Variants to Function & Mechanism

Variants to Function & Mechanism2024-07-02T14:12:09-04:00

Determining the detailed mechanisms by which variants in the human genome or genes associated with human genetic variants operate to contribute to disease or health/wellness.

News | Variants to Function & Mechanism

Association of Soluble ST2 With Functional Outcome, Perihematomal Edema, and Immune Response After Intraparenchymal Hemorrhage

This manuscript builds on the Kimberly Lab’s work that highlights the role of the interleukin-33/ST2 pathway and its link to post-stroke inflammation and brain edema. The lab had previously shown that this inflammatory signaling cascade is associated with brain edema and activation of innate immunity after ischemic stroke and subarachnoid hemorrhage. This paper extends previous work to show a similarly damaging activation after intracerebral hemorrhage. Collectively, this work highlights that modulation of the IL-33/ST2 pathway is a candidate target to reduce the severity of edema and inflammation after all major forms of acute brain injury.

Read more in Neurology

March 20, 2023

Publication

CGM Primary Investigator

March 20, 2023|

Uridine and RNA as energy

To identify genes and pathways that cells can use to survive when glucose — an important source of energy and carbon — is limited, Vamsi Mootha, and colleagues performed genome-wide genetic screens and a PRISM growth assay. They found that cells ranging from healthy immune cells to cancer cells can use uridine, a component of RNA, as an energy source when glucose is unavailable. Targeting the biochemical pathway that cells use to break down uridine-derived sugar could help treat cancers and metabolic disorders and tune the immune response.

Read more in Nature Metabolism, a Broad news story, and a tweetorial by Alexis Jourdain.

March 19, 2023

Publication

CGM Primary Investigator

March 19, 2023|

Clonal haematopoiesis and risk of chronic liver disease.

Through advances in population-based genomic sequencing an analysis, the Natarajan lab and others showed that ‘clonal hematopoiesis of indeterminate potential’ (CHIP) is a surprisingly common feature as we age. They also showed that CHIP plays a role in coronary artery disease, the leading contributor to death in the US and now globally. As inflammation appeared to be a principal driver, the Natarajan lab has since then attempted to understand whether CHIP plays a role in other conditions where inflammation has been invoked as a key driver. This study focused on chronic liver disease because, which has become increasingly common with the rising prevalence of obesity and metabolic syndrome. However, therapeutic options for chronic liver disease have remained limited for decades except for hepatitis C. Fatty liver disease is increasingly recognized but the reasons by inflammation and downstream liver disease occur remain limited. They therefore hypothesized that CHIP could play a role. It was found that CHIP offered to confer a relatively large risk for chronic liver disease, sometimes larger than currently recognized risk factors. And causal inference approaches, such as Mendelian randomization, supported a potential causal relationship. Liver MRIs and liver biopsies were consistent with greater steatohepatitis and not greater steatosis. Murine models similarly showed greater steatohepatitis without greater steatosis, and also greater fibrosis when followed for longer periods of time. Genetic deficiency of the NLRP3 inflammasome appeared to ameliorate this phenotype in the mice. This inflammatory pathway has also been invoked in CHIP-associated coronary artery disease. The relationship between CHIP and liver disease was previously unknown. These observations highlight a new potential precision medicine paradigm for chronic liver disease prevention. The findings support the scientific premise that, particularly for TET2 CHIP, inhibition of the NLRP3 inflammasome may reduce the risk of chronic liver disease.

Read more in Nature.

Read more in Nature.

March 18, 2023

Publication

CGM Primary Investigator

March 18, 2023|

Nucleosides Associated With Incident Ischemic Stroke in the REGARDS and JHS Cohorts

This manuscript is the first to show a link between specific nucleoside metabolites and the risk of future stroke, independent of traditional stroke risk factors. In this study, CGM Investigator Taylor Kimberly and colleagues also sought to determine whether these candidates were a reflection of genes or environment through GWA studies. Their findings suggest that the top metabolites were related to environmental or behavioral patterns, ultimately leading our group to focus on potential links between diet, the gut microbiome, and stroke risk.

Read more in Neurology.

December 9, 2022

Publication

CGM Primary Investigator

W. Taylor Kimberly
December 9, 2022|

Brain-specific deletion of GIT1 impairs cognition and alters phosphorylation of synaptic protein networks implicated in schizophrenia susceptibility

The molecular and cellular basis of cognitive deficits in schizophrenia remains poorly understood. Recent progress in elucidating the genetic architecture of schizophrenia has highlighted the association of multiple loci and rare variants that may impact susceptibility. A critical next step is to delineate specifically how such genetic variation impacts synaptic plasticity and to determine if and how the encoded proteins interact biochemically. Towards this goal, CGM Investigator Steve Haggarty and colleagues studied the roles of GPCR-kinase interacting protein 1 (GIT1), a synaptic scaffolding protein with damaging coding variants found in schizophrenia patients, as well as copy number variants found in patients with neurodevelopmental disorders. Profiling GIT1 knockout mice revealed memory deficits and reduced cortical dendritic spine density. Using global quantitative phospho-proteomics, we revealed that GIT1 deletion perturbs specific networks of synaptic proteins, suggesting that GIT1 regulates the phosphorylation of critical regulators of neuroplasticity.

