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  1. Article ; Online: Genetic sex validation for sample tracking in next-generation sequencing clinical testing.

    Hu, Jianhong / Korchina, Viktoriya / Zouk, Hana / Harden, Maegan V / Murdock, David / Macbeth, Alyssa / Harrison, Steven M / Lennon, Niall / Kovar, Christie / Balasubramanian, Adithya / Zhang, Lan / Chandanavelli, Gauthami / Pasham, Divya / Rowley, Robb / Wiley, Ken / Smith, Maureen E / Gordon, Adam / Jarvik, Gail P / Sleiman, Patrick /
    Kelly, Melissa A / Bland, Harris T / Murugan, Mullai / Venner, Eric / Boerwinkle, Eric / Prows, Cynthia / Mahanta, Lisa / Rehm, Heidi L / Gibbs, Richard A / Muzny, Donna M

    BMC research notes

    2024  Volume 17, Issue 1, Page(s) 62

    Abstract: Objective: Data from DNA genotyping via a 96-SNP panel in a study of 25,015 clinical samples were utilized for quality control and tracking of sample identity in a clinical sequencing network. The study aimed to demonstrate the value of both the precise ...

    Abstract Objective: Data from DNA genotyping via a 96-SNP panel in a study of 25,015 clinical samples were utilized for quality control and tracking of sample identity in a clinical sequencing network. The study aimed to demonstrate the value of both the precise SNP tracking and the utility of the panel for predicting the sex-by-genotype of the participants, to identify possible sample mix-ups.
    Results: Precise SNP tracking showed no sample swap errors within the clinical testing laboratories. In contrast, when comparing predicted sex-by-genotype to the provided sex on the test requisition, we identified 110 inconsistencies from 25,015 clinical samples (0.44%), that had occurred during sample collection or accessioning. The genetic sex predictions were confirmed using additional SNP sites in the sequencing data or high-density genotyping arrays. It was determined that discrepancies resulted from clerical errors (49.09%), samples from transgender participants (3.64%) and stem cell or bone marrow transplant patients (7.27%) along with undetermined sample mix-ups (40%) for which sample swaps occurred prior to arrival at genome centers, however the exact cause of the events at the sampling sites resulting in the mix-ups were not able to be determined.
    MeSH term(s) Humans ; High-Throughput Nucleotide Sequencing ; Bone Marrow Transplantation ; Clinical Laboratory Services ; Genotype ; Laboratories
    Language English
    Publishing date 2024-03-03
    Publishing country England
    Document type Journal Article
    ZDB-ID 2413336-X
    ISSN 1756-0500 ; 1756-0500
    ISSN (online) 1756-0500
    ISSN 1756-0500
    DOI 10.1186/s13104-024-06723-w
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  2. Article ; Online: Neptune: an environment for the delivery of genomic medicine.

    Eric, Venner / Yi, Victoria / Murdock, David / Kalla, Sara E / Wu, Tsung-Jung / Sabo, Aniko / Li, Shoudong / Meng, Qingchang / Tian, Xia / Murugan, Mullai / Cohen, Michelle / Kovar, Christie / Wei, Wei-Qi / Chung, Wendy K / Weng, Chunhua / Wiesner, Georgia L / Jarvik, Gail P / Muzny, Donna / Gibbs, Richard A

    Genetics in medicine : official journal of the American College of Medical Genetics

    2021  Volume 23, Issue 10, Page(s) 1838–1846

    Abstract: Purpose: Genomic medicine holds great promise for improving health care, but integrating searchable and actionable genetic data into electronic health records (EHRs) remains a challenge. Here we describe Neptune, a system for managing the interaction ... ...

