scholarly journals Assessing computational variant effect predictors with a large prospective cohort

2021 ◽  
Author(s):  
Da Kuang ◽  
Roujia Li ◽  
Yingzhou Wu ◽  
Jochen Weile ◽  
Robert A. Hegele ◽  
...  
Keyword(s):  
Performance Measures ◽  
Genetic Variants ◽  
Prospective Cohort ◽  
Missense Variant ◽  
Uk Biobank ◽  
High Quality ◽  
Whole Exome ◽  
Unbiased Test ◽  
Variant Effect ◽  
Large Prospective Cohort

Computational predictors can help interpret pathogenicity of human genetic variants, especially for the majority of variants where no experimental data are available. However, because we lack a high-quality unbiased test set, identifying the best-performing predictors remains a challenge. To address this issue, we evaluated missense variant effect predictors using genotypes and traits from a prospective cohort. We considered 139 gene-trait combinations with rare-variant burden association based on at least one of four systematic studies using phenotypes and whole-exome sequences from ~200K UK Biobank participants. Using an evaluation set of 35,525 rare missense variants and the relevant associated traits, we assessed the correlation of participants' traits with scores derived from 20 computational variant effect predictors. We found that two predictors—VARITY and REVEL—outperformed all others according to multiple performance measures. We expect that this study will help in selecting variant effect predictors, for both research and clinical purposes, while providing an unbiased benchmarking strategy that can be applied to additional cohorts and predictors.

scholarly journals Transthyretin-stabilizing mutation T119M is not associated with protection against vascular disease or death in the UK Biobank

2019 ◽  
Author(s):  
Margaret M. Parker ◽  
Simina Ticau ◽  
James Butler ◽  
David Erbe ◽  
Madeline Merkel ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Cerebrovascular Disease ◽  
Vascular Disease ◽  
Prospective Cohort ◽  
Proportional Hazards ◽  
Disease Diagnosis ◽  
Cox Proportional Hazards ◽  
Uk Biobank ◽  
The Uk ◽  
Large Prospective Cohort

AbstractBackgroundDestabilized transthyretin (TTR) can result in the progressive, fatal disease transthyretin-mediated (ATTR) amyloidosis. A stabilizing TTR mutation, T119M, is the basis for a therapeutic strategy to reduce destabilized TTR. Recently, T119M was associated with extended lifespan and lower risk of cerebrovascular disease in a Danish cohort. We aimed to determine whether this finding could be replicated in the UK Biobank.MethodsTTR T119M carriers were identified in the UK Biobank, a large prospective cohort of ∼500,000 individuals. Association between T119M genotype and inpatient diagnosis of vascular disease, cardiovascular disease, cerebrovascular disease, and mortality was analyzed.ResultsFrequency of T119M within the white UK Biobank population (n=337,148) was 0.4%. Logistic regression comparing T119M carriers to non-carriers found no association between T119M and vascular disease (odds ratio [OR]=1.08; p=.27), cardiovascular disease (OR=1.08; p=.31), cerebrovascular disease (OR=1.1; p=.42), or death (OR=1.2; p=.06). Cox proportional hazards regression showed similar results (hazard ratio>1, p>.05). Age at death and vascular disease diagnosis were similar between T119M carriers and non-carriers (p=.12 and p=.38, respectively).ConclusionsThere was no association between the TTR T119M genotype and risk of vascular disease or death in a large prospective cohort study, indicating that TTR tetramer stabilization through T119M is not protective in this setting.

scholarly journals A proactive genotype-to-patient-phenotype map for cystathionine beta-synthase

2018 ◽  
Author(s):  
Song Sun ◽  
Jochen Weile ◽  
Marta Verby ◽  
Atina G. Cote ◽  
Yingzhou Wu ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Rare Variants ◽  
Missense Variant ◽  
Response To Therapy ◽  
Yeast Cells ◽  
Vitamin B ◽  
Patient Response ◽  
Cystathionine Beta Synthase ◽  
Growth Selection ◽  
Variant Effect

AbstractSuccess in precision medicine depends on our ability to determine which rare human genetic variants have functional effects. Classical homocystinuria—characterized by elevated homocyst(e)ine in plasma and urine—is caused by primarily-rare variants in the cystathionine beta-synthase (CBS) gene. About half of patients respond to vitamin B6 therapy. With early detection in newborns, existing therapies are highly effective. Functional CBS variants, especially those that respond to vitamin B6, can be detected based on their ability to restore growth in yeast cells lacking CYS4 (the yeast ortholog of CBS). This assay has previously been carried out only ‘reactively’ after first observation of a variant in patients. Here we describe a ‘proactive’ comprehensive missense variant effect map for human CBS. Together, saturation codon-replacement mutagenesis, en masse growth selection at different vitamin B6 levels, and sequencing yielded a ‘look-up table’ for CBS missense variant function and vitamin B6-remediability in yeast. The CBS variant effect map identified disease variants and predicted both disease severity (r = 0.82) and human clinical response to vitamin B6 (r = 0.89). Thus, highly-multiplexed cell-based assays can yield proactive maps of variant function and patient response to therapy, even for rare variants not previously seen in the clinic.

scholarly journals The burden of rare protein-truncating genetic variants on human lifespan

