Evidence map›Paper›PMID 38991381›Full record

ArticleEBioMedicine2024

Single nucleus RNA-sequencing integrated into risk variant colocalization discovers 17 cell-type-specific abdominal obesity genes for metabolic dysfunction-associated steatotic liver disease.

Seung Hyuk T Lee, Kristina M Garske, Uma Thanigai Arasu, Asha Kar, Zong Miao, Marcus Alvarez, Amogha Koka, Nicholas Darci-Maher, Jihane N Benhammou, David Z Pan and 12 more

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Article in EBioMedicine, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.

0numbers the graph read from it
0cells of the map it votes in
19citing 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

19 citing papers in PubMed.

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  16. MASH: the nexus of metabolism, inflammation, and fibrosis.The Journal of clinical investigation · 2025
    Review
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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

22 authors.

Seung Hyuk T LeeDepartment of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Kristina M GarskeDepartment of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Uma Thanigai ArasuA. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
Asha KarDepartment of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Bioinformatics Interdepartmental Program, UCLA, Los Angeles, CA, USA.
Zong MiaoDepartment of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Bioinformatics Interdepartmental Program, UCLA, Los Angeles, CA, USA.
Marcus AlvarezDepartment of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Amogha KokaDepartment of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Nicholas Darci-MaherDepartment of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Jihane N BenhammouVatche and Tamar Manoukian Division of Digestive Diseases and Gastroenterology, Hepatology and Parenteral Nutrition, David Geffen School of Medicine at UCLA and VA Greater Los Angeles HCS, Los Angeles, CA, USA.
David Z PanDepartment of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Bioinformatics Interdepartmental Program, UCLA, Los Angeles, CA, USA.
Tiit ÖrdA. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
Dorota KaminskaInstitute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland; Division of Cardiology, Department of Medicine, UCLA, Los Angeles, CA, USA.
Ville MännistöInstitute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland; Department of Internal Medicine, Kuopio University Hospital, Kuopio, Finland.
Sini HeinonenObesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Martin WabitschDivision of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, University of Ulm, Ulm, Germany.
Markku LaaksoInstitute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland.
Vatche G AgopianDepartment of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Joseph R PisegnaDepartment of Medicine and Human Genetics, Division of Gastroenterology, Hepatology and Parenteral Nutrition, David Geffen School of Medicine at UCLA and VA Greater Los Angeles HCS, Los Angeles, CA, USA.
Kirsi H PietiläinenObesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Healthy WeightHub, Endocrinology, Abdominal Center, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland.
Jussi PihlajamäkiInstitute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland; Department of Medicine, Endocrinology and Clinical Nutrition, Kuopio University Hospital, Kuopio, Finland.
Minna U KaikkonenA. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
Päivi PajukantaDepartment of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Bioinformatics Interdepartmental Program, UCLA, Los Angeles, CA, USA; Institute for Precision Health, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. Electronic address: ppajukanta@mednet.ucla.edu.

Funding

Pilot and Feasibility ProgramP30DK041301 · NIDDK · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI ROZENGURT, JUAN ENRIQUE · 1990 to 2019
$18.0M
Multimodal omics approach to identify health to cardiometabolic disease transitionsR01HL170604 · NHLBI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI Paivi Pajukanta · 2023 to 2026
$2.8M
Methods for Genomic Analysis in Heterogeneous TissuesR01HG010505 · NHGRI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI HALPERIN, ERAN · 2019 to 2022
$2.6M
Genetics of adipose cell-type expression and cardiometabolic traitsR01DK132775 · NIDDK · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI MOHLKE, KAREN L., PAJUKANTA, PAIVI · 2022 to 2025
$2.4M
Understanding the contribution of genotype-by-lifestyle interactions to cardiometabolic risk in individuals of east African ancestryF32ES034668 · NIEHS · PRINCETON UNIVERSITY · PI GARSKE, KRISTINA MARIE · 2022 to 2024
$213k
NHGRI NIH HHS R01 HG010505NHLBI NIH HHS R01 HL170604NIDDK NIH HHS P30 DK041301NIDDK NIH HHS R01 DK132775NIEHS NIH HHS F32 ES034668
6 · The paper itself

Abstract

backgroundAbdominal obesity increases the risk for non-alcoholic fatty liver disease (NAFLD), now known as metabolic dysfunction-associated steatotic liver disease (MASLD).

methodsTo elucidate the directional cell-type level biological mechanisms underlying the association between abdominal obesity and MASLD, we integrated adipose and liver single nucleus RNA-sequencing and bulk cis-expression quantitative trait locus (eQTL) data with the UK Biobank genome-wide association study (GWAS) data using colocalization. Then we used colocalized cis-eQTL variants as instrumental variables in Mendelian randomization (MR) analyses, followed by functional validation experiments on the target genes of the cis-eQTL variants.

findingsWe identified 17 colocalized abdominal obesity GWAS variants, regulating 17 adipose cell-type marker genes. Incorporating these 17 variants into MR discovers a putative tissue-of-origin, cell-type-aware causal effect of abdominal obesity on MASLD consistently with multiple MR methods without significant evidence for pleiotropy or heterogeneity. Single cell data confirm the adipocyte-enriched mean expression of the 17 genes. Our cellular experiments across human adipogenesis identify risk variant -specific epigenetic and transcriptional mechanisms. Knocking down two of the 17 genes, PPP2R5A and SH3PXD2B, shows a marked decrease in adipocyte lipidation and significantly alters adipocyte function and adipogenesis regulator genes, including DGAT2, LPL, ADIPOQ, PPARG, and SREBF1. Furthermore, the 17 genes capture a characteristic MASLD expression signature in subcutaneous adipose tissue.

interpretationOverall, we discover a significant cell-type level effect of abdominal obesity on MASLD and trace its biological effect to adipogenesis.

fundingNIH grants R01HG010505, R01DK132775, and R01HL170604; the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (Grant No. 802825), Academy of Finland (Grants Nos. 333021), the Finnish Foundation for Cardiovascular Research the Sigrid Jusélius Foundation and the Jane and Aatos Erkko Foundation; American Association for the Study of Liver Diseases (AASLD) Advanced Transplant Hepatology award and NIH/NIDDK (P30DK41301) Pilot and Feasibility award; NIH/NIEHS F32 award (F32ES034668); Finnish Diabetes Research Foundation, Kuopio University Hospital Project grant (EVO/VTR grants 2005-2021), the Academy of Finland grant (Contract no. 138006); Academy of Finland (Grant Nos 335443, 314383, 272376 and 266286), Sigrid Jusélius Foundation, Finnish Medical Foundation, Finnish Diabetes Research Foundation, Novo Nordisk Foundation (#NNF20OC0060547, NNF17OC0027232, NNF10OC1013354) and Government Research Funds to Helsinki University Hospital; Orion Research Foundation, Maud Kuistila Foundation, Finish Medical Foundation, and University of Helsinki.

Indexed as

Genetic Predisposition to DiseaseGenome-Wide Association StudyObesity, AbdominalQuantitative Trait LociAdipogenesisCell NucleusGene Expression RegulationHumansNon-alcoholic Fatty Liver DiseasePolymorphism, Single NucleotideProtein Phosphatase 2Sequence Analysis, RNASingle-Cell AnalysisProtein Phosphatase 2Abdominal obesityColocalizationExpression quantitative trait loci (eQTL)Genome-wide association study (GWAS)Metabolic dysfunction-associated steatotic liver disease (MASLD)Single-nucleus RNA-sequencing (snRNA-seq)Waist-hip ratio adjusted for body mass index (WHRadjBMI)

Identifiers

PMID38991381
PMCPMC11663762

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