    Abstract Purpose: Genomic medicine holds great promise for improving health care, but integrating searchable and actionable genetic data into electronic health records (EHRs) remains a challenge. Here we describe Neptune, a system for managing the interaction between a clinical laboratory and an EHR system during the clinical reporting process.
    Methods: We developed Neptune and applied it to two clinical sequencing projects that required report customization, variant reanalysis, and EHR integration.
    Results: Neptune has been applied for the generation and delivery of over 15,000 clinical genomic reports. This work spans two clinical tests based on targeted gene panels that contain 68 and 153 genes respectively. These projects demanded customizable clinical reports that contained a variety of genetic data types including single-nucleotide variants (SNVs), copy-number variants (CNVs), pharmacogenomics, and polygenic risk scores. Two variant reanalysis activities were also supported, highlighting this important workflow.
    Conclusion: Methods are needed for delivering structured genetic data to EHRs. This need extends beyond developing data formats to providing infrastructure that manages the reporting process itself. Neptune was successfully applied on two high-throughput clinical sequencing projects to build and deliver clinical reports to EHR systems. The software is open source and available at https://gitlab.com/bcm-hgsc/neptune .
    MeSH term(s) Electronic Health Records ; Genomics ; High-Throughput Nucleotide Sequencing ; Humans ; Neptune ; Software
    Language English
    Publishing date 2021-07-13
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1455352-1
    ISSN 1530-0366 ; 1098-3600
    ISSN (online) 1530-0366
    ISSN 1098-3600
    DOI 10.1038/s41436-021-01230-w
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  3. Article: Genetic Sex Validation for Sample Tracking in Clinical Testing.

    Hu, Jianhong / Korchina, Viktoriya / Zouk, Hana / Harden, Maegan V / Murdock, David / Macbeth, Alyssa / Harrison, Steven M / Lennon, Niall / Kovar, Christie / Balasubramanian, Adithya / Zhang, Lan / Chandanavelli, Gauthami / Pasham, Divya / Rowley, Robb / Wiley, Ken / Smith, Maureen E / Gordon, Adam / Jarvik, Gail P / Sleiman, Patrick /
    Kelly, Melissa A / Bland, Harris T / Murugan, Mullai / Venner, Eric / Boerwinkle, Eric / Prows, Cynthia / Mahanta, Lisa / Rehm, Heidi L / Gibbs, Richard A / Muzny, Donna M

    Research square

    2023  

    Abstract: Objective: Data from DNA genotyping via a 96-SNP panel in a study of 25,015 clinical samples were utilized for quality control and tracking of sample identity in a clinical sequencing network. The study aimed to demonstrate the value of both the precise ...

    Abstract Objective: Data from DNA genotyping via a 96-SNP panel in a study of 25,015 clinical samples were utilized for quality control and tracking of sample identity in a clinical sequencing network. The study aimed to demonstrate the value of both the precise SNP tracking and the utility of the panel for predicting the sex-by-genotype of the participants, to identify possible sample mix-ups.
    Results: Precise SNP tracking showed no sample swap errors within the clinical testing laboratories. In contrast, when comparing predicted sex-by-genotype to the provided sex on the test requisition, we identified 110 inconsistencies from 25,015 clinical samples (0.44%), that had occurred during sample collection or accessioning. The genetic sex predictions were confirmed using additional SNP sites in the sequencing data or high-density genotyping arrays. It was determined that discrepancies resulted from clerical errors, samples from transgender participants and stem cell or bone marrow transplant patients along with undetermined sample mix-ups.
    Language English
    Publishing date 2023-09-11
    Publishing country United States
    Document type Preprint
    DOI 10.21203/rs.3.rs-3304685/v1
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  4. Article ; Online: Whole-exome sequencing of 14 389 individuals from the ESP and CHARGE consortia identifies novel rare variation associated with hemostatic factors.

