scholarly journals Exome sequencing of 628,388 individuals identifies common and rare variant associations with clonal hematopoiesis phenotypes

2022 ◽  
Author(s):  
Michael D Kessler ◽  
Amy Damask ◽  
Sean O'Keeffe ◽  
Michael Michael Van Meter ◽  
Nilanjana Banerjee ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Sequence Data ◽  
Subsequent Development ◽  
Repair Gene ◽  
Association Analyses ◽  
Clonal Hematopoiesis ◽  
Adverse Health Outcomes ◽  
Exome Sequence Data ◽  
Dna Repair Gene ◽  
The Uk

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 identify 27 loci (24 novel) where germline genetic variation influences CH/CHIP predisposition, including missense variants in the DNA-repair gene PARP1 and the lymphocytic antigen coding gene LY75 that are associated with reduced incidence of CH/CHIP. Analysis of 5,194 health traits from the UK Biobank (UKB) found relationships between CHIP and severe COVID outcomes, cardiovascular disease, hematologic traits, malignancy, smoking, obesity, infection, and all-cause mortality. Longitudinal analyses revealed that one of the CHIP subtypes, DNMT3A-CHIP, is associated with the subsequent development of myeloid but not lymphoid leukemias, and with solid cancers including prostate and lung. Additionally, contrary to previous findings from the initial 50,000 UKB exomes, our results in the full sample do not support a role for IL-6 inhibition in reducing the risk of cardiovascular disease among CHIP carriers. Our findings demonstrate that CHIP represents a complex set of heterogenous phenotypes with shared and unique germline genetic causes and varied clinical implications.

scholarly journals Analysis of exome-sequenced UK Biobank subjects implicates genes affecting risk of hyperlipidaemia

2020 ◽  
Author(s):  
David Curtis
Keyword(s):  
Rare Variants ◽  
Sequence Data ◽  
Lipid Lowering ◽  
P Value ◽  
Data Sets ◽  
Uk Biobank ◽  
Functional Studies ◽  
Exome Sequence Data ◽  
Rare Genetic Variants ◽  
The Uk

Rare genetic variants in LDLR, APOB and PCSK9 are known causes of familial hypercholesterolaemia and it is expected that rare variants in other genes will also have effects on hyperlipidaemia risk although such genes remain to be identified. The UK Biobank consists of a sample of 500,000 volunteers and exome sequence data is available for 50,000 of them. 11,490 of these were classified as hyperlipidaemia cases on the basis of having a relevant diagnosis recorded and/or taking lipid-lowering medication while the remaining 38,463 were treated as controls. Variants in each gene were assigned weights according to rarity and predicted impact and overall weighted burden scores were compared between cases and controls, including population principal components as covariates. One biologically plausible gene, HUWE1, produced statistically significant evidence for association after correction for testing 22,028 genes with a signed log10 p value (SLP) of -6.15, suggesting a protective effect of variants in this gene. Other genes with uncorrected p<0.001 are arguably also of interest, including LDLR (SLP=3.67), RBP2 (SLP=3.14), NPFFR1 (SLP=3.02) and ACOT9 (SLP=-3.19). Gene set analysis indicated that rare variants in genes involved in metabolism and energy can influence hyperlipidaemia risk. Overall, the results provide some leads which might be followed up with functional studies and which could be tested in additional data sets as these become available. This research has been conducted using the UK Biobank Resource.

Rare DNA repair gene mutations predispose to young onset and lethal prostate cancer in the UK

2018 ◽  
Vol 44 ◽  
pp. S23
Author(s):  
Rosalind Eeles ◽  
Daniel Leongamornlert ◽  
Edward Saunders ◽  
Sarah Wakerell ◽  
Ian Whitmore ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Gene Mutations ◽  
Repair Gene ◽  
Young Onset ◽  
Dna Repair Gene ◽  
The Uk ◽  
Lethal Prostate Cancer

Effect of germline ATM mutations on clonal hematopoiesis.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 1509-1509
Author(s):  
Thomas Paul Slavin ◽  
Kar Wing Kevin Tsang ◽  
Jeffrey Longmate ◽  
Danielle Castillo ◽  
Josef Herzog ◽  
...  
Keyword(s):  
Germline Mutation ◽  
White Blood Cells ◽  
Germline Mutations ◽  
Lymphocytic Leukemia ◽  
Repair Gene ◽  
Clonal Hematopoiesis ◽  
Mutation Carriers ◽  
Dna Repair Gene ◽  
Increased Risk ◽  
Allele Fraction

