About
Welcome to the Claussnitzer Lab
Based at the Broad Institute of MIT and Harvard in Cambridge Massachusetts, the Claussnitzer lab strives to pioneer novel ways to convert large-scale genetic association study results to their underlying disease biology (Variant-to-Function, V2F), and thereby create a path between cardiometabolic disease genetics and disease biology toward patient-oriented research.
Large-scale genetic studies have succeeded in identifying thousands of associations between genetic loci and obesity, type 2 diabetes and other cardiometabolic 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 yet 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 genetic variants to genes to cells to biological pathways to provide actionable therapeutic hypotheses, first for the strongest genetic association with obesity, the FTO obesity risk locus (NEJM 2015) (Fig. 1). The Claussnitzer lab has further shown that this V2F framework generalizes to other genetic risk loci (Cell 2014, Biochim Biophys Acta Gene Regul Mech. 2020, Cell Metabol. 2021, Nat Commun. 2020, Sci Adv. 2021, Science 2021, Nat Genet. 2022, Nat Metabol. 2023).
The goal of our lab
While V2F studies help us to learn useful functional insights for metabolic disease, the 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 applies 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.
What are we up to
The Claussnitzer lab is part of a series of national and international V2F consortia and alliances including the UM1 NEWS team, the Accelerated Medicine Partnership Common Metabolic Disease (AMP CMD), the International Common Disease Alliance (ICDA), the Atlas of Variant Effects (AVE), and the Novo Nordisk Foundation Center for Genomic Mechanism of Disease.
Current Projects
- 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.
- 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.
- 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.