    Pankratz, Nathan / Wei, Peng / Brody, Jennifer A / Chen, Ming-Huei / de Vries, Paul S / Huffman, Jennifer E / Stimson, Mary Rachel / Auer, Paul L / Boerwinkle, Eric / Cushman, Mary / de Maat, Moniek P M / Folsom, Aaron R / Franco, Oscar H / Gibbs, Richard A / Haagenson, Kelly K / Hofman, Albert / Johnsen, Jill M / Kovar, Christie L / Kraaij, Robert /
    McKnight, Barbara / Metcalf, Ginger A / Muzny, Donna / Psaty, Bruce M / Tang, Weihong / Uitterlinden, André G / van Rooij, Jeroen G J / Dehghan, Abbas / O'Donnell, Christopher J / Reiner, Alex P / Morrison, Alanna C / Smith, Nicholas L

    Human molecular genetics

    2022  Volume 31, Issue 18, Page(s) 3120–3132

    Abstract: Plasma levels of fibrinogen, coagulation factors VII and VIII and von Willebrand factor (vWF) are four intermediate phenotypes that are heritable and have been associated with the risk of clinical thrombotic events. To identify rare and low-frequency ... ...

    Abstract Plasma levels of fibrinogen, coagulation factors VII and VIII and von Willebrand factor (vWF) are four intermediate phenotypes that are heritable and have been associated with the risk of clinical thrombotic events. To identify rare and low-frequency variants associated with these hemostatic factors, we conducted whole-exome sequencing in 10 860 individuals of European ancestry (EA) and 3529 African Americans (AAs) from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium and the National Heart, Lung and Blood Institute's Exome Sequencing Project. Gene-based tests demonstrated significant associations with rare variation (minor allele frequency < 5%) in fibrinogen gamma chain (FGG) (with fibrinogen, P = 9.1 × 10-13), coagulation factor VII (F7) (with factor VII, P = 1.3 × 10-72; seven novel variants) and VWF (with factor VIII and vWF; P = 3.2 × 10-14; one novel variant). These eight novel rare variant associations were independent of the known common variants at these loci and tended to have much larger effect sizes. In addition, one of the rare novel variants in F7 was significantly associated with an increased risk of venous thromboembolism in AAs (Ile200Ser; rs141219108; P = 4.2 × 10-5). After restricting gene-based analyses to only loss-of-function variants, a novel significant association was detected and replicated between factor VIII levels and a stop-gain mutation exclusive to AAs (rs3211938) in CD36 molecule (CD36). This variant has previously been linked to dyslipidemia but not with the levels of a hemostatic factor. These efforts represent the largest integration of whole-exome sequence data from two national projects to identify genetic variation associated with plasma hemostatic factors.
    MeSH term(s) Factor VII/genetics ; Factor VIII/genetics ; Fibrinogen/genetics ; Hemostatics ; Humans ; Polymorphism, Single Nucleotide/genetics ; Exome Sequencing ; von Willebrand Factor/analysis ; von Willebrand Factor/genetics
    Chemical Substances Hemostatics ; von Willebrand Factor ; Factor VII (9001-25-6) ; Factor VIII (9001-27-8) ; Fibrinogen (9001-32-5)
    Language English
    Publishing date 2022-05-10
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1108742-0
    ISSN 1460-2083 ; 0964-6906
    ISSN (online) 1460-2083
    ISSN 0964-6906
    DOI 10.1093/hmg/ddac100
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  5. Article ; Online: An open access pilot freely sharing cancer genomic data from participants in Texas.

    Becnel, Lauren B / Pereira, Stacey / Drummond, Jennifer A / Gingras, Marie-Claude / Covington, Kyle R / Kovar, Christie L / Doddapaneni, Harsha Vardhan / Hu, Jianhong / Muzny, Donna / McGuire, Amy L / Wheeler, David A / Gibbs, Richard A

    Scientific data

    2016  Volume 3, Page(s) 160010

    Abstract: Genomic data sharing in cancer has been restricted to aggregate or controlled-access initiatives to protect the privacy of research participants. By limiting access to these data, it has been argued that the autonomy of individuals who decide to ... ...

