Variants to Diseases & Traits

Variants to Diseases & Traits2024-07-02T14:11:11-04:00

Process of associating human genetic variation that has been identified with specific traits, including diseases or wellness.

News | Variants to Disease & Traits

Mono- and biallelic variant effects on disease at biobank scale

Identifying causal factors for Mendelian and common diseases is an ongoing challenge in medical genetics. Population bottleneck events, such as those that occurred in the history of the Finnish population, enrich some homozygous variants to higher frequencies, which facilitates the identification of variants that cause diseases with recessive inheritance. In this work published in Nature by CGM Investigators Mark Daly, Aarno Palotie, Heidi Rehm, and colleagues, the richness of FinnGen was leveraged to examine homozygous and heterozygous effects of 44,370 coding variants on 2,444 disease phenotypes using data from the nationwide electronic health records of 176,899 Finnish individuals. They found associations for homozygous genotypes across a broad spectrum of phenotypes, including recessive disease associations that would have been missed by the additive model that is typically used in genome-wide association studies. Importantly, the group also found variants that are known to cause diseases with recessive inheritance with significant heterozygous phenotypic effects, and presumed benign variants with disease effects. This work powerfully illuminates how biobanks, particularly in founder populations, can broaden our understanding of complex dosage effects of Mendelian variants on disease.

Read more in Nature

February 21, 2023

Publication

CGM Primary Investigators

Mark Daly

Aarno Palotie

Heidi Rehm

February 21, 2023|

Polygenic architecture of rare coding variation across 394,783 exomes

Both common and rare genetic variants influence complex traits and common diseases. Genome-wide association studies have identified thousands of common-variant associations, and more recently, large-scale exome sequencing studies have identified rare-variant associations in hundreds of genes. However, rare-variant genetic architecture is not well characterized, and the relationship between common-variant and rare-variant architecture is unclear. In this manuscript in Nature, CGM investigators Konrad Karczewski, Elise Robinson, and Ben Neale leverage the UK biobank exomes resource to quantify the heritability explained by the gene-wise burden of rare coding variants across 22 common traits and diseases in 394,783 exomes. In this analysis, rare coding variants explain 1.3% of phenotypic variance on average. This variance is much less than that explained by common variants-and most burden heritability is explained by ultrarare loss-of-function variants (allele frequency < 1 × 10-5). Overall, the results indicate that common and rare associations are mechanistically convergent, and that rare coding variants will contribute only modestly to missing heritability and population risk stratification.

Read more in Nature

February 20, 2023

Publication

CGM Primary Investigators

February 20, 2023|

A cross-disorder dosage sensitivity map of the human genome

Large copy number variants (CNVs) are strong risk factors for human developmental disorders, yet interpretation of their functional consequences remains a considerable challenge, particularly for partial or complete duplication of a gene. Here, CGM Investigators Mike Talkowski and Harrison Brand jointly analyzed genetic data from nearly one-million individuals across 54 disorders to produce a ‘dosage sensitivity’ map of human diseases. This catalog nominated 163 disease-relevant loci and used a machine learning approach to create dosage sensitive metrics (pHaplo and pTriplo) that predicted 2,987 genes intolerant to deletion and 1,559 triplosensitive genes that were intolerant to duplication. These metrics were openly distributed and have been integrated into the DECIPHER database.

Read more in Science Direct

December 21, 2022

Publication

CGM Primary Investigator

Mike Talkowski

Harrison Brand

December 21, 2022|

The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources

Documenting the evidence supporting the relationships between genes and disease is a critical element to enable clinical implementation of genes for rare disease diagnosis. The Gene Curation Coalition (GenCC), a large international consortium led by Heidi Rehm and Marina DiStefano, released their first paper on the GenCC’s work to build a public database (https://thegencc.org) of monogenic gene-disease relationships that have been curated using harmonized standards. The GenCC database functions like a “ClinVar for Genes” accepting and sharing submissions from the community (over 16,000 to date) and then facilitating discrepancy resolution through the collaborating GenCC members which includes ClinGen, OMIM, Orphanet, Genomics England, Australia Genomics, HUGO, and many private commercial testing labs.

To hear more about the GenCC, listen to the Genetics in Medicine GenePod podcast featuring an interview of Rehm and Marina DiStefano.

December 19, 2022

CGM Primary Investigator

Heidi Rehm
December 19, 2022|

SLALOM suggests caution with meta-analysis fine-mapping interpretation

After researchers combine multiple genome-wide association studies into a meta-analysis, they often seek causal variants using methods built for single-cohort studies. CGM PI’s Hilary FinucaneMark Daly, and colleagues showed that this fine-mapping approach is often miscalibrated due to heterogeneous characteristics of the individual cohorts, such as different genotyping arrays or imputation panels. They built a quality control method, SLALOM, and applied it to 14 disease endpoints from the Global Biobank Meta-analysis Initiative (GBMI), finding that 68 percent of fine-mapped loci showed signs of potential inaccuracy. The findings suggest caution when interpreting meta-analysis fine-mapping results until improved methods are available.

Read more in Cell Genomics and Masa Kanai’s tweetorial.

December 15, 2022

Publication

CGM Primary Investigator

December 15, 2022|

Faculty | Variants to Disease & Traits

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

Alicia Martin, PhD

Categories: Populations to Variants, Training Program Faculty, Variants to Diagnosis, Variants to Disease & Traits
Harvard Medical School: Assistant Professor of Medicine
Massachusetts General Hospital: Assistant Investigator
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

Heidi L. Rehm, PhD

Categories: Populations to Variants, Training Program Faculty, Variants to Diagnosis, Variants to Disease & Traits
Harvard Medical School: Professor of Pathology
Massachusetts General Hospital: Chief Genomics Officer
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

Elise B. Robinson, ScD

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

Our lab’s research focuses on the genetic epidemiology of behavior and cognition. We are interested in using genetic data to understand the biology of neurodevelopmental variation, and to study differences within and between neuropsychiatric disorders. The Robinson lab uses techniques from statistical genetics and epidemiology to study how common and rare genetic risk factors for severe neuropsychiatric disorders may differ and develops approaches for examining these questions in large samples.

Elise B. Robinson, ScD

Assistant Professor of Psychiatry, 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

Richa Saxena, PhD

Categories: Populations to Variants, Variants to Disease & Traits

Professor of Anesthesia, Harvard Medical School

Richa Saxena, PhD

Professor of Anesthesia, 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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