The Claussnitzer lab pioneers Variant-to-Function (V2F) strategies for metabolic diseases.

Large-scale genetic studies have succeeded in identifying more than 1,800 associations between genetic loci and obesity-, and type 2 diabetes-related traits in humans. Yet, the next grand challenge — dissecting the molecular and cellular mechanisms by which these variants affect disease (Variant-to-Function, V2F) — has still to be solved and requires being able to determine the effect of genetic variants on molecular and cellular programs.

The Claussnitzer lab has pioneered a principled V2F framework for going from variants to genes to cells to biological pathways in the context of metabolic disease (Fig. 1). While these V2F studies help us to learn useful functional insights for metabolic disease, such one-locus-at-a-time approaches are currently not scalable, and it would take us decades to unlock the mechanisms encoded by the 1000s of genetic risk loci for metabolic disease.

The long-term goal of the Claussnitzer lab is to pioneer scalable V2F strategies to systematically unlock the consequences of genetic metabolic risk variation at the molecular and cellular level using adipocytes as model systems. To achieve this, the Claussnitzer lab develops and appplies high-dimensional molecular and cellular profiling techniques to large-scale natural genetic variation screens and CRISPR perturbation screens to generate a foundational data set that will allow to systematically link genetic variants (V) to regulatory elements (RE) to genes (G) to morphological and cellular functions (M/F) in disease across adipocyte cell state transitions. Adipocytes are the ideal model system for modeling V2F effects and learning fundamental rules of genetic networks since they play a major role in the pathogenesis of metabolic disease and undergo substantial remodeling at the regulatory and cellular level over the course of differentiation and in response to metabolic stimuli.

1. Single locus V2F studies in cardiometabolic cell types: The Claussnitzer lab uses a combination of computational and experimental strategies to dissect genetic risk loci associated with cardiometabolic disease by tracing the variant effect from V-RE-G-M/F providing  actionable targets and mechanisms of action.
2. CellGenBank: The Claussnitzer team is actively collaborating with Dr. Cornelia Griggs at the MGH Weight Center to establish a population-scale cellular biobank of adipose-derived mesenchymal stem cells (AMSCs) derived from subcutaneous and visceral adipose tissues from thousands of individuals (CellGenBank). These AMSCs are used for in vitro natural genetic variation screen (GWAS-in-a-dish) studies and high-throughput CRISPR perturbation screens combined with high-dimensional phenotypic profiling read-outs to systematically map the phenotypic impact of metabolic genetic risk variants on cellular phenotypes across cell state transitions.
3. PRS2F: The Claussnitzer lab links aggregated genome-wide polygenic risk scores for cardiometabolic traits and diseases to their context-dependent molecular and cellular effects using a series of high-dimensional read-outs.
4. Novo Nordisk Foundation Center for Genomic Mechanisms of Disease (NNFC) at the Broad Institute: The Claussnitzer lab is a major contributor to the NNF Center at the Broad Institute. The NNFC is a bridgehead center and joint initiative by the Novo Nordisk Foundation in Denmark and the Broad Institute to pioneer technologies, tools, and methods to enable biomedical researchers worldwide to systematically turn genetic insights in common diseases into biological mechanisms—a key step towards developing new generations of medicines.