1509 Background: Clonal hematopoiesis (CH) in myeloid related-genes is associated with development of primary and secondary leukemia and atherosclerotic disease, as well as, decreased overall survival. Identification of factors beyond age and cytotoxic exposures that predispose to CH may be useful to both recognize individuals at increased risk for CH and to better understand how CH develops. We have previously shown that germline mutations in the DNA repair gene ATM may predispose to CH. We hypothesized here that heterozygous ATM germline mutation carriers would have higher rates of CH in myeloid genes compared to controls. Methods: Germline DNA samples from 34 heterozygous ATM germline mutation carriers (cases) and 22 controls without ATM germline mutations were sequenced on an Illumina 2500 using a custom 79-gene-myeloid-CH-coding-exon-amplicon-based Qiaseq panel. Read depth averaged 130x. Pathogenic and likely pathogenic CH variants (PV) above an allele fraction of 2% were used for analyses. Cases and controls were compared using a rank-sum test. Results: Cases had a higher median age (56 years, range 30-82) than controls (48 years, range 5-72). Cases and controls were similar in solid tumor cancer history and known exposure to cancer cytotoxic therapy; 73.5% vs 86.4%, and 18.1 vs 20.6%, respectively. The number of CH PV was similarly associated with age in both cases and controls (cor = 0.31, p = 0.01). Cases displayed more CH PVs than controls (total 62 vs 3 PVs, median 2 PVs vs 0, p = 10-6). Of note, cases frequently had a concomitant second (n = 10; 29% of cases) or third (n = 4; 11.8% of cases) unique ATM CH PV, whereas no ATM CH PVs were seen in controls. Even after excluding ATM CH PVs, CH PVs were more frequent in cases (p = 0.00003). After ATM CH PVs, the most frequent CH PVs in cases were in NF1 (5 PVs), BCORL1 (4 PVs), and DMNT3A (4 PVs). Conclusions: Our study supports ATM as a strong predisposition locus for myeloid gene CH. CH in ATM germline mutation carriers frequently involved unique low allele fraction PVs in ATM, suggesting ATM germline PVs are driving production of likely bi-allelic ATM inactivation in white blood cells, or complete ATM loss. Complete ATM loss may be a nidus particularly for lymphocytic leukemia, as bi-allelic ATM inactivation is a frequent somatic finding.

scholarly journals Investigation of association of rare, functional genetic variants with heavy drinking and problem drinking in exome sequenced UK Biobank participants

2021 ◽  
Author(s):  
David Curtis
Keyword(s):  
Genetic Variants ◽  
Multiple Testing ◽  
Sequence Data ◽  
Problem Drinking ◽  
Heavy Drinking ◽  
Uk Biobank ◽  
Exome Sequence Data ◽  
The Uk ◽  
Or Genes ◽  
Mental Health Questionnaire

AbstractAimsThe study aimed to identify specific genes and functional genetic variants affecting susceptibility to two alcohol related phenotypes: heavy drinking and problem drinking.MethodsPhenotypic and exome sequence data was downloaded from the UK Biobank. Reported drinks in the last 24 hours was used to define heavy drinking while responses to a mental health questionnaire defined problem drinking. Gene-wise weighted burden analysis was applied, with genetic variants which were rarer and/or had a more severe functional effect being weighted more highly. Additionally, previously reported variants of interest were analysed inidividually.ResultsOf exome sequenced subjects, for heavy drinking there were 8,166 cases and 84,461 controls while for problem drinking there were 7,811 cases and 59,606 controls. No gene was formally significant after correction for multiple testing but three genes possibly related to autism were significant at p < 0.001, FOXP1, ARHGAP33 and CDH9, along with VGF which may also be of psychiatric interest. Well established associations with rs1229984 in ADH1B and rs671 in ALDH2 were confirmed but previously reported variants in ALDH1B1 and GRM3 were not associated with either phenotype.ConclusionsThis large study fails to conclusively implicate any novel genes or variants. It is possible that more definitive results will be obtained when sequence data for the remaining UK Biobank participants becomes available and/or if data can be obtained for a more extreme phenotype such as alcohol dependence disorder. This research has been conducted using the UK Biobank Resource.Short summaryTests for association of rare, functional genetic variants with heavy drinking and problem drinking confirm the known effects of variants in ADH1B and ALDH2 but fail to implicate novel variants or genes. Results for three genes potentially related to autism suggest they might exert a protective effect.

