Jack A. Kosmicki's research while affiliated with Regeneron and other places
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Publications (112)
Missense variants can have a range of functional impacts depending on factors such as the specific amino acid substitution and location within the gene. To interpret their deleteriousness, studies have sought to identify regions within genes that are specifically intolerant of missense variation. Here, we leverage the patterns of rare missense vari...
The Mexico City Prospective Study is a prospective cohort of more than 150,000 adults recruited two decades ago from the urban districts of Coyoacán and Iztapalapa in Mexico City ¹ . Here we generated genotype and exome-sequencing data for all individuals and whole-genome sequencing data for 9,950 selected individuals. We describe high levels of re...
In this study, we leveraged the combined evidence of rare coding variants and common alleles to identify therapeutic targets for osteoporosis. We undertook a large-scale multiancestry exome-wide association study for estimated bone mineral density, which showed that the burden of rare coding alleles in 19 genes was associated with estimated bone mi...
Gene-based burden tests are a popular and powerful approach for analysis of exome-wide association studies. These approaches combine sets of variants within a gene into a single burden score that is then tested for association. Typically, a range of burden scores are calculated and tested across a range of annotation classes and frequency bins. Cor...
Clonal haematopoiesis involves the expansion of certain blood cell lineages and has been associated with ageing and adverse health outcomes1–5. Here we use exome sequence data on 628,388 individuals to identify 40,208 carriers of clonal haematopoiesis of indeterminate potential (CHIP). Using genome-wide and exome-wide association analyses, we ident...
Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare vari...
Background
Up to one of every six individuals diagnosed with one cancer will be diagnosed with a second primary cancer in their lifetime. Genetic factors contributing to the development of multiple primary cancers, beyond known cancer syndromes, have been underexplored.
Methods
To characterize genetic susceptibility to multiple cancers, we conduct...
Glaucoma is a leading cause of blindness. Current glaucoma medications work by lowering intraocular pressure (IOP), a risk factor for glaucoma, but most treatments do not directly target the pathological changes leading to increased IOP, which can manifest as medication resistance as disease progresses. To identify physiological modulators of IOP,...
Enlargement of the aorta is an important risk factor for aortic aneurysm and dissection, a leading cause of morbidity in the developed world. Here we performed automated extraction of ascending aortic diameter from cardiac magnetic resonance images of 36,021 individuals from the UK Biobank, followed by genome-wide association. We identified lead va...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters human host cells via angiotensin-converting enzyme 2 (ACE2) and causes coronavirus disease 2019 (COVID-19). Here, through a genome-wide association study, we identify a variant (rs190509934, minor allele frequency 0.2–2%) that downregulates ACE2 expression by 37% (P = 2.7 × 10−8) a...
Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare vari...
Critical Covid-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalisation2–4 following SARS-CoV-2 infection. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from critically-ill cases with population c...
Background
Open-label platform trials and a prospective meta-analysis suggest efficacy of anti–IL-6R therapies in hospitalized patients with COVID-19 receiving corticosteroids. This study evaluated the efficacy and safety of sarilumab, an anti–IL-6R monoclonal antibody, in the treatment of hospitalized patients with COVID-19.
Methods
In this adapt...
Clonal hematopoiesis (CH) refers to the expansion of certain blood cell lineages and has been associated with aging and adverse health outcomes. Here, we use exome sequence data on 628,388 individuals to identify 40,208 carriers of clonal hematopoiesis of indeterminate potential (CHIP). Using genome-wide and exome-wide association analyses, we iden...
A major goal in human genetics is to use natural variation to understand the phenotypic consequences of altering each protein-coding gene in the genome. Here we used exome sequencing1 to explore protein altering variants and their consequences in 454,787 UK Biobank study participants2. We identified 12 million coding variants, including ~1 million...
Purpose:
Birdshot chorioretinopathy (BSCR) is strongly associated with HLA-A29. This study was designed to elucidate the genetic modifiers of BSCR in HLA-A29 carriers.
Methods:
We sequenced the largest BSCR cohort to date, including 286 cases and 108 HLA-A29-positive controls to determine genome-wide common and rare variant associations. We furt...
Purpose: Birdshot Chorioretinopathy (BSCR) is strongly associated with HLA-A29. This study was designed to elucidate the genetic modifiers of BSCR in HLA-A29 carriers.