Read more in Molecular Psychiatry

December 8, 2022

Publication

CGM Primary Investigator

December 8, 2022|

Distinct effects of interleukin-6 and interferon-γ on differentiating human cortical neurons

The Karmacharya lab interrogated neurodevelopmental effects of exposure to interleukin-6 (IL-6) and interferon-γ (IFN-γ) in differentiating human cortical neurons. Transcriptomic analyses showed IL-6 exposure affected genes regulating extracellular matrix, actin cytoskeleton and TGF-β signaling while IFN-γ exposure impacted genes regulating antigen processing, major histocompatibility complex and endoplasmic reticulum biology. IL-6 altered mitochondrial respiration in the differentiated neurons while IFN-γ induced reduction in dendritic spine density. Pretreatment with folic acid ameliorated IL-6 effects on mitochondrial respiration and IFN-γ effects on dendritic spine density. These findings suggest cellular processes that mediate maternal immune activation in developing brains and how folic acid mitigates such risk.

December 7, 2022

Publication

CGM Primary Investigator

Rakesh Karmacharya
December 7, 2022|

Faculty | Variants to Function & Mechanism

Rakesh Karmacharya, MD, PhD

Categories: Training Program Faculty, Variants to Disease & Traits, Variants to Function & Mechanism
Harvard Medical School: Associate Professor of Psychiatry
Massachusetts General Hospital: Physician Investigator
Physician Investigator, Massachusetts General Hospital
Associate Professor, Harvard Medical School

Our lab uses experimental approaches at the intersection of chemical biology, genetics and stem cell biology to investigate cellular pathways relevant to schizophrenia, bipolar disorder, autism and related neuropsychiatric disorders. We utilize complementary approaches in specific cellular subtypes and in three-dimensional cerebral organoids generated from human iPSCs. We employ a range of methods including high-content imaging to investigate synaptic biology, multi-electrode arrays to examine neuronal function along with transcriptomic, proteomic and metabolomic experiments. We seek to develop new small molecules that can modulate disease-related processes in patient-derived neurons and develop new therapeutic approaches for targeting cognitive deficits in psychiatric disorders.

Rakesh Karmacharya, MD, PhD

Associate Professor of Psychiatry, Harvard Medical School

W. Taylor Kimberly, MD, PhD

Categories: Variants to Disease & Traits, Variants to Function & Mechanism
Harvard Medical School: Associate Professor of Neurology
Massachusetts General Hospital: Chief, Division of Neurocritical Care
Chief, Division of Neurocritical Care, Massachusetts General Hospital
Associate Professor of Neurology, Harvard Medical School

The Kimberly Lab is committed to reducing the devastating effects of acute brain injury by focusing on translational studies that bridge basic science and clinical research. We believe that therapeutic discovery is not a linear path from fundamental mechanism to new drug, but instead a cycle that requires bi-directional and multidisciplinary integration of basic and patient-oriented research. A presence at each stage of discovery—both directly and through strategic collaboration—is central to our mission to advancing new treatments. Consequently, our laboratory is highly multidisciplinary and collaborative, and our work could not be accomplished without our collaborative partners.

W. Taylor Kimberly, MD, PhD

Associate Professor of Neurology, Harvard Medical School

Ben P. Kleinstiver, PhD

Categories: Variants to Disease & Traits, Variants to Function & Mechanism
Harvard Medical School: Assistant Professor of Pathology
Massachusetts General Hospital: Investigator; Kayden-Lambert MGH Research Scholar 2023-2028
Investigator; Kayden-Lambert MGH Research Scholar 2023-2028, Massachusetts General Hospital
Assistant Professor, Harvard Medical School

The Kleinstiver lab develops genome editing technologies for research applications and for the treatment of human diseases. We develop new approaches and methods to engineer genome editing enzymes, to optimize the properties of CRISPR tools, and to add new functionalities to the editor toolbox, all with the ambition of enabling new treatments for disease.

Ben P. Kleinstiver, PhD

Assistant Professor of Pathology, Harvard Medical School

Phil H. Lee, PhD

Categories: Variants to Diagnosis, Variants to Disease & Traits, Variants to Function & Mechanism
Harvard Medical School: Assistant Professor of Psychiatry
Massachusetts General Hospital: Assistant in Research
Assistant in Research, Massachusetts General Hospital
Assistant Professor, Harvard Medical School

We use computational and statistical approaches to understand the genetic bases of complex neuropsychiatric traits and mental disorders. Multivariate pathway analysis forms the backbone of our research on identifying disease risk genes and mechanisms. We also apply multi-modal data analysis integrating genomic and neuroimaging data.

