInstitute for Aging Research, Hebrew SeniorLife and Harvard Medical School, Boston, MA 02131, USA; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02131, USA.
Melina ClaussnitzerMetabolism Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Cell Circuits and Epigenomics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02131, USA; University of Hohenheim, Institute of Nutritional Science, Stuttgart 70599, Germany. Electronic address: melina@broadinstitute.org.
Harvard University · USStanford University · USBroad Institute · USMaine Medical Center Research Institute · USOpen Data Institute · GBUniversity of Bergen · NOBeth Israel Deaconess Medical Center · USCenter for Systems Biology · USMaine Medical Center · USMedical Research Council · GBTechnical University of Munich · DEUniversity of Oxford · GB

Funding

RISK FACTORS FOR VERTEBRAL FRACTURE AND BONE LOSSR01AR041398 · NIAMS · RHODE ISLAND HOSPITAL (PROVIDENCE, RI) · PI KIEL, DOUGLAS P. · 1991 to 2025
$16.1M
Interdisciplinary Study of Marrow Adiposity, Mineral Metabolism & Energy BalanceR24DK092759 · NIDDK · MAINEHEALTH · PI HOROWITZ, MARK C, MACDOUGALD, ORMOND A · 2011 to 2019
$13.0M
Identifying Osteoporosis Genes by Whole Genome Sequencing and Functional Validation in Zebra FishR01AR072199 · NIAMS · HEBREW REHABILITATION CENTER FOR AGED · PI HSU, YI-HSIANG · 2017 to 2022
$3.2M
Mechanisms by which adipocytes adapt to cool environmental temperaturesR01DK121759 · NIDDK · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI MACDOUGALD, ORMOND A · 2020 to 2024
$2.0M
Medical Research Council MC_U142661184NIAMS NIH HHS R01 AR041398NIAMS NIH HHS R01 AR072199NIDDK NIH HHS R01 DK121759NIDDK NIH HHS R24 DK092759Wellcome TrustWellcome Trust 203141/Z/16/Z
6 · The paper itself

Abstract

Skeletal and glycemic traits have shared etiology, but the underlying genetic factors remain largely unknown. To identify genetic loci that may have pleiotropic effects, we studied Genome-wide association studies (GWASs) for bone mineral density and glycemic traits and identified a bivariate risk locus at 3q21. Using sequence and epigenetic modeling, we prioritized an adenylate cyclase 5 (ADCY5) intronic causal variant, rs56371916. This SNP changes the binding affinity of SREBP1 and leads to differential ADCY5 gene expression, altering the chromatin landscape from poised to repressed. These alterations result in bone- and type 2 diabetes-relevant cell-autonomous changes in lipid metabolism in osteoblasts and adipocytes. We validated our findings by directly manipulating the regulator SREBP1, the target gene ADCY5, and the variant rs56371916, which together imply a novel link between fatty acid oxidation and osteoblast differentiation. Our work, by systematic functional dissection of pleiotropic GWAS loci, represents a framework to uncover biological mechanisms affecting pleiotropic traits.

Indexed as

Polymorphism, Single NucleotideAdenylyl CyclasesAdipocytesAdultBone DensityCell DifferentiationCells, CulturedDiabetes Mellitus, Type 2FemaleGenetic LociGenome-Wide Association StudyHaplotypesHumansLipid PeroxidationMaleMiddle AgedAdenylyl Cyclasesadenylyl cyclase type VSREBF1 protein, humanSterol Regulatory Element Binding Protein 1CRISPR-Cas9 variant editingosteoblast and adipocyte metabolismpleiotropy of type 2 diabetes and bone mineral densityregulatory genomicsvariant-to-function study

Identifiers

PMID33513366
PMCPMC7928941
OpenAlexW3122979510

What OpenQuestion holds

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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.