Methods: We sequenced the largest BSCR cohort to date, including 286 cases and 108 HLA-A29 positive controls to perform genome wide common and rare variant associations. We further t...
How genes affect human obesity
Obesity is linked to many human diseases, including diabetes, cancer, and heart disease. There is thus great interest in understanding how genes predispose individuals to, or protect individuals from, obesity. Akbari et al. sequenced more than 600,000 exomes from the United Kingdom, the United States, and Mexico and i...
Genome-wide association analysis of cohorts with thousands of phenotypes is computationally expensive, particularly when accounting for sample relatedness or population structure. Here we present a novel machine-learning method called REGENIE for fitting a whole-genome regression model for quantitative and binary phenotypes that is substantially fa...
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease-19 (COVID-19), a respiratory illness that can result in hospitalization or death. We used exome-sequence data to investigate associations between rare genetic variants and seven COVID-19 outcomes in 586,157 individuals, including 20,952 with COVID-19. After acco...
BACKGROUND
Sarilumab (anti-interleukin-6 receptor-alpha; monoclonal antibody) may attenuate the inflammatory response in Covid-19.
METHODS
We performed an adaptive, phase 2/3, randomized, double-blind, placebo-controlled trial of intravenous sarilumab 200 mg or 400 mg in adults hospitalized with Covid-19. The phase 3 primary analysis population (co...
A Correction to this paper has been published: https://doi.org/10.1038/s41586-020-03175-7
In this Article, author Marquis P. Vawter was missing from the Genome Aggregation Database Consortium list. They are associated with the affiliation: ‘Department of Psychiatry & Human Behavior, University of California Irvine, Irvine, CA, USA’, and contributed to the generation of the primary data incorporated into the gnomAD resource. The original...
In this Article, author Marquis P. Vawter was missing from the Genome Aggregation Database Consortium list. They are associated with the affiliation: ‘Department of Psychiatry & Human Behavior, University of California Irvine, Irvine, CA, USA’, and contributed to the generation of the primary data incorporated into the gnomAD resource. In addition,...
The need to identify and effectively treat COVID-19 cases at highest risk for severe disease is critical. We identified seven common genetic variants (three novel) that modulate COVID-19 susceptibility and severity, implicating IFNAR2, CCHCR1, TCF19, SLC6A20 and the hyaluronan pathway as potential therapeutic targets. A high genetic burden was stro...
A major challenge in genetic association studies is that most associated variants fall in the non-coding part of the human genome. We searched for variants associated with bone mineral density (BMD) after enriching the discovery cohort for loss-of-function (LoF) mutations by sequencing a subset of the Nord-Trøndelag Health Study, followed by imputa...
Background Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes Coronavirus disease-19 (COVID-19), a respiratory illness with influenza-like symptoms that can result in hospitalization or death. We investigated human genetic determinants of COVID-19 risk and severity in 455,838 UK Biobank participants, including 2,003 with COVID-19.M...
Genome-wide association analysis of cohorts with thousands of phenotypes is computationally expensive, particularly when accounting for sample relatedness or population structure. Here we present a novel machine learning method called REGENIE for fitting a whole genome regression model that is orders of magnitude faster than alternatives, while mai...
Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences of gene disruption: genes that are crucial for the function of an organism will be depleted of such variants in natural populations, whereas non-essential genes will tolerate their accumulation. However, predicted loss-of-fun...
The acceleration of DNA sequencing in samples from patients and population studies has resulted in extensive catalogues of human genetic variation, but the interpretation of rare genetic variants remains problematic. A notable example of this challenge is the existence of disruptive variants in dosage-sensitive disease genes, even in apparently hea...
Alterations in non-driver genes represent an emerging class of potential therapeutic targets in cancer. Hundreds to thousands of non-driver genes undergo loss of heterozygosity (LOH) events per tumor, generating discrete differences between tumor and normal cells. Here we interrogate LOH of polymorphisms in essential genes as a novel class of thera...
Background: Classifying pathogenicity of missense variants represents a major challenge in clinical practice during the diagnoses of rare and genetic heterogeneous neurodevelopmental disorders (NDDs). While orthologous gene conservation is commonly employed in variant annotation, approximately 80% of known disease-associated genes belong to gene fa...