scholarly journals DNA repair gene panel mutations in young onset and aggressive vs non aggressive prostate cancer cases in the UK

2017 ◽  
Vol 28 ◽  
pp. v270
Author(s):  
R. Eeles ◽  
E. Saunders ◽  
S. Wakerell ◽  
I. Whitmore ◽  
C. Cieza-Borrella ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Gene Panel ◽  
Repair Gene ◽  
Aggressive Prostate Cancer ◽  
Young Onset ◽  
Dna Repair Gene ◽  
The Uk

scholarly journals Germline DNA Repair Gene Mutations in Young-onset Prostate Cancer Cases in the UK: Evidence for a More Extensive Genetic Panel

2019 ◽  
Vol 76 (3) ◽  
pp. 329-337 ◽  
Author(s):  
Daniel A. Leongamornlert ◽  
Edward J. Saunders ◽  
Sarah Wakerell ◽  
Ian Whitmore ◽  
Tokhir Dadaev ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Gene Mutations ◽  
Repair Gene ◽  
Young Onset ◽  
Dna Repair Gene ◽  
The Uk

scholarly journals Variants in ACE2 and TMPRSS2 genes are not major determinants of COVID-19 severity in UK Biobank subjects

2020 ◽  
Author(s):  
David Curtis
Keyword(s):  
Rare Variants ◽  
Sequence Data ◽  
Severe Disease ◽  
Major Effect ◽  
Uk Biobank ◽  
Exome Sequence Data ◽  
Dna Sequence Variants ◽  
The Uk ◽  
And Function ◽  
Exome Sequence

AbstractIt is plausible that variants in the ACE2 and TMPRSS2 genes might contribute to variation in COVID-19 severity and that these could explain why some people become very unwell whereas most do not. Exome sequence data was obtained for 49,953 UK Biobank subjects of whom 74 had tested positive for SARS-CoV-2 and could be presumed to have severe disease. A weighted burden analysis was carried out using SCOREASSOC to determine whether there were differences between these cases and the other sequenced subjects in the overall burden of rare, damaging variants in ACE2 or TMPRSS2. There were no statistically significant differences in weighted burden scores between cases and controls for either gene. There were no individual DNA sequence variants with a markedly different frequency between cases and controls. Whether there are small effects on severity, or whether there might be rare variants with major effect sizes, would require studies in much larger samples. Genetic variants affecting the structure and function of the ACE2 and TMPRSS2 proteins are not a major determinant of whether infection with SARS-CoV-2 results in severe symptoms. This research has been conducted using the UK Biobank Resource.

scholarly journals Systematic single-variant and gene-based association testing of 3,700 phenotypes in 281,850 UK Biobank exomes

2021 ◽  
Author(s):  
Konrad Karczewski ◽  
Matthew Solomonson ◽  
Katherine R Chao ◽  
Julia K Goodrich ◽  
Grace Tiao ◽  
...  
Keyword(s):  
Sequence Data ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
Genetic Associations ◽  
Allelic Series ◽  
Association Analyses ◽  
Wide Range ◽  
The Uk ◽  
The Impact

Genome-wide association studies have successfully discovered thousands of common variants associated with human diseases and traits, but the landscape of rare variation in human disease has not been explored at scale. Exome sequencing studies of population biobanks provide an opportunity to systematically evaluate the impact of rare coding variation across a wide range of phenotypes to discover genes and allelic series relevant to human health and disease. Here, we present results from systematic association analyses of 3,700 phenotypes using single-variant and gene tests of 281,850 individuals in the UK Biobank with exome sequence data. We find that the discovery of genetic associations is tightly linked to frequency as well as correlated with metrics of deleteriousness and natural selection. We highlight biological findings elucidated by these data and release the dataset as a public resource alongside a browser framework for rapidly exploring rare variant association results.

scholarly journals Exome sequencing and characterization of 49,960 individuals in the UK Biobank

Nature ◽  
2020 ◽  
Vol 586 (7831) ◽  
pp. 749-756 ◽  
Author(s):  
Cristopher V. Van Hout ◽  
◽  
Ioanna Tachmazidou ◽  
Joshua D. Backman ◽  
Joshua D. Hoffman ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Sequence Data ◽  
Varicose Veins ◽  
Large Population ◽  
Clinical Importance ◽  
Fold Increase ◽  
Uk Biobank ◽  
Loss Of Function ◽  
Association Analyses ◽  
The Uk

