Use of understanding gained in the genomic medicine cycle to refine treatment, diagnosis, or promote new therapeutics for rare or common human disease.
News | Variants to Diagnosis & Treatment
Oxygen restriction’s effects on lifespan
Oxygen restriction has been linked to longer lifespan in some organisms, but its effects on aging in mammals have been unclear. A team led by CGM faculty member, Vamsi Mootha, and Robert Rogers explored the effects of oxygen restriction on mammalian lifespan using a mouse model of accelerated aging. The researchers discovered that the mice living in an oxygen-restricted environment lived about 50 percent longer compared to those exposed to standard levels of oxygen, with delayed onset of aging-associated neurological deficits.
Read more in news releases from PLOS and Harvard Medical School, and coverage in The Daily Beast and Medical News Today.
Development of an oral treatment that rescues gait ataxia and retinal degeneration in a phenotypic mouse model of familial dysautonomia.
Familial dysautonomia (FD) is a rare neurodegenerative disease caused by a mutation in the gene encoding for the Elongator complex protein 1 (ELP1). This mutation leads to a reduction of ELP1 protein, mainly in the nervous system. Due to the crucial function of ELP1 in neuronal development and survival, FD patients exhibit many neurological symptoms, including retinal degeneration and inability to coordinate movements. In our recently published study, the Slaugenhaupt and Morini lab describes the optimization of an oral treatment for FD that restores the expression of functional ELP1 protein in every tissue, including brain, and rescues retinal degeneration and motor coordination in a mouse model of FD.
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.
Polygenic Scores Help Reduce Racial Disparities in Predictive Accuracy of Automated Type 1 Diabetes Classification Algorithms
In a study, led by CGM PI, Miriam Udler, and her colleagues they implemented an automated clinical algorithm and a type 1 diabetes polygenic score to identify individuals with type 1 diabetes in two large biobanks: MGB Biobank and BioMe (Mt. Sinai). They assessed the accuracy of the clinical algorithm compared to a gold standard of clinician diagnosis on chart review. The authors found that the clinical algorithm more accurately predicted type 1 diabetes status for self-reported White individuals, compared to other race/ethnicity groups. However, after updating the clinical algorithm to incorporate type 1 diabetes polygenic scores, the accuracy improved for all individuals, and the racial/ethnic disparity was reduced. These results demonstrate the potential for polygenic scores to aid in clinical phenotyping and to help reduce health disparities.
Read more in Diabetes Care and a podcast here.
Distinct patterns of emotional and behavioral change in child psychiatry outpatients during the COVID-19 pandemic
This was the first publication on pandemic-related mental health changes in child psychiatric outpatients in the United States. Empirically-derived multivariate models showed that child psychiatric outpatients had highly variable emotional and behavioral reactions to the pandemic, with some showing stability, others even showing improvement, and two groups manifesting distinctive patterns of worsening symptoms predicted by their prior psychopathology. Results have implications for clinical care as well as ongoing research on genetic contributions to youth mental health.
Read more in Child and Adolescent Psychiatry and Mental Health
December 14, 2022
Publication
CGM Primary Investigator
Improving polygenic prediction in ancestrally diverse populations
Polygenic risk scores (PRS) have attenuated cross-population predictive performance, which reduces their clinical value in non-European populations and exacerbates healthcare disparities. This study, conducted by CGM Investigators Tian Ge, Hailiang Huang, Alicia Martin and colleagues, developed a computational framework, termed PRS-CSx, that can integrate genomic data from multiple populations to improve polygenic prediction in diverse populations. Leveraging large-scale global biobanks and disease-focused cohorts, the investigators showed that PRS-CSx substantially improved the prediction accuracy of biomarkers and disease risk in non-European populations. This work represents an important step towards the implementation of PRS into routine healthcare.
Read more in Nature Genetics
December 13, 2022
Publication Name
CGM Primary Investigators
Faculty | Variants to Diagnosis & Treatment
Susan L. Cotman, PhD
Assistant in Neuroscience, Massachusetts General Hospital
Assistant Professor of Neurology, Harvard Medical School
The Cotman laboratory’s research is focused on understanding the role of the endosomal-lysosomal system in human disease, with a particular emphasis on NCL (Batten disease), the most common cause of neurodegeneration in childhood that also more rarely affects adults.