2020 ◽  
Author(s):  
Jimmy Z. Liu ◽  
Chia-Yen Chen ◽  
Ellen A. Tsai ◽  
Christopher D. Whelan ◽  
David Sexton ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Complex Traits ◽  
Gene Loss ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
Loss Of Function ◽  
Human Lifespan ◽  
Genome Wide ◽  
Whole Exome

AbstractGenetic predisposition is believed to contribute substantially to the age at which we die. Genome-wide association studies (GWAS) have implicated more than 20 genetic loci to phenotypes related to human lifespan1. However, little is known about how lifespan is impacted by gene loss-of-function. Through whole-exome sequencing of 238,239 UK Biobank participants, we assessed the relevance of protein-truncating variant (PTV) gene burden on individual and parental survival. We identified exome-wide (P<2.5e-6) significant associations between BRCA2, BRCA1, TET2, PPM1D, LDLR, EML2 and DEDD2 PTV-burden with human lifespan. Gene and gene-set PTV-burden phenome-wide association studies (PheWAS) further highlighted the roles of these genes in cancer and cardiovascular disease as relevant for overall survival. The overlap between PTV-burden and prior GWAS results was modest, underscoring the value of sequencing in well-powered cohorts to complement GWAS for identifying loci associated with complex traits and disease.

scholarly journals Neonatal case of dilated cardiomyopathy associated with novel MYH7 and TBX5 genetic variants

2020 ◽  
pp. 16-17
Author(s):  
А.М. Злотина ◽  
Ю.В. Фомичева ◽  
Т.Л. Вершинина ◽  
А.А. Козырева ◽  
А.М. Киселёв ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Genetic Variants ◽  
High Throughput Sequencing ◽  
Heart Defects ◽  
Missense Variant ◽  
Sequencing Technology ◽  
Full Spectrum ◽  
T Box ◽  
Whole Exome ◽  
Family Medical History

В настоящем исследовании описан новый случай выраженной дилатационной кардиомиопатии (ДКМП) с ранним дебютом. В семейном анамнезе присутствуют как фенотипы ДКМП разной степени тяжести, так и врожденные структурные пороки сердца. С использованием технологии высокопроизводительного секвенирования был охарактеризован полный спектр генетических вариантов в экзоме пациентки. В результате анализа выявлен новый вероятно-патогенный миссенс вариант в гене MYH7, кодирующем бета тяжелую цепь сердечного миозина (экзон 27, c.G3578T, p.R1193L). Кроме того, найден новый миссенс вариант с неопределенной клинической значимостью в гене TBX5, кодирующем транскрипционный фактор T-box 5 (экзон 7, c.T988A, p.C330S, ENST00000526441). Полученные данные свидетельствуют о том, что комбинация двух генетических вариантов в кардиальных генах может приводить к усилению клинического фенотипа ДКМП. In the present study we report on a new case of severe early-onset dilated cardiomyopathy (DCM). In family medical history, both DCM phenotypes of different expressivity and congenital structural heart defects (CHDs) were revealed. Using high-throughput sequencing technology, we analyzed a full spectrum of genetic variants in the proband`s exome. On the results of whole-exome sequencing, we identified a novel likely-pathogenic missense variant in MYH7 encoding beta heavy chain of cardiac myosin (exon 27, c.G3578T, p.R1193L). Additionally, the proband possessed a novel missense variant of uncertain clinical significance in TBX5 (exon 7, c.T988A, p.C330S, ENST00000526441). The data obtained suggest that combination of two genetic variants in cardiac genes could cause the deterioration of the DCM clinical phenotype.

scholarly journals Genetic predictors of participation in optional components of UK Biobank

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jessica Tyrrell ◽  
Jie Zheng ◽  
Robin Beaumont ◽  
Kathryn Hinton ◽  
Tom G. Richardson ◽  
...  
Keyword(s):  
Sensitivity Analysis ◽  
Genetic Variants ◽  
Genetic Factors ◽  
Mendelian Randomization ◽  
Genetic Correlations ◽  
Mr Studies ◽  
Uk Biobank ◽  
Factors Affecting ◽  
Participation Bias ◽  
Genetic Predictors

AbstractLarge studies such as UK Biobank are increasingly used for GWAS and Mendelian randomization (MR) studies. However, selection into and dropout from studies may bias genetic and phenotypic associations. We examine genetic factors affecting participation in four optional components in up to 451,306 UK Biobank participants. We used GWAS to identify genetic variants associated with participation, MR to estimate effects of phenotypes on participation, and genetic correlations to compare participation bias across different studies. 32 variants were associated with participation in one of the optional components (P < 6 × 10−9), including loci with links to intelligence and Alzheimer’s disease. Genetic correlations demonstrated that participation bias was common across studies. MR showed that longer educational duration, older menarche and taller stature increased participation, whilst higher levels of adiposity, dyslipidaemia, neuroticism, Alzheimer’s and schizophrenia reduced participation. Our effect estimates can be used for sensitivity analysis to account for selective participation biases in genetic or non-genetic analyses.

scholarly journals Body composition and risk of major gynecologic malignancies: Results from the UK Biobank prospective cohort

2021 ◽  
Author(s):  
Peng Yun ◽  
Bin Xia ◽  
Xiao‐hui Tian ◽  
Ting Gong ◽  
An‐ran Liu ◽  
...  
Keyword(s):  
Body Composition ◽  
Prospective Cohort ◽  
Uk Biobank ◽  
Gynecologic Malignancies ◽  
The Uk
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