AbstractThe UK Biobank is a prospective study of 502,543 individuals, combining extensive phenotypic and genotypic data with streamlined access for researchers around the world1. Here we describe the release of exome-sequence data for the first 49,960 study participants, revealing approximately 4 million coding variants (of which around 98.6% have a frequency of less than 1%). The data include 198,269 autosomal predicted loss-of-function (LOF) variants, a more than 14-fold increase compared to the imputed sequence. Nearly all genes (more than 97%) had at least one carrier with a LOF variant, and most genes (more than 69%) had at least ten carriers with a LOF variant. We illustrate the power of characterizing LOF variants in this population through association analyses across 1,730 phenotypes. In addition to replicating established associations, we found novel LOF variants with large effects on disease traits, including PIEZO1 on varicose veins, COL6A1 on corneal resistance, MEPE on bone density, and IQGAP2 and GMPR on blood cell traits. We further demonstrate the value of exome sequencing by surveying the prevalence of pathogenic variants of clinical importance, and show that 2% of this population has a medically actionable variant. Furthermore, we characterize the penetrance of cancer in carriers of pathogenic BRCA1 and BRCA2 variants. Exome sequences from the first 49,960 participants highlight the promise of genome sequencing in large population-based studies and are now accessible to the scientific community.

scholarly journals Premature Menopause, Clonal Hematopoiesis, and Coronary Artery Disease in Postmenopausal Women

Circulation ◽  
2020 ◽  
Author(s):  
Michael C. Honigberg ◽  
S. Maryam Zekavat ◽  
Abhishek Niroula ◽  
Gabriel K. Griffin ◽  
Alexander G. Bick ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Postmenopausal Women ◽  
Premature Menopause ◽  
Cox Models ◽  
Clonal Hematopoiesis ◽  
Age Related ◽  
Artery Disease ◽  
The Uk

Background: Premature menopause is an independent risk factor for cardiovascular disease in women, but mechanisms underlying this association remain unclear. Clonal hematopoiesis of indeterminate potential (CHIP), the age-related expansion of hematopoietic cells with leukemogenic mutations without detectable malignancy, is associated with accelerated atherosclerosis. Whether premature menopause is associated with CHIP is unknown. Methods: We included postmenopausal women from the UK Biobank (N=11,495) aged 40-70 years with whole exome sequences and from the Women's Health Initiative (WHI, N=8,111) aged 50-79 years with whole genome sequences. Premature menopause was defined as natural or surgical menopause occurring before age 40 years. Co-primary outcomes were the presence of (1) any CHIP and (2) CHIP with variant allele frequency (VAF) >0.1. Logistic regression tested the association of premature menopause with CHIP, adjusted for age, race, the first 10 principal components of ancestry, smoking, diabetes mellitus, and hormone therapy use. Secondary analyses considered natural vs. surgical premature menopause and gene-specific CHIP subtypes. Multivariable-adjusted Cox models tested the association between CHIP and incident coronary artery disease (CAD). Results: The sample included 19,606 women, including 418 (2.1%) with natural premature menopause and 887 (4.5%) with surgical premature menopause. Across cohorts, CHIP prevalence in postmenopausal women with vs. without a history of premature menopause was 8.8% vs. 5.5% (P<0.001), respectively. After multivariable adjustment, premature menopause was independently associated with CHIP (all CHIP: OR 1.36, 95% 1.10-1.68, P=0.004; CHIP with VAF >0.1: OR 1.40, 95% CI 1.10-1.79, P=0.007). Associations were larger for natural premature menopause (all CHIP: OR 1.73, 95% CI 1.23-2.44, P=0.001; CHIP with VAF >0.1: OR 1.91, 95% CI 1.30-2.80, P<0.001) but smaller and non-significant for surgical premature menopause. In gene-specific analyses, only DNMT3A CHIP was significantly associated with premature menopause. Among postmenopausal middle-aged women, CHIP was independently associated with incident coronary artery disease (HR associated with all CHIP: 1.36, 95% CI 1.07-1.73, P=0.012; HR associated with CHIP with VAF >0.1: 1.48, 95% CI 1.13-1.94, P=0.005). Conclusions: Premature menopause, especially natural premature menopause, is independently associated with CHIP among postmenopausal women. Natural premature menopause may serve as a risk signal for predilection to develop CHIP and CHIP-associated cardiovascular disease.

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