Protein-coding de novo mutations (DNMs) are significant risk factors in many neurodevelopmental disorders, whereas schizophrenia (SCZ) risk associated with DNMs has thus far been shown to be modest. We analyzed DNMs from 1,695 SCZ-affected trios and 1,077 published SCZ-affected trios to better understand the contribution to SCZ risk. Among 2,772 SC...
(Abstracted from Nat Comm 2019;10:3043)
Epidemiologic associations have been made between advanced paternal age and increased offspring risk of autism spectrum disorder (ASD), schizophrenia (SCZ), congenital heart disease (CHD), epilepsy (EPI), and intellectual disability (ID). This association have been often attributed to de novo single nucleotid...
We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n = 35,584 total samples, 11,986 with ASD). Using an enhanced analytical framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate of 0.1 or less. Of these genes, 49 show higher frequencies of disruptiv...
The exome sequences of approximately 8,000 children with autism spectrum disorder (ASD) and/or attention deficit hyperactivity disorder (ADHD) and 5,000 controls were analyzed, finding that individuals with ASD and individuals with ADHD had a similar burden of rare protein-truncating variants in evolutionarily constrained genes, both significantly...
There are established associations between advanced paternal age and offspring risk for psychiatric and developmental disorders. These are commonly attributed to genetic mutations, especially de novo single nucleotide variants (dnSNVs), that accumulate with increasing paternal age. However, the actual magnitude of risk from such mutations in the ma...
The fate of alleles in the human population is believed to be highly affected by the stochastic force of genetic drift. Estimation of the strength of natural selection in humans generally necessitates a careful modeling of drift including complex effects of the population history and structure. Protein-truncating variants (PTVs) are expected to evo...
The acceleration of DNA sequencing in patients and population samples has resulted in unprecedented catalogues of human genetic variation, but the interpretation of rare genetic variants discovered using such technologies remains extremely challenging. A striking example of this challenge is the existence of disruptive variants in dosage-sensitive...
In the version of this article originally published, the name of author Serafim Batzoglou was misspelled. The error has been corrected in the HTML and PDF versions of the article.
Alterations in non-driver genes represent an emerging class of potential therapeutic targets in cancer. Hundreds to thousands of non-driver genes undergo loss of heterozygosity (LOH) events per tumor, generating discrete differences between tumor and normal cells. Here we interrogate LOH of polymorphisms in essential genes as a novel class of thera...
Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences of gene disruption: genes critical for an organism's function will be depleted for such variants in natural populations, while non-essential genes will tolerate their accumulation. However, predicted loss-of-function (pLoF) v...
The splicing of pre-mRNAs into mature transcripts is remarkable for its precision, but the mechanisms by which the cellular machinery achieves such specificity are incompletely understood. Here, we describe a deep neural network that accurately predicts splice junctions from an arbitrary pre-mRNA transcript sequence, enabling precise prediction of...
We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n = 35,584 total samples, 11,986 with ASD). Using an enhanced analytical framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate of 0.1 or less. Of these genes, 49 show higher frequencies of disruptiv...
Background
Studies of de novo variation, which is identified by exome sequencing parent-offspring families, have successfully identified over 100 genes associated with neurodevelopmental disorders, most notably intellectual disability / developmental delay (ID/DD) or autism spectrum disorders (ASDs). Mutations in the genes first discovered in de no...
Protein-coding de novo mutations (DNMs) in the form of single nucleotide changes and short insertions/deletions are significant genetic risk factors for autism, intellectual disability, developmental delay, and epileptic encephalopathy. In contrast, the burden of DNMs has thus far only had a modest documented impact on schizophrenia (SCZ) risk. Her...
We present the largest exome sequencing study to date focused on rare variation in autism spectrum disorder (ASD) (n=35,584). Integrating de novo and case-control variation with an enhanced Bayesian framework incorporating evolutionary constraint against mutation, we implicate 99 genes in ASD risk at a false discovery rate (FDR) ≤ 0.1. Of these 99...
The fate of alleles in the human population is believed to be highly affected by the stochastic force of genetic drift. Estimation of the strength of natural selection in humans generally necessitates a careful modeling of drift including complex effects of the population history and structure. Protein truncating variants (PTVs) are expected to evo...