Phil H. Lee, PhD

Assistant Professor of Psychiatry, Harvard Medical School

Marcy E. MacDonald, PhD

Categories: Populations to Variants, Variants to Diagnosis, Variants to Disease & Traits, Variants to Function & Mechanism
Harvard Medical School: Professor of Neurology
Massachusetts General Hospital: Research (Non-Clinical) Staff
Research (Non-Clinical) Staff, Massachusetts General Hospital
Professor of Neurology, Harvard Medical School

Our research, evolving from the discovery of the genetic causes of inherited brain disorders (hereditary spastic paraparesis, neurofibromatosis, neuronal ceroid lipofuscinosis, Huntington’s disease), is now largely focused on the DNA variants that modify the effects of the unstable expanded CAG repeat that causes Huntington’s disease. We do molecular genetic studies with disease and population cohorts and genetically precise model systems. Our goal is to enable timely intervention, diagnosis and disease-management.

Marcy E. MacDonald, PhD

Professor of Neurology, Harvard Medical School

Jonathan Rosand, MD, MSc

Categories: Training Program Faculty, Variants to Disease & Traits, Variants to Function & Mechanism
Harvard Medical School: Professor of Neurology
Massachusetts General Hospital: J. P. Kistler Endowed Chair in Neurology
J. P. Kistler Endowed Chair in Neurology, Massachusetts General Hospital
Professor of Neurology, Harvard Medical School

The hallmark of our work is the combination of careful clinical characterization of patients with the most rigorous approaches to genetics. We work in partnership with patients and their families to understand the factors that contribute to maintaining vascular brain health across the lifespan. We are a leading contributor to the performance and analysis of high-throughput genome-wide association and sequencing studies in stroke and related traits. At our core, we serve as a training ground for outstanding scientists and clinician-scientists who go on to become world-class leaders in the field. The lab has created a legacy of multidisciplinary teams that are successfully tackling some of the most pressing challenges in brain disease. Among these teams is the International Stroke Genetics Consortium, which we founded in 2007 to bring together the world’s pre-eminent stroke investigators.

Jonathan Rosand, MD, MSc

Professor of Neurology, Harvard Medical School

Jeremiah M. Scharf, MD, PhD

Categories: Populations to Variants, Training Program Faculty, Variants to Diagnosis, Variants to Disease & Traits, Variants to Function & Mechanism
Harvard Medical School: Assistant Professor of Neurology
Massachusetts General Hospital: Physician-Scientist
Physician-Scientist, Massachusetts General Hospital
Assistant Professor of Neurology, Harvard Medical School

The Scharf lab investigates the genetic and neurobiological mechanisms of Tourette Syndrome (TS) and related developmental neuropsychiatric disorders that lie at the interface between traditional concepts of neurologic and psychiatric disease, including obsessive compulsive spectrum disorders (OCD/OCSD) and attention-deficit hyperactivity disorder (ADHD). We conduct genetic and clinical research to identify both genetic and non-genetic risk factors that contribute to the predisposition of TS, ADHD, and OCD in patients and families. We hope to identify novel targets for treatment, to understand the course of TS and related conditions at a patient-specific level, and to better predict treatment response.

Jeremiah M. Scharf, MD, PhD

Assistant Professor of Neurology, Harvard Medical School

Jordan W. Smoller, MD, ScD

Categories: Training Program Faculty, Variants to Diagnosis, Variants to Disease & Traits, Variants to Function & Mechanism
Harvard Medical School: Professor of Psychiatry
Massachusetts General Hospital: MGH Trustees Endowed Chair in Psychiatric Neuroscience
Massachusetts General Hospital: MGH Trustees Endowed Chair in Psychiatric Neuroscience
MGH Trustees Endowed Chair in Psychiatric Neuroscience, Massachusetts General Hospital
MGH Trustees Endowed Chair in Psychiatric Neuroscience, Massachusetts General Hospital
Professor of Psychiatry, Harvard Medical School

The focus of Dr. Smoller’s research interests has been:

  • Understanding the genetic and environmental determinants of psychiatric disorders across the lifespan.
  • Integrating genomics and neuroscience to unravel how genes affect brain structure and function.
  • Using “big data”, including electronic health records and genomics, to advance precision medicine.

Jordan W. Smoller, MD, ScD

Professor of Psychiatry, Harvard Medical School

We are hiring! We are inviting applications for full-time CGM faculty with an Assistant or Associate Professor of Neurology appointment at Harvard Medical School (HMS), commensurate with accomplishments and experiences. See more and apply on our careers page >

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