Susan L. Cotman, PhD
Assistant Professor of Neurology, Harvard Medical School
Mark J. Daly, PhD
Chief, ATGU, Massachusetts General Hospital
Associate Professor of Medicine, Harvard Medical School
The Daly Lab focuses on computational approaches to understanding the genetics of human disease using integrative genomics approaches. The lab has extensive experience in linkage and association analysis, with a focus on developing statistical methods for the design and interpretation of association studies, and applying these approaches specifically to major common disease areas such as neuropsychiatric disease, inflammatory bowel and autoimmune diseases, and diabetes.
Mark J. Daly, PhD
Associate Professor of Medicine, Harvard Medical School
Alysa E. Doyle, PhD
Psychologist, Massachusetts General Hospital
Assistant Professor of Psychiatry, Harvard Medical School
We study neuropsychiatric illness and related outcomes across the lifespan. Our research aims to promote a better understanding of the development of neuropsychiatric illness across the lifespan by investigating risk mechanisms, phenotypic variation, and moderators of youth trajectories.
Alysa E. Doyle, PhD
Assistant Professor of Psychiatry, Harvard Medical School
Florian Eichler, MD
Director, Center for Rare Neurological Diseases, Massachusetts General Hospital
Professor of Neurology, Harvard Medical School
Our laboratory at MGH explores the relationship of mutant genes to specific biochemical defects and their contribution to neurodegeneration. To develop novel treatments, our laboratory assesses the consequences of disease causing genes.
Florian Eichler, MD
Professor of Neurology, Harvard Medical School
Jose C. Florez, MD, PhD
Chief, Endocrine Division and Diabetes Unit, Massachusetts General Hospital
Professor of Medicine, Harvard Medical School
The Florez lab aims to unravel the genetic basis of type 2 diabetes, related metabolic traits and its vascular complications, and provide the rationale for effective, precision-tailored therapies. The overarching goal is to bring the clinical treatment of diabetes and its complications into the new paradigm of molecular medicine, using genomic, metabolomic, experimental, physiological and pharmacogenetic approaches.
Jose C. Florez, MD, PhD
Professor of Medicine, Harvard Medical School
Yulia Grishchuk, PhD
Assistant Investigator, Massachusetts General Hospital
Assistant Professor of Neurology, Harvard Medical School
Our research is focused on pre-clinical studies and biomarker discovery for rare pediatric neurologic diseases with high unmet need to enable further development of therapies. Our therapeutic strategies have been focused on use of adeno-associated viral vectors for optimized transduction and transgene delivery to central nervous system, including brain, retina, and optic nerve.
Yulia Grishchuk, PhD
Assistant Professor of Neurology, Harvard Medical School
James F. Gusella, PhD
Research Staff, Massachusetts General Hospital
Bullard Professor of Neurogenetics in the Department of Genetics, Harvard Medical School
Dr. Gusella’s laboratory is currently pursuing collaborative studies at all stages of the genetic research cycle aimed at discovering genes that cause, predispose to or modify neurological and behavioral disorders or caused abnormal development in subjects with balanced chromosomal aberrations and developmental phenotypes, delineating mechanisms of pathogenesis and modifiers in Huntington’s disease, the neurofibromatosis, and autism and exploring the potential for mechanism-based treatments.
James F. Gusella, PhD
Bullard Professor of Neurogenetics in the Department of Genetics, Harvard...
Hailiang Huang, PhD
Assistant Investigator, Massachusetts General Hospital
Assistant Professor of Medicine, Harvard Medical School
The Huang Lab develops and applies cutting-edge statistical genetics and computational techniques to understand the genetic architecture of human complex disorders, especially autoimmune and psychiatric disorders. We are especially interested in novel methods to leverage cross-ancestry genomics data for insights into the disease pathogenesis.
Hailiang Huang, PhD
Assistant Professor of Medicine, Harvard Medical School
Konrad J. Karczewski, PhD
Assistant in Investigation, Massachusetts General Hospital
Instructor in Medicine, Harvard Medical School
Our research is focused on interpreting putative disease variants in common and rare diseases to improve our understanding of human disease and the regulation of the human genome. We do so by assembling and analyzing massive public datasets of genetic variation and functional genomics, building scalable tools and methods to keep pace with the exponential growth of these data types.