Millions of human genomes and exomes have been sequenced, but their clinical applications remain limited due to the difficulty of distinguishing disease-causing mutations from benign genetic variation. Here we demonstrate that common missense variants in other primate species are largely clinically benign in human, enabling pathogenic mutations to...
Despite progress in precision cancer drug discovery, few highly selective therapies exist in the clinic, creating the need for additional therapeutic targets. We have shown that copy number alterations (CNAs) in essential genes represent novel non-driver gene vulnerabilities in cancer. Here we interrogate loss of heterozygosity (LOH) of single nucl...
Epilepsy is a frequent feature of neurodevelopmental disorders (NDDs), but little is known about genetic differences between NDDs with and without epilepsy. We analyzed de novo variants (DNVs) in 6,753 parent–offspring trios ascertained to have different NDDs. In the subset of 1,942 individuals with NDDs with epilepsy, we identified 33 genes with a...
Epilepsy is a frequent feature of neurodevelopmental disorders (NDD) but little is known about genetic differences between NDD with and without epilepsy. We analyzed de novo variants (DNV) in 6753 parent-offspring trios ascertained for different NDD. In the subset of 1942 individuals with NDD with epilepsy, we identified 33 genes with a significant...
Background
There are well-established epidemiologic associations between advanced paternal age and increased offspring risk for several psychiatric and developmental disorders. These associations are commonly attributed to age-related de novo mutations. However, the actual magnitude of risk conferred by age-related de novo mutations in the male ger...
Based on targeted sequencing of 208 genes in 11,730 neurodevelopmental disorder cases, Stessman et al. report the identification of 91 genes associated (at a False Discovery Rate [FDR] of 0.1) with autism spectrum disorders (ASD), intellectual disability (ID), and developmental delay (DD)-including what they characterize as 38 novel genes, not prev...
Differentiating risk-conferring from benign missense variants, and therefore optimal calculation of gene-variant burden, represent a major challenge in particular for rare and genetic heterogeneous disorders. While orthologous gene conservation is commonly employed in variant annotation, approximately 80% of known disease-associated genes are paral...
Given increasing numbers of patients who are undergoing exome or genome sequencing, it is critical to establish tools and methods to interpret the impact of genetic variation. While the ability to predict deleteriousness for any given variant is limited, missense variants remain a particularly challenging class of variation to interpret, since they...
Autism spectrum disorder (ASD) risk is influenced by common polygenic and de novo variation. We aimed to clarify the influence of polygenic risk for ASD and to identify subgroups of ASD cases, including those with strongly acting de novo variants, in which polygenic risk is relevant. Using a novel approach called the polygenic transmission disequil...
Recent research has uncovered an important role for de novo variation in neurodevelopmental disorders. Using aggregated data from 9,246 families with autism spectrum disorder, intellectual disability, or developmental delay, we found that ∼1/3 of de novo variants are independently present as standing variation in the Exome Aggregation Consortium's...
Recent research has uncovered an important role for de novo variation in neurodevelopmental disorders. Using aggregated data from 9246 families with autism spectrum disorder, intellectual disability, or developmental delay, we show ~1/3 of de novo variants are independently observed as standing variation in the Exome Aggregation Consortium’s cohort...
Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortiu...
With the rise of sequencing technologies, it is now feasible to assess the role rare variants play in the genetic contribution to complex trait variation. While some of the earlier targeted sequencing studies successfully identified rare variants of large effect, unbiased gene discovery using exome sequencing has experienced limited success for com...
Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) sequence data for 60,706 individuals of diverse ethnicities generated as part of the Exome Aggregation Consortium (...
Almost all genetic risk factors for autism spectrum disorders (ASDs) can be found in the general population, but the effects of this risk are unclear in people not ascertained for neuropsychiatric symptoms. Using several large ASD consortium and population-based resources (total n > 38,000), we find genome-wide genetic links between ASDs and typica...
Almost all genetic risk factors for autism spectrum disorders (ASDs) can be found in the general population, but the effects of that risk are unclear in people not ascertained for neuropsychiatric symptoms. Using several large ASD consortia and population based resources, we find genetic links between ASDs and typical variation in social behavior a...