    Abstract Genomic data sharing in cancer has been restricted to aggregate or controlled-access initiatives to protect the privacy of research participants. By limiting access to these data, it has been argued that the autonomy of individuals who decide to participate in data sharing efforts has been superseded and the utility of the data as research and educational tools reduced. In a pilot Open Access (OA) project from the CPRIT-funded Texas Cancer Research Biobank, many Texas cancer patients were willing to openly share genomic data from tumor and normal matched pair specimens. For the first time, genetic data from 7 human cancer cases with matched normal are freely available without requirement for data use agreements nor any major restriction except that end users cannot attempt to re-identify the participants (http://txcrb.org/open.html).
    MeSH term(s) Access to Information ; Biological Specimen Banks ; DNA, Neoplasm ; Databases, Genetic ; Genome, Human ; Humans ; Information Dissemination ; Pancreatic Neoplasms/genetics ; Texas
    Chemical Substances DNA, Neoplasm
    Language English
    Publishing date 2016-02-16
    Publishing country England
    Document type Dataset ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2775191-0
    ISSN 2052-4463 ; 2052-4463
    ISSN (online) 2052-4463
    ISSN 2052-4463
    DOI 10.1038/sdata.2016.10
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  6. Article: Exome sequencing resolves apparent incidental findings and reveals further complexity of SH3TC2 variant alleles causing Charcot-Marie-Tooth neuropathy.

    Lupski, James R / Gonzaga-Jauregui, Claudia / Yang, Yaping / Bainbridge, Matthew N / Jhangiani, Shalini / Buhay, Christian J / Kovar, Christie L / Wang, Min / Hawes, Alicia C / Reid, Jeffrey G / Eng, Christine / Muzny, Donna M / Gibbs, Richard A

    Genome medicine

    2013  Volume 5, Issue 6, Page(s) 57

    Abstract: Background: The debate regarding the relative merits of whole genome sequencing (WGS) versus exome sequencing (ES) centers around comparative cost, average depth of coverage for each interrogated base, and their relative efficiency in the identification ...

    Abstract Background: The debate regarding the relative merits of whole genome sequencing (WGS) versus exome sequencing (ES) centers around comparative cost, average depth of coverage for each interrogated base, and their relative efficiency in the identification of medically actionable variants from the myriad of variants identified by each approach. Nevertheless, few genomes have been subjected to both WGS and ES, using multiple next generation sequencing platforms. In addition, no personal genome has been so extensively analyzed using DNA derived from peripheral blood as opposed to DNA from transformed cell lines that may either accumulate mutations during propagation or clonally expand mosaic variants during cell transformation and propagation.
    Methods: We investigated a genome that was studied previously by SOLiD chemistry using both ES and WGS, and now perform six independent ES assays (Illumina GAII (x2), Illumina HiSeq (x2), Life Technologies' Personal Genome Machine (PGM) and Proton), and one additional WGS (Illumina HiSeq).
    Results: We compared the variants identified by the different methods and provide insights into the differences among variants identified between ES runs in the same technology platform and among different sequencing technologies. We resolved the true genotypes of medically actionable variants identified in the proband through orthogonal experimental approaches. Furthermore, ES identified an additional SH3TC2 variant (p.M1?) that likely contributes to the phenotype in the proband.
    Conclusions: ES identified additional medically actionable variant calls and helped resolve ambiguous single nucleotide variants (SNV) documenting the power of increased depth of coverage of the captured targeted regions. Comparative analyses of WGS and ES reveal that pseudogenes and segmental duplications may explain some instances of apparent disease mutations in unaffected individuals.
    Language English
    Publishing date 2013-06-27
    Publishing country England
    Document type Journal Article
    ZDB-ID 2484394-5
    ISSN 1756-994X
    ISSN 1756-994X
    DOI 10.1186/gm461
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  7. Article ; Online: Analysis of loss-of-function variants and 20 risk factor phenotypes in 8,554 individuals identifies loci influencing chronic disease.

    Li, Alexander H / Morrison, Alanna C / Kovar, Christie / Cupples, L Adrienne / Brody, Jennifer A / Polfus, Linda M / Yu, Bing / Metcalf, Ginger / Muzny, Donna / Veeraraghavan, Narayanan / Liu, Xiaoming / Lumley, Thomas / Mosley, Thomas H / Gibbs, Richard A / Boerwinkle, Eric

    Nature genetics

    2015  Volume 47, Issue 6, Page(s) 640–642

    Abstract: A typical human exome harbors dozens of loss-of-function (LOF) variants, which can lower disease risk factor levels and affect drug efficacy. We hypothesized that LOF variants are enriched in genes influencing risk factor levels and the onset of common ... ...

