Publications by authors named "Kimberly F Doheny"

78 Publications

PhenoDB, GeneMatcher and VariantMatcher, tools for analysis and sharing of sequence data.

Orphanet J Rare Dis 2021 Aug 18;16(1):365. Epub 2021 Aug 18.

Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: With the advent of whole exome (ES) and genome sequencing (GS) as tools for disease gene discovery, rare variant filtering, prioritization and data sharing have become essential components of the search for disease genes and variants potentially contributing to disease phenotypes. The computational storage, data manipulation, and bioinformatic interpretation of thousands to millions of variants identified in ES and GS, respectively, is a challenging task. To aid in that endeavor, we constructed PhenoDB, GeneMatcher and VariantMatcher.

Results: PhenoDB is an accessible, freely available, web-based platform that allows users to store, share, analyze and interpret their patients' phenotypes and variants from ES/GS data. GeneMatcher is accessible to all stakeholders as a web-based tool developed to connect individuals (researchers, clinicians, health care providers and patients) around the globe with interest in the same gene(s), variant(s) or phenotype(s). Finally, VariantMatcher was developed to enable public sharing of variant-level data and phenotypic information from individuals sequenced as part of multiple disease gene discovery projects. Here we provide updates on PhenoDB and GeneMatcher applications and implementation and introduce VariantMatcher.

Conclusion: Each of these tools has facilitated worldwide data sharing and data analysis and improved our ability to connect genes to phenotypic traits. Further development of these platforms will expand variant analysis, interpretation, novel disease-gene discovery and facilitate functional annotation of the human genome for clinical genomics implementation and the precision medicine initiative.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13023-021-01916-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8371856PMC
August 2021

Germline Sequencing DNA Repair Genes in 5545 Men With Aggressive and Nonaggressive Prostate Cancer.

J Natl Cancer Inst 2021 May;113(5):616-625

Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Background: There is an urgent need to identify factors specifically associated with aggressive prostate cancer (PCa) risk. We investigated whether rare pathogenic, likely pathogenic, or deleterious (P/LP/D) germline variants in DNA repair genes are associated with aggressive PCa risk in a case-case study of aggressive vs nonaggressive disease.

Methods: Participants were 5545 European-ancestry men, including 2775 nonaggressive and 2770 aggressive PCa cases, which included 467 metastatic cases (16.9%). Samples were assembled from 12 international studies and germline sequenced together. Rare (minor allele frequency < 0.01) P/LP/D variants were analyzed for 155 DNA repair genes. We compared single variant, gene-based, and DNA repair pathway-based burdens by disease aggressiveness. All statistical tests are 2-sided.

Results: BRCA2 and PALB2 had the most statistically significant gene-based associations, with 2.5% of aggressive and 0.8% of nonaggressive cases carrying P/LP/D BRCA2 alleles (odds ratio [OR] = 3.19, 95% confidence interval [CI] = 1.94 to 5.25, P = 8.58 × 10-7) and 0.65% of aggressive and 0.11% of nonaggressive cases carrying P/LP/D PALB2 alleles (OR = 6.31, 95% CI = 1.83 to 21.68, P = 4.79 × 10-4). ATM had a nominal association, with 1.6% of aggressive and 0.8% of nonaggressive cases carrying P/LP/D ATM alleles (OR = 1.88, 95% CI = 1.10 to 3.22, P = .02). In aggregate, P/LP/D alleles within 24 literature-curated candidate PCa DNA repair genes were more common in aggressive than nonaggressive cases (carrier frequencies = 14.2% vs 10.6%, respectively; P = 5.56 × 10-5). However, this difference was non-statistically significant (P = .18) on excluding BRCA2, PALB2, and ATM. Among these 24 genes, P/LP/D carriers had a 1.06-year younger diagnosis age (95% CI = -1.65 to 0.48, P = 3.71 × 10-4).