Citations
... This study utilised two population sequencing datasets to gather genomic variants in various ancestries -gnomAD v4.1 11 and Mexico City Prospective Study (MCPS) 12 . Only single nucleotide variants with a "PASS" quality filter were extracted from the variant calling files provided by the two projects. ...
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... Such knowledge should allow obvious problems like bone loss to be ameliorated without deleterious off-target effects on other organ systems. In Earth gravity, it is well established that susceptibility to bone loss and osteoporotic fractures is genetically linked [238][239][240][241]. Genetic links have also been identified for susceptibility to the medicine-related osteonecrosis of the jaw (MRONJ), a pathology that occurs when people are treated with antiresorptives, including bisphosphonates and denosumab [242]. ...
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... Summary statistics used to derive the CHIP instrument were from a large discovery GWAS of 628,388 individuals from the UK Biobank and Geisinger MyCode Community Health Initiative (GHS). 30 Genetic instruments were independent GWAS-significant SNPs (p<5x10 -8 ) for any CHIP that were clumped at an r 2 of less than 0.1. Summary data for the association of the genetic instruments with eGFR decline were extracted from a meta-analysis of GWAS of eGFR decline among 116,870 participants with CKD (defined by two outpatient eGFR measurements of < 60 ml/min/1.73m 2 ) from the Million Veteran Program and BioVU 28 , wherein eGFR decline was defined using the annualized relative slope in outpatient eGFR. ...
... Most of the variants identified in our study have allele frequencies (< 1%). A growing number of studies support the key role of rare variants in causing susceptibility/severity to COVID-19 12,[26][27][28][29][30][31][32] . Thus, apart from common variants in East Asian and African population, rare variants predicted from various other populations are predicted to be affinity-enhancing, which could affect COVID-19 susceptibility and cause increased risk of infection in individuals carrying them. ...
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... However, simultaneous sequencing of somatic and germline mutations may prove vital for investigating the interplay between the context of susceptibility genes and distinct tumor combinations. [16] Herein, we present a rare case of metachronous MPCs, including esophageal cancer followed by extensive-stage small cell lung cancer 6 years later. Small cell lung carcinoma is a highly aggressive type of cancer, characterized by rapid growth and early metastasis. ...
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... In line with these observations, ANGPTL7 is highly expressed in TM cells, the prominent cell type in the conventional outflow tract. [4][5][6] Variants that destabilize ANGPTL7 and decrease the secretion of ANGPTL7 are associated with reduced IOP, 7 and increased levels of secreted ANGPTL7 have been found in the aqueous humor of human patients with glaucoma compared to controls. 8 In addition, ANGPTL7 gene expression has been shown to increase in response to stressors associated with glaucoma pathobiology, including the glucocorticoid dexamethasone (Dex) and transforming growth factor-β. ...
Reference: ANGPTL7 and Its Role in IOP and Glaucoma
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... Two variants were pLoF on a non-canonical transcript that was poorly expressed across tissues, 21 and intronic on the MANE Select transcript. Whilst one option would be to limit our method to variants on the MANE Select and MANE Plus Clinical transcripts, this is potentially problematic not all genes have been curated to define additional transcripts to be included in the MANE Plus Clinical resource. ...
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... It is known that SARS-CoV-2 infects epithelial cells in the nasopharynx via the angiotensin-converting enzyme 2 (ACE2) receptor [90]. Previous genome-wide association studies (GWASs) suggested that a variant upstream of the ACE2 gene may be associated with susceptibility to SARS-CoV-2 infection [91,92]. In addition, GWASs have been conducted to explore the genetic variants associated with the severity of COVID-19 in addition to susceptibility to SARS-CoV-2 [93]. ...
Reference: TAFRO Syndrome and COVID-19
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... In the past decade, GWAS have made significant advancements in identifying genetic variants associated with CAD 8,45,46 . However, the translation of this knowledge into functional validation and mechanistic insights remains a challenging task. ...
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... In addition to GWAS and the associated data, TLR7 located in the X chromosome was considered a potential monogenic cause that predisposed young male patients without comorbidities to severe COVID-19 [13,14]. The most recent research from 21 cohorts across 12 countries also reported that rare, deleterious TLR7 variants are risk factors that predisposed the severity of COVID-19 (13.1-fold increase) [15]. ...