    Abstract A typical human exome harbors dozens of loss-of-function (LOF) variants, which can lower disease risk factor levels and affect drug efficacy. We hypothesized that LOF variants are enriched in genes influencing risk factor levels and the onset of common chronic diseases, such as cardiovascular disease and diabetes. To test this hypothesis, we sequenced the exomes of 8,554 individuals and analyzed the effects of predicted LOF variants on 20 chronic disease risk factor phenotypes. Analysis of this sample as discovery and replication strata of equal size verified two relationships in well-studied genes (PCSK9 and APOC3) and identified eight new loci. Previously unknown relationships included elevated fasting glucose in carriers of heterozygous LOF variation in TXNDC5, which encodes a biomarker for type 1 diabetes progression, and apparent recessive effects of C1QTNF8 on serum magnesium levels. These data demonstrate the utility of functional-variant annotation within a large sample of deeply phenotyped individuals for gene discovery.
    MeSH term(s) Atherosclerosis/genetics ; Chronic Disease ; Exome ; Gene Frequency ; Genetic Association Studies ; Genetic Loci ; Genetic Predisposition to Disease ; Genome, Human ; Humans ; Molecular Sequence Annotation ; Phenotype ; Polymorphism, Single Nucleotide ; Risk Factors
    Language English
    Publishing date 2015-06
    Publishing country United States
    Document type Journal Article ; Research Support, American Recovery and Reinvestment Act ; Research Support, N.I.H., Extramural
    ZDB-ID 1108734-1
    ISSN 1546-1718 ; 1061-4036
    ISSN (online) 1546-1718
    ISSN 1061-4036
    DOI 10.1038/ng.3270
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  8. Article ; Online: Genetic testing in ambulatory cardiology clinics reveals high rate of findings with clinical management implications.

    Murdock, David R / Venner, Eric / Muzny, Donna M / Metcalf, Ginger A / Murugan, Mullai / Hadley, Trevor D / Chander, Varuna / de Vries, Paul S / Jia, Xiaoming / Hussain, Aliza / Agha, Ali M / Sabo, Aniko / Li, Shoudong / Meng, Qingchang / Hu, Jianhong / Tian, Xia / Cohen, Michelle / Yi, Victoria / Kovar, Christie L /
    Gingras, Marie-Claude / Korchina, Viktoriya / Howard, Chad / Riconda, Daniel L / Pereira, Stacey / Smith, Hadley S / Huda, Zohra A / Buentello, Alexandria / Marino, Patricia R / Leiber, Lee / Balasubramanyam, Ashok / Amos, Christopher I / Civitello, Andrew B / Chelu, Mihail G / Maag, Ronald / McGuire, Amy L / Boerwinkle, Eric / Wehrens, Xander H T / Ballantyne, Christie M / Gibbs, Richard A

    Genetics in medicine : official journal of the American College of Medical Genetics

    2021  Volume 23, Issue 12, Page(s) 2404–2414

    Abstract: Purpose: Cardiovascular disease (CVD) is the leading cause of death in adults in the United States, yet the benefits of genetic testing are not universally accepted.: Methods: We developed the "HeartCare" panel of genes associated with CVD, ... ...