Konrad J. Karczewski, PhD
Instructor in Medicine, Harvard Medical School
Phil H. Lee, PhD
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
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
Alicia Martin, PhD
Assistant Investigator, Massachusetts General Hospital
Assistant Professor, Harvard Medical School
As a population and statistical genetics lab, our research examines the role of human history in shaping global genetic and phenotypic diversity. Given vast Eurocentric study biases, we investigate the generalizability of knowledge gained from large-scale genetic studies across globally diverse populations. We are focused on ensuring that the translation of genetic technologies particularly via polygenic risk does not exacerbate health disparities induced by these study biases. Towards this end, we are developing statistical methods, community resources for genomics, and research capacity for multi-ancestry studies especially in underrepresented populations.
Alicia Martin, PhD
Assistant Professor, Harvard Medical School
Patricia L. Musolino, MD, PhD
Physician-Scientist, Massachusetts General Hospital
Assistant Professor of Neurology, Harvard Medical School
The Musolino Laboratory at the Center for Genomic Medicine at Massachusetts General Hospital and Harvard Medical School is a translational neuroscience laboratory focusing on developing gene targeted therapies for inherited inborn errors of metabolism and cerebrovascular disorders that lead to stroke and leukodystrophy.
Patricia L. Musolino, MD, PhD
Assistant Professor of Neurology, Harvard Medical School
Pradeep Natarajan, MD, MMSc
Director of Preventive Cardiology, Massachusetts General Hospital
Associate Professor of Medicine, Harvard Medical School
The Natarajan Lab focuses on the germline and somatic genetic drivers of human atherosclerosis applying advances in genomic profiling with concomitant methods development. The interdisciplinary group spans human genetics, computational biology, and clinical medicine. The lab spearheads and contributes to several research consortia, often spanning hundreds of investigators and millions of participants to achieve project goals.
Pradeep Natarajan, MD, MMSc
Associate Professor of Medicine, Harvard Medical School
Aarno Palotie
Lecturer, Harvard Medical School
Group Leader, Massachusetts General Hospital
Understanding disease genetics using the Finnish founder population
Aarno Palotie
Lecturer, Harvard Medical School Group Leader, Massachusetts General Hospital Understanding...
Roy H. Perlis, MD
Associate Chief for Research, Department of Psychiatry, Massachusetts General Hospital
Professor of Psychiatry, Harvard Medical School
Our lab focuses on developing clinical and genomic predictors of treatment response, and on developing novel therapeutics based on cellular models of brain disease. We use cellular modeling, transcriptomics, clinical phenotyping, and small molecule screening to study psychiatric disorders including schizophrenia, bipolar disorder, and depression.
Roy H. Perlis, MD
Professor of Psychiatry, Harvard Medical School
Vijaya Ramesh, PhD
Neuroscientist, Massachusetts General Hospital
Professor of Neurology, Harvard Medical School
My lab has been primarily working on understanding the pathophysiology of two different inherited neurocutaneous syndromes, Neurofibromatosis 2 (NF2) and Tuberous Sclerosis Complex (TSC). We have collaborative studies with investigators outside MGH for these studies. We also collaborate with Dr. Xandra Breakefield and Dr. Casey Maguire labs for gene therapy studies of NF2 and TSC.
Vijaya Ramesh, PhD
Professor of Neurology, Harvard Medical School
Heidi L. Rehm, PhD
Chief Genomics Officer, Massachusetts General Hospital
Professor of Pathology, Harvard Medical School
The Translational Genomics Group (TGG) has a mission to support the discovery of the genetic basis of rare disease and translate our work into medical practice by focusing on community-centered projects that promote collaboration, data sharing and open science. Heidi Rehm leads the TGG, with co-leadership by Anne O’Donnell-Luria for the rare disease group and Mark Daly for the gnomAD project. TGG is composed of a multidisciplinary team of researchers, clinicians, computational biologists, and software engineers. We are located at Massachusetts General Hospital and the Broad Institute of MIT and Harvard.
Heidi L. Rehm, PhD
Professor of Pathology, Harvard Medical School
Kaitlin E. Samocha, PhD
Assistant Investigator, Massachusetts General Hospital
Our group studies patterns of rare genetic variation in large collections of human genomic data, both from patients and reference population individuals, and designs tools and methods to help interpret that variation. We are focused on moving from studying single variants at a time to understanding how they impact disease in their genomic context.
