Partitioned polygenic risk scores identify distinct types of metabolic dysfunction-associated steatotic liver disease
Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by an excess of lipids, mainly triglycerides, in the liver and components of the metabolic syndrome, which can lead to cirrhosis and liver cancer. While there is solid epidemiological evidence that MASLD clusters with cardiometabolic disease, several leading genetic risk factors for MASLD do not increase the risk of cardiovascular disease, suggesting no causal relationship between MASLD and cardiometabolic derangement. In this work, we leveraged measurements of visceral adiposity identifying 27 previously unknown genetic loci associated with MASLD (n = 36,394), six replicated in four independent cohorts (n = 3,903). Next, we generated two partitioned polygenic risk scores based on the presence of lipoprotein retention in the liver. The two polygenic risk scores suggest the presence of at least two distinct types of MASLD, one confined to the liver resulting in a more aggressive liver disease and one that is systemic and results in a higher risk of cardiometabolic disease. These findings shed light on the heterogeneity of MASLD and have the potential to improve the prediction of clinical trajectories and inform precision medicine approaches.
Authors
- François Pattou (ORCID: https://orcid.org/0000-0001-8388-3766)
- Oveis Jamialahmadi (ORCID: https://orcid.org/0000-0001-7139-4738)
- Stefano Romeo (ORCID: https://orcid.org/0000-0001-9168-4898)
- Umberto Vespasiani‐Gentilucci (ORCID: https://orcid.org/0000-0002-1138-1967)
- Frits R. Rosendaal (ORCID: https://orcid.org/0000-0003-2558-7496)
- Julia Kozlitina (ORCID: https://orcid.org/0000-0001-7720-2290)
- Luca Valenti (ORCID: https://orcid.org/0000-0001-8909-0345)
- Päivi Pajukanta (ORCID: https://orcid.org/0000-0002-6423-8056)
- Marcus Alvarez (ORCID: https://orcid.org/0000-0002-6369-5028)
- Ruifang Li‐Gao (ORCID: https://orcid.org/0000-0003-0650-1351)
- Samantha Maurotti (ORCID: https://orcid.org/0000-0001-7644-1337)
- Antonio De Vincentis (ORCID: https://orcid.org/0000-0003-0220-0500)
- Francesco Malvestiti (ORCID: https://orcid.org/0000-0002-2430-5883)
- Kyla Z. Gelev (ORCID: https://orcid.org/0000-0003-3980-7189)
- Rosellina Margherita Mancina (ORCID: https://orcid.org/0000-0002-1126-3071)
- Federica Tavaglione (ORCID: https://orcid.org/0000-0002-1720-4355)
Institutions
- Karolinska University Hospital (SE)
- Inserm (FR)
- Università Campus Bio-Medico (IT)
- University of California, Los Angeles (US)
- University of Milan (IT)
- Université de Lille (FR)
- Leiden University Medical Center (NL)
- Sahlgrenska University Hospital (SE)
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT)
- Karolinska Institutet (SE)
- Centre Hospitalier Universitaire de Lille (FR)
- Magna Graecia University (IT)
- Campus Bio Medico University Hospital (IT)
- European Genomic Institute for Diabetes (FR)
- Link Campus University (IT)
- The University of Texas Southwestern Medical Center (US)
- University of Gothenburg (SE)
Publication Details
- Journal
- Nature Medicine
- Published
- 2024-12-01
- DOI
- https://doi.org/10.1038/s41591-024-03284-0
- Citations
- 76
- Primary Topic
- Liver Disease Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 29.38
Funders
- Gilead Sciences
- European Federation of Pharmaceutical Industries and Associations
- European Commission
- Universiteit Leiden
- Cancerfonden
- Ministero della Salute
- Knut och Alice Wallenbergs Stiftelse
- Novo Nordisk
- Vetenskapsrådet
- Leids Universitair Medisch Centrum
- Göteborgs Universitet
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
- Novo Nordisk Fonden
- National Institutes of Health
- Horizon 2020 Framework Programme