    Abstract Purpose: Cardiovascular disease (CVD) is the leading cause of death in adults in the United States, yet the benefits of genetic testing are not universally accepted.
    Methods: We developed the "HeartCare" panel of genes associated with CVD, evaluating high-penetrance Mendelian conditions, coronary artery disease (CAD) polygenic risk, LPA gene polymorphisms, and specific pharmacogenetic (PGx) variants. We enrolled 709 individuals from cardiology clinics at Baylor College of Medicine, and samples were analyzed in a CAP/CLIA-certified laboratory. Results were returned to the ordering physician and uploaded to the electronic medical record.
    Results: Notably, 32% of patients had a genetic finding with clinical management implications, even after excluding PGx results, including 9% who were molecularly diagnosed with a Mendelian condition. Among surveyed physicians, 84% reported medical management changes based on these results, including specialist referrals, cardiac tests, and medication changes. LPA polymorphisms and high polygenic risk of CAD were found in 20% and 9% of patients, respectively, leading to diet, lifestyle, and other changes. Warfarin and simvastatin pharmacogenetic variants were present in roughly half of the cohort.
    Conclusion: Our results support the use of genetic information in routine cardiovascular health management and provide a roadmap for accompanying research.
    MeSH term(s) Adult ; Cardiology ; Cardiovascular Diseases/diagnosis ; Cardiovascular Diseases/genetics ; Cardiovascular Diseases/therapy ; Genetic Testing ; Humans ; Pharmacogenetics/methods ; Pharmacogenomic Testing ; United States
    Language English
    Publishing date 2021-08-06
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1455352-1
    ISSN 1530-0366 ; 1098-3600
    ISSN (online) 1530-0366
    ISSN 1098-3600
    DOI 10.1038/s41436-021-01294-8
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  9. Article ; Online: Complete genome sequence of Enterococcus faecium strain TX16 and comparative genomic analysis of Enterococcus faecium genomes

    Qin Xiang / Galloway-Peña Jessica R / Sillanpaa Jouko / Roh Jung / Nallapareddy Sreedhar R / Chowdhury Shahreen / Bourgogne Agathe / Choudhury Tina / Muzny Donna M / Buhay Christian J / Ding Yan / Dugan-Rocha Shannon / Liu Wen / Kovar Christie / Sodergren Erica / Highlander Sarah / Petrosino Joseph F / Worley Kim C / Gibbs Richard A /
    Weinstock George M / Murray Barbara E

    BMC Microbiology, Vol 12, Iss 1, p

    2012  Volume 135

    Abstract: Abstract Background Enterococci are among the leading causes of hospital-acquired infections in the United States and Europe, with Enterococcus faecalis and Enterococcus faecium being the two most common species isolated from enterococcal infections. In ... ...

    Abstract Abstract Background Enterococci are among the leading causes of hospital-acquired infections in the United States and Europe, with Enterococcus faecalis and Enterococcus faecium being the two most common species isolated from enterococcal infections. In the last decade, the proportion of enterococcal infections caused by E. faecium has steadily increased compared to other Enterococcus species. Although the underlying mechanism for the gradual replacement of E. faecalis by E. faecium in the hospital environment is not yet understood, many studies using genotyping and phylogenetic analysis have shown the emergence of a globally dispersed polyclonal subcluster of E. faecium strains in clinical environments. Systematic study of the molecular epidemiology and pathogenesis of E. faecium has been hindered by the lack of closed, complete E. faecium genomes that can be used as references. Results In this study, we report the complete genome sequence of the E. faecium strain TX16, also known as DO, which belongs to multilocus sequence type (ST) 18, and was the first E. faecium strain ever sequenced. Whole genome comparison of the TX16 genome with 21 E. faecium draft genomes confirmed that most clinical, outbreak, and hospital-associated (HA) strains (including STs 16, 17, 18, and 78), in addition to strains of non-hospital origin, group in the same clade (referred to as the HA clade) and are evolutionally considerably more closely related to each other by phylogenetic and gene content similarity analyses than to isolates in the community-associated (CA) clade with approximately a 3–4% average nucleotide sequence difference between the two clades at the core genome level. Our study also revealed that many genomic loci in the TX16 genome are unique to the HA clade. 380 ORFs in TX16 are HA-clade specific and antibiotic resistance genes are enriched in HA-clade strains. Mobile elements such as IS 16 and transposons were also found almost exclusively in HA strains, as previously reported. Conclusions Our findings along with other studies show that HA clonal lineages harbor specific genetic elements as well as sequence differences in the core genome which may confer selection advantages over the more heterogeneous CA E. faecium isolates. Which of these differences are important for the success of specific E. faecium lineages in the hospital environment remain(s) to be determined.
    Keywords Microbiology ; QR1-502 ; Science ; Q ; DOAJ:Microbiology ; DOAJ:Biology ; DOAJ:Biology and Life Sciences
    Subject code 572
    Language English
    Publishing date 2012-07-01T00:00:00Z
    Publisher BioMed Central
    Document type Article ; Online
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  10. Article ; Online: ADAM19 and HTR4 variants and pulmonary function: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study.