Kaitlin E. Samocha, PhD
Assistant Professor of Medicine, Massachusetts General Hospital
Jeremiah M. Scharf, MD, PhD
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
Susan A. Slaugenhaupt, PhD
Professor of Neurology (Genetics), Harvard Medical School
Investigator, Massachusetts General Hospital
My research focuses on two neurological disorders, familial dysautonomia (FD) and mucolipidosis type IV (MLIV), as well as the common cardiac disorder mitral valve prolapse (MVP). Our work is focused on gene discovery and therapeutic development, specifically targeting mRNA splicing.
Susan A. Slaugenhaupt, PhD
Professor of Neurology (Genetics), Harvard Medical School
Jordan W. Smoller, MD, ScD
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
Alexander Soukas, MD, PhD
Associate Professor of Medicine, Harvard Medical School
Associate Professor of Medicine, Massachusetts General Hospital
Aging is the single, greatest contributor to nearly every disease and condition that affects us after our youth. Diabetes, obesity, heart disease, stroke, cancer, osteoporosis, and dementia are all diseases of aging. In the Soukas Laboratory, we endeavor to figure out how things go wrong in the cells of the body in aging, and more excitingly, how to fix what goes wrong. Our findings have the ability to impact not one, but nearly every disease that impacts humankind. We have the major goal of identifying molecular “switches” that can be thrown to turn back the clock on the aging process, promoting healthy aging and staving off aging-associated diseases.
Alexander Soukas, MD, PhD
Associate Professor of Medicine, Harvard Medical School
David A. Sweetser MD, PhD
Pediatrician, Massachusetts General Hospital
Assistant Professor of Pediatrics, Harvard Medical School
The Sweetser Lab has two areas of focus. One is rare disease work. Our work with the Undiagnosed Diseases Network takes a deep dive into phenotyping, evaluations, and genome sequencing, and functional characterization to identify novel genetic disorders. We also have focused projects in Pitt Hopkins syndrome, IQSEC2, and epileptic encephalopathies with Natural History studies and creating patient derived stem cell models. The second area of research seeks to characterize the leukemic stem cell niche and develop targeted cancer therapies.
David A. Sweetser MD, PhD
Assistant Professor of Pediatrics, Harvard Medical School
Michael E. Talkowski, PhD
Associate Investigator, Massachusetts General Hospital
Associate Professor of Neurology, Harvard Medical School
The Talkowski lab integrates molecular and computational genomics methods to study the genetic etiology of disorders affecting prenatal, neonatal, and early childhood development, as well as neurodevelopmental and psychiatric disorders. Our lab is also interested in variant-to-function studies to understand genomic perturbations to regulatory pathways in rare diseases and the applications of emerging technologies to clinical diagnostic screening.
Michael E. Talkowski, PhD
Director, CGM; Associate Professor of Neurology, Harvard Medical School
Miriam Udler, MD, PhD
Assistant Professor, Harvard Medical School
Attending in Endocrinology, Massachusetts General Hospital
Director, MGH Diabetes Genetics Clinic
We focus on advancing precision diagnosis and management of metabolic diseases.
Miriam Udler, MD, PhD
Attending in Endocrinology, Massachusetts General Hospital
Vanessa C. Wheeler, PhD
Research Geneticist, Massachusetts General Hospital
Associate Professor of Neurology, Harvard Medical School
Repeat expansion diseases such as Huntington’s disease (HD) are characterized by the instability of their causative repeat mutations. The inherited repeat undergoes further somatic expansion that drives disease pathogenesis. Our lab uses patients and model systems to characterize and uncover the underlying modifiers and mechanisms of repeat instability in order to identify targets for disease-modifying therapies.
Vanessa C. Wheeler, PhD
Associate Professor of Neurology, Harvard Medical School
The Center for Genomic Medicine (CGM) comprises one of the largest and most vibrant hubs of genomic medicine research in the world. The CGM includes 46 faculty collaborating to define the ‘genomic medicine cycle’ – which envisages a genomics community seeking to advance research from basic genomics research to ultimately using genome information for diagnostics and targeted therapeutics. All of our investigators are faculty at Harvard Medical School, and many members of our community are also investigators at the Broad Institute of Harvard and MIT.
