Our approach
Humans as the model system: recall-by-genotype deep phenotyping
Millions of people carry naturally occurring genetic variants that alter how the body handles fat. Academic medical biobanks allow us to identify these individuals and — with their consent — invite them back for detailed study: a direct measurement, in humans, of what each variant does.
Most variant biology is inferred from cells and mice. We take the complementary route: recall-by-genotype studies, in which carriers identified in academic medical biobanks are deeply phenotyped alongside matched controls, complemented by iPSC-based cellular models. Both projects below are built on this platform.
Key paper: Ko YA*, Fisher G*, Scorletti E* et al., Leveraging academic medical biobanks for recall-by-genotype deep phenotyping studies. Human Molecular Genetics, 2025 (*co-first).
Project 1
Lipid Droplet Variants in Cardiometabolic Disease
Cells store fat in specialized compartments called lipid droplets. Inherited differences in the proteins that manage these droplets help explain why some people with fatty liver disease remain well while others develop progressive scarring. We study carriers of these genetic differences to understand who is at risk and how disease can be prevented.
Steatotic liver disease (SLD) is strikingly heterogeneous, and much of that heterogeneity is genetic. We focus on coding variants in lipid droplet proteins — beginning with PNPLA3 I148M, the strongest common genetic risk factor for SLD, and PLIN2 Ser251Pro, a missense variant in the major hepatic lipid droplet coat protein. Using hepatocyte-specific mouse models and analyses across the Million Veteran Program, Penn Medicine Biobank and UK Biobank, we have defined how these variants alter hepatic lipid storage and disease progression. Ongoing work builds on these findings in human cohorts and cellular models.
Key papers: PLIN2 Ser251Pro reduces hepatic steatosis in mice (JHEP Reports, 2024) · A new perspective on NAFLD: focusing on lipid droplets (J Hepatology, 2022)
Project 2
Gene–Aging Interactions in Adipose Dysfunction
Adipose tissue is an endocrine organ: it releases chemical signals that act throughout the body. We study how these signals — and the genes that shape them — influence the way we age.
Supported by an NIH/NIA R21, we investigate how lipid-mediator signaling in adipose tissue — and the genetic variation that shapes it — influences the aging process, combining human cellular models with adipose tissue from clinical cohorts. The long-term aim is to understand, and ultimately modify, the contribution of adipose tissue to aging.