Populations to Variants

Populations to Variants2024-07-02T14:09:11-04:00

Describes comprehensive identification of human genetic variation (agnostic to disease process or phenotype).

News | Population to Variants

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 | Population to Variants

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

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

Brian G. Skotko, MD, MPP

Categories: Populations to Variants
Harvard Medical School: Associate Professor of Pediatrics
Massachusetts General Hospital: Director, Down Syndrome Program
Director, Down Syndrome Program, Massachusetts General Hospital
Associate Professor of Pediatrics, Harvard Medical School

We are a research team composed of enthusiastic healthcare providers committed to innovation in Down syndrome research. Our team is motivated to offer research opportunities that can help maximize the life potential for all people with Down syndrome. Working collaboratively with researchers around the globe, we are dedicated to advancing our shared understanding of biological processes associated with Down syndrome. To this extent, we are proud to offer families a portfolio of research opportunities.

Brian G. Skotko, MD, MPP

Associate Professor of Pediatrics, 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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