Single nucleus RNA-sequencing integrated into risk variant colocalization discovers 17 cell-type-specific abdominal obesity genes for metabolic dysfunction-associated steatotic liver diseaseResearch in context
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,
Tiit Örd,
Dorota Kaminska,
Ville Männistö,
Sini Heinonen,
Martin Wabitsch,
Markku Laakso,
Vatche G. Agopian,
Joseph R. Pisegna,
Kirsi H. Pietiläinen,
Jussi Pihlajamäki,
Minna U. Kaikkonen,
Päivi Pajukanta
Affiliations
Seung Hyuk T. Lee
Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
Kristina M. Garske
Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
Uma Thanigai Arasu
A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
Asha Kar
Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Bioinformatics Interdepartmental Program, UCLA, Los Angeles, CA, USA
Zong Miao
Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Bioinformatics Interdepartmental Program, UCLA, Los Angeles, CA, USA
Marcus Alvarez
Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
Amogha Koka
Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
Nicholas Darci-Maher
Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
Jihane N. Benhammou
Vatche 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. Pan
Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Bioinformatics Interdepartmental Program, UCLA, Los Angeles, CA, USA
Tiit Örd
A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
Dorota Kaminska
Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland; Division of Cardiology, Department of Medicine, UCLA, Los Angeles, CA, USA
Ville Männistö
Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland; Department of Internal Medicine, Kuopio University Hospital, Kuopio, Finland
Sini Heinonen
Obesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
Martin Wabitsch
Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, University of Ulm, Ulm, Germany
Markku Laakso
Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland
Vatche G. Agopian
Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
Joseph R. Pisegna
Department 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. Pietiläinen
Obesity 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 Pihlajamäki
Institute 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. Kaikkonen
A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
Päivi Pajukanta
Department 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; Corresponding author. Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Summary: Background: Abdominal obesity increases the risk for non-alcoholic fatty liver disease (NAFLD), now known as metabolic dysfunction-associated steatotic liver disease (MASLD). Methods: To 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. Findings: We 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. Interpretation: Overall, we discover a significant cell-type level effect of abdominal obesity on MASLD and trace its biological effect to adipogenesis. Funding: NIH 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.