    London, Stephanie J / Gao, Wei / Gharib, Sina A / Hancock, Dana B / Wilk, Jemma B / House, John S / Gibbs, Richard A / Muzny, Donna M / Lumley, Thomas / Franceschini, Nora / North, Kari E / Psaty, Bruce M / Kovar, Christie L / Coresh, Josef / Zhou, Yanhua / Heckbert, Susan R / Brody, Jennifer A / Morrison, Alanna C / Dupuis, Josée

    Circulation. Cardiovascular genetics

    2014  Volume 7, Issue 3, Page(s) 350–358

    Abstract: Background: The pulmonary function measures of forced expiratory volume in 1 second (FEV1) and its ratio to forced vital capacity (FVC) are used in the diagnosis and monitoring of lung diseases and predict cardiovascular mortality in the general ... ...

    Abstract Background: The pulmonary function measures of forced expiratory volume in 1 second (FEV1) and its ratio to forced vital capacity (FVC) are used in the diagnosis and monitoring of lung diseases and predict cardiovascular mortality in the general population. Genome-wide association studies (GWASs) have identified numerous loci associated with FEV1 and FEV1/FVC, but the causal variants remain uncertain. We hypothesized that novel or rare variants poorly tagged by GWASs may explain the significant associations between FEV1/FVC and 2 genes: ADAM19 and HTR4.
    Methods and results: We sequenced ADAM19 and its promoter region along with the ≈21-kb portion of HTR4 harboring GWAS single-nucleotide polymorphisms for pulmonary function and analyzed associations with FEV1/FVC among 3983 participants of European ancestry from Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Meta-analysis of common variants in each region identified statistically significant associations (316 tests; P<1.58×10(-4)) with FEV1/FVC for 14 ADAM19 single-nucleotide polymorphisms and 24 HTR4 single-nucleotide polymorphisms. After conditioning on the sentinel GWASs hit in each gene (ADAM19 rs1422795, minor allele frequency=0.33 and HTR4 rs11168048, minor allele frequency=0.40], 1 single-nucleotide polymorphism remained statistically significant (ADAM19 rs13155908, minor allele frequency=0.12; P=1.56×10(-4)). Analysis of rare variants (minor allele frequency <1%) using sequence kernel association test did not identify associations with either region.
    Conclusions: Sequencing identified 1 common variant associated with FEV1/FVC independent of the sentinel ADAM19 GWAS hit and supports the original HTR4 GWAS findings. Rare variants do not seem to underlie GWAS associations with pulmonary function for common variants in ADAM19 and HTR4.
    MeSH term(s) ADAM Proteins/genetics ; Aged ; Aged, 80 and over ; Aging/genetics ; Cohort Studies ; Female ; Genetic Variation ; Genome-Wide Association Study ; Genomics ; Heart Diseases/epidemiology ; Heart Diseases/genetics ; Heart Diseases/physiopathology ; Humans ; Lung/physiopathology ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; Sequence Analysis, DNA
    Chemical Substances ADAM Proteins (EC 3.4.24.-) ; ADAM19 protein, human (EC 3.4.24.-)
    Language English
    Publishing date 2014-06-20
    Publishing country United States
    Document type Journal Article ; Research Support, American Recovery and Reinvestment Act ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2477394-3
    ISSN 1942-3268 ; 1942-325X
    ISSN (online) 1942-3268
    ISSN 1942-325X
    DOI 10.1161/CIRCGENETICS.113.000066
    Database MEDical Literature Analysis and Retrieval System OnLINE

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