Conclusions: Risk conveyed by DNA repair genes is largely driven by rare P/LP/D alleles within BRCA2, PALB2, and ATM. These findings support the importance of these genes in both screening and disease management considerations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jnci/djaa132DOI Listing
May 2021

Insights into genetics, human biology and disease gleaned from family based genomic studies.

Genet Med 2019 04 18;21(4):798-812. Epub 2019 Jan 18.

Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.

Identifying genes and variants contributing to rare disease phenotypes and Mendelian conditions informs biology and medicine, yet potential phenotypic consequences for variation of >75% of the ~20,000 annotated genes in the human genome are lacking. Technical advances to assess rare variation genome-wide, particularly exome sequencing (ES), enabled establishment in the United States of the National Institutes of Health (NIH)-supported Centers for Mendelian Genomics (CMGs) and have facilitated collaborative studies resulting in novel "disease gene" discoveries. Pedigree-based genomic studies and rare variant analyses in families with suspected Mendelian conditions have led to the elucidation of hundreds of novel disease genes and highlighted the impact of de novo mutational events, somatic variation underlying nononcologic traits, incompletely penetrant alleles, phenotypes with high locus heterogeneity, and multilocus pathogenic variation. Herein, we highlight CMG collaborative discoveries that have contributed to understanding both rare and common diseases and discuss opportunities for future discovery in single-locus Mendelian disorder genomics. Phenotypic annotation of all human genes; development of bioinformatic tools and analytic methods; exploration of non-Mendelian modes of inheritance including reduced penetrance, multilocus variation, and oligogenic inheritance; construction of allelic series at a locus; enhanced data sharing worldwide; and integration with clinical genomics are explored. Realizing the full contribution of rare disease research to functional annotation of the human genome, and further illuminating human biology and health, will lay the foundation for the Precision Medicine Initiative.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-018-0408-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691975PMC
April 2019

Discovery of common and rare genetic risk variants for colorectal cancer.

Nat Genet 2019 01 3;51(1):76-87. Epub 2018 Dec 3.

Department of Epidemiology, German Institute of Human Nutrition (DIfE), Potsdam-Rehbrücke, Germany.

To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 × 10, bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Krüppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-018-0286-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358437PMC
January 2019

A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer.

Nat Genet 2018 07 18;50(7):968-978. Epub 2018 Jun 18.

Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.

The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P < 5.82 × 10, including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new insights into breast cancer genetics and biology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-018-0132-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6314198PMC
July 2018

Multi-Omics Analysis Reveals a HIF Network and Hub Gene EPAS1 Associated with Lung Adenocarcinoma.

EBioMedicine 2018 Jun 31;32:93-101. Epub 2018 May 31.

Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA. Electronic address:

Recent technological advancements have permitted high-throughput measurement of the human genome, epigenome, metabolome, transcriptome, and proteome at the population level. We hypothesized that subsets of genes identified from omic studies might have closely related biological functions and thus might interact directly at the network level. Therefore, we conducted an integrative analysis of multi-omic datasets of non-small cell lung cancer (NSCLC) to search for association patterns beyond the genome and transcriptome. A large, complex, and robust gene network containing well-known lung cancer-related genes, including EGFR and TERT, was identified from combined gene lists for lung adenocarcinoma. Members of the hypoxia-inducible factor (HIF) gene family were at the center of this network. Subsequent sequencing of network hub genes within a subset of samples from the Transdisciplinary Research in Cancer of the Lung-International Lung Cancer Consortium (TRICL-ILCCO) consortium revealed a SNP (rs12614710) in EPAS1 associated with NSCLC that reached genome-wide significance (OR = 1.50; 95% CI: 1.31-1.72; p = 7.75 × 10). Using imputed data, we found that this SNP remained significant in the entire TRICL-ILCCO consortium (p = .03). Additional functional studies are warranted to better understand interrelationships among genetic polymorphisms, DNA methylation status, and EPAS1 expression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ebiom.2018.05.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6021270PMC
June 2018

Patients with a Kabuki syndrome phenotype demonstrate DNA methylation abnormalities.

Eur J Hum Genet 2017 12 7;25(12):1335-1344. Epub 2017 Nov 7.

McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Kabuki syndrome is a monogenic disorder caused by loss of function variants in either of two genes encoding histone-modifying enzymes. We performed targeted sequencing in a cohort of 27 probands with a clinical diagnosis of Kabuki syndrome. Of these, 12 had causative variants in the two known Kabuki syndrome genes. In 2, we identified presumptive loss of function de novo variants in KMT2A (missense and splice site variants), a gene that encodes another histone modifying enzyme previously exclusively associated with Wiedermann-Steiner syndrome. Although Kabuki syndrome is a disorder of histone modification, we also find alterations in DNA methylation among individuals with a Kabuki syndrome diagnosis relative to matched normal controls, regardless of whether they carry a variant in KMT2A or KMT2D or not. Furthermore, we observed characteristic global abnormalities of DNA methylation that distinguished patients with a loss of function variant in KMT2D or missense or splice site variants in either KMT2D or KMT2A from normal controls. Our results provide new insights into the relationship of genotype to epigenotype and phenotype and indicate cross-talk between histone and DNA methylation machineries exposed by inborn errors of the epigenetic apparatus.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41431-017-0023-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865196PMC
December 2017

Association analysis identifies 65 new breast cancer risk loci.

Nature 2017 11 23;551(7678):92-94. Epub 2017 Oct 23.

Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.

Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10. The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nature24284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5798588PMC
November 2017

Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer.

Nat Genet 2017 Dec 23;49(12):1767-1778. Epub 2017 Oct 23.

Department of Epidemiology, University of California, Irvine, Irvine, California, USA.

Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10 with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ng.3785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5808456PMC
December 2017

Concordance between Research Sequencing and Clinical Pharmacogenetic Genotyping in the eMERGE-PGx Study.

J Mol Diagn 2017 07 11;19(4):561-566. Epub 2017 May 11.

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.

There has been extensive debate about both the necessity of orthogonal confirmation of next-generation sequencing (NGS) results in Clinical Laboratory Improvement Amendments-approved laboratories and return of research NGS results to participants enrolled in research studies. In eMERGE-PGx, subjects underwent research NGS using PGRNseq and orthogonal targeted genotyping in clinical laboratories, which prompted a comparison of genotyping results between platforms. Concordance (percentage agreement) was reported for 4077 samples tested across nine combinations of research and clinical laboratories. Retesting was possible on a subset of 1792 samples, and local laboratory directors determined sources of genotype discrepancy. Research NGS and orthogonal clinical genotyping had an overall per sample concordance rate of 0.972 and per variant concordance rate of 0.997. Genotype discrepancies attributed to research NGS were because of sample switching (preanalytical errors), whereas the majority of genotype discrepancies (92.3%) attributed to clinical genotyping were because of allele dropout as a result of rare variants interfering with primer hybridization (analytical errors). These results highlight the analytical quality of clinically significant pharmacogenetic variants derived from NGS and reveal important areas for research and clinical laboratories to address with quality management programs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jmoldx.2017.04.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5500823PMC
July 2017

Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

Nat Genet 2017 May 27;49(5):680-691. Epub 2017 Mar 27.

N.N. Alexandrov National Cancer Centre of Belarus, Minsk, Belarus.

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ng.3826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5612337PMC
May 2017

Generating Exome Enriched Sequencing Libraries from Formalin-Fixed, Paraffin-Embedded Tissue DNA for Next-Generation Sequencing.

Curr Protoc Hum Genet 2017 01 11;92:18.10.1-18.10.25. Epub 2017 Jan 11.

Center for Inherited Disease Research, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland.

This unit describes a technique for generating exome-enriched sequencing libraries using DNA extracted from formalin-fixed paraffin-embedded (FFPE) samples. Utilizing commercially available kits, we present a low-input FFPE workflow starting with 50 ng of DNA. This procedure includes a repair step to address damage caused by FFPE preservation that improves sequence quality. Subsequently, libraries undergo an in-solution-targeted selection for exons, followed by sequencing using the Illumina next-generation short-read sequencing platform. © 2017 by John Wiley & Sons, Inc.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cphg.27DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228582PMC
January 2017

A multi-ethnic genome-wide association study identifies novel loci for non-syndromic cleft lip with or without cleft palate on 2p24.2, 17q23 and 19q13.

Hum Mol Genet 2016 07 30;25(13):2862-2872. Epub 2016 Mar 30.

Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.

Orofacial clefts (OFCs), which include non-syndromic cleft lip with or without cleft palate (CL/P), are among the most common birth defects in humans, affecting approximately 1 in 700 newborns. CL/P is phenotypically heterogeneous and has a complex etiology caused by genetic and environmental factors. Previous genome-wide association studies (GWASs) have identified at least 15 risk loci for CL/P. As these loci do not account for all of the genetic variance of CL/P, we hypothesized the existence of additional risk loci. We conducted a multiethnic GWAS in 6480 participants (823 unrelated cases, 1700 unrelated controls and 1319 case-parent trios) with European, Asian, African and Central and South American ancestry. Our GWAS revealed novel associations on 2p24 near FAM49A, a gene of unknown function (P = 4.22 × 10), and 19q13 near RHPN2, a gene involved in organizing the actin cytoskeleton (P = 4.17 × 10). Other regions reaching genome-wide significance were 1p36 (PAX7), 1p22 (ARHGAP29), 1q32 (IRF6), 8q24 and 17p13 (NTN1), all reported in previous GWASs. Stratification by ancestry group revealed a novel association with a region on 17q23 (P = 2.92 × 10) among individuals with European ancestry. This region included several promising candidates including TANC2, an oncogene required for development, and DCAF7, a scaffolding protein required for craniofacial development. In the Central and South American ancestry group, significant associations with loci previously identified in Asian or European ancestry groups reflected their admixed ancestry. In summary, we have identified novel CL/P risk loci and suggest new genes involved in craniofacial development, confirming the highly heterogeneous etiology of OFCs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddw104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5181632PMC
July 2016

A Genome-wide Association Study of Nonsyndromic Cleft Palate Identifies an Etiologic Missense Variant in GRHL3.

Am J Hum Genet 2016 Apr 24;98(4):744-54. Epub 2016 Mar 24.

Fundación Clínica Noel, Medellin 050012, Colombia.

Cleft palate (CP) is a common birth defect occurring in 1 in 2,500 live births. Approximately half of infants with CP have a syndromic form, exhibiting other physical and cognitive disabilities. The other half have nonsyndromic CP, and to date, few genes associated with risk for nonsyndromic CP have been characterized. To identify such risk factors, we performed a genome-wide association study of this disorder. We discovered a genome-wide significant association with a missense variant in GRHL3 (p.Thr454Met [c.1361C>T]; rs41268753; p = 4.08 × 10(-9)) and replicated the result in an independent sample of case and control subjects. In both the discovery and replication samples, rs41268753 conferred increased risk for CP (OR = 8.3, 95% CI 4.1-16.8; OR = 2.16, 95% CI 1.43-3.27, respectively). In luciferase transactivation assays, p.Thr454Met had about one-third of the activity of wild-type GRHL3, and in zebrafish embryos, perturbed periderm development. We conclude that this mutation is an etiologic variant for nonsyndromic CP and is one of few functional variants identified to date for nonsyndromic orofacial clefting. This finding advances our understanding of the genetic basis of craniofacial development and might ultimately lead to improvements in recurrence risk prediction, treatment, and prognosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2016.02.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4833215PMC
April 2016

Association of Arrhythmia-Related Genetic Variants With Phenotypes Documented in Electronic Medical Records.

JAMA 2016 Jan;315(1):47-57

Marshfield Clinic Research Foundation, Marshfield, Wisconsin.

Importance: Large-scale DNA sequencing identifies incidental rare variants in established Mendelian disease genes, but the frequency of related clinical phenotypes in unselected patient populations is not well established. Phenotype data from electronic medical records (EMRs) may provide a resource to assess the clinical relevance of rare variants.

Objective: To determine the clinical phenotypes from EMRs for individuals with variants designated as pathogenic by expert review in arrhythmia susceptibility genes.

Design, Setting, And Participants: This prospective cohort study included 2022 individuals recruited for nonantiarrhythmic drug exposure phenotypes from October 5, 2012, to September 30, 2013, for the Electronic Medical Records and Genomics Network Pharmacogenomics project from 7 US academic medical centers. Variants in SCN5A and KCNH2, disease genes for long QT and Brugada syndromes, were assessed for potential pathogenicity by 3 laboratories with ion channel expertise and by comparison with the ClinVar database. Relevant phenotypes were determined from EMRs, with data available from 2002 (or earlier for some sites) through September 10, 2014.

Exposures: One or more variants designated as pathogenic in SCN5A or KCNH2.

Main Outcomes And Measures: Arrhythmia or electrocardiographic (ECG) phenotypes defined by International Classification of Diseases, Ninth Revision (ICD-9) codes, ECG data, and manual EMR review.

Results: Among 2022 study participants (median age, 61 years [interquartile range, 56-65 years]; 1118 [55%] female; 1491 [74%] white), a total of 122 rare (minor allele frequency <0.5%) nonsynonymous and splice-site variants in 2 arrhythmia susceptibility genes were identified in 223 individuals (11% of the study cohort). Forty-two variants in 63 participants were designated potentially pathogenic by at least 1 laboratory or ClinVar, with low concordance across laboratories (Cohen κ = 0.26). An ICD-9 code for arrhythmia was found in 11 of 63 (17%) variant carriers vs 264 of 1959 (13%) of those without variants (difference, +4%; 95% CI, -5% to +13%; P = .35). In the 1270 (63%) with ECGs, corrected QT intervals were not different in variant carriers vs those without (median, 429 vs 439 milliseconds; difference, -10 milliseconds; 95% CI, -16 to +3 milliseconds; P = .17). After manual review, 22 of 63 participants (35%) with designated variants had any ECG or arrhythmia phenotype, and only 2 had corrected QT interval longer than 500 milliseconds.

Conclusions And Relevance: Among laboratories experienced in genetic testing for cardiac arrhythmia disorders, there was low concordance in designating SCN5A and KCNH2 variants as pathogenic. In an unselected population, the putatively pathogenic genetic variants were not associated with an abnormal phenotype. These findings raise questions about the implications of notifying patients of incidental genetic findings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jama.2015.17701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4758131PMC
January 2016

A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.

Nat Genet 2016 Feb 21;48(2):134-43. Epub 2015 Dec 21.

Department of Ophthalmology, Erasmus Medical Center, Rotterdam, the Netherlands.

Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ng.3448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4745342PMC
February 2016

Prospective participant selection and ranking to maximize actionable pharmacogenetic variants and discovery in the eMERGE Network.

Genome Med 2015 3;7(1):67. Epub 2015 Jul 3.

Department of Medicine, Division of Medical Genetics, University of Washington, 1705 NE Pacific Street, Seattle, 98195 WA USA ; Department of Genome Sciences, University of Washington, 3720 15th Avenue NE, Seattle, 98195 WA USA.

Background: In an effort to return actionable results from variant data to electronic health records (EHRs), participants in the Electronic Medical Records and Genomics (eMERGE) Network are being sequenced with the targeted Pharmacogenomics Research Network sequence platform (PGRNseq). This cost-effective, highly-scalable, and highly-accurate platform was created to explore rare variation in 84 key pharmacogenetic genes with strong drug phenotype associations.

Methods: To return Clinical Laboratory Improvement Amendments (CLIA) results to our participants at the Group Health Cooperative, we sequenced the DNA of 900 participants (61 % female) with non-CLIA biobanked samples. We then selected 450 of those to be re-consented, to redraw blood, and ultimately to validate CLIA variants in anticipation of returning the results to the participant and EHR. These 450 were selected using an algorithm we designed to harness data from self-reported race, diagnosis and procedure codes, medical notes, laboratory results, and variant-level bioinformatics to ensure selection of an informative sample. We annotated the multi-sample variant call format by a combination of SeattleSeq and SnpEff tools, with additional custom variables including evidence from ClinVar, OMIM, HGMD, and prior clinical associations.

Results: We focused our analyses on 27 actionable genes, largely driven by the Clinical Pharmacogenetics Implementation Consortium. We derived a ranking system based on the total number of coding variants per participant (75.2±14.7), and the number of coding variants with high or moderate impact (11.5±3.9). Notably, we identified 11 stop-gained (1 %) and 519 missense (20 %) variants out of a total of 1785 in these 27 genes. Finally, we prioritized variants to be returned to the EHR with prior clinical evidence of pathogenicity or annotated as stop-gain for the following genes: CACNA1S and RYR1 (malignant hyperthermia); SCN5A, KCNH2, and RYR2 (arrhythmia); and LDLR (high cholesterol).

Conclusions: The incorporation of genetics into the EHR for clinical decision support is a complex undertaking for many reasons including lack of prior consent for return of results, lack of biospecimens collected in a CLIA environment, and EHR integration. Our study design accounts for these hurdles and is an example of a pilot system that can be utilized before expanding to an entire health system.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13073-015-0181-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4517371PMC
July 2015

Biology-Driven Gene-Gene Interaction Analysis of Age-Related Cataract in the eMERGE Network.

Genet Epidemiol 2015 Jul 17;39(5):376-84. Epub 2015 May 17.

Department of Biochemistry and Molecular Biology, Center for Systems Genomics, Eberly College of Science, The Pennsylvania State University, University Park, Pennsylvania, United States of America.

Bioinformatics approaches to examine gene-gene models provide a means to discover interactions between multiple genes that underlie complex disease. Extensive computational demands and adjusting for multiple testing make uncovering genetic interactions a challenge. Here, we address these issues using our knowledge-driven filtering method, Biofilter, to identify putative single nucleotide polymorphism (SNP) interaction models for cataract susceptibility, thereby reducing the number of models for analysis. Models were evaluated in 3,377 European Americans (1,185 controls, 2,192 cases) from the Marshfield Clinic, a study site of the Electronic Medical Records and Genomics (eMERGE) Network, using logistic regression. All statistically significant models from the Marshfield Clinic were then evaluated in an independent dataset of 4,311 individuals (742 controls, 3,569 cases), using independent samples from additional study sites in the eMERGE Network: Mayo Clinic, Group Health/University of Washington, Vanderbilt University Medical Center, and Geisinger Health System. Eighty-three SNP-SNP models replicated in the independent dataset at likelihood ratio test P < 0.05. Among the most significant replicating models was rs12597188 (intron of CDH1)-rs11564445 (intron of CTNNB1). These genes are known to be involved in processes that include: cell-to-cell adhesion signaling, cell-cell junction organization, and cell-cell communication. Further Biofilter analysis of all replicating models revealed a number of common functions among the genes harboring the 83 replicating SNP-SNP models, which included signal transduction and PI3K-Akt signaling pathway. These findings demonstrate the utility of Biofilter as a biology-driven method, applicable for any genome-wide association study dataset.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/gepi.21902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4550090PMC
July 2015

Novel genetic locus implicated for HIV-1 acquisition with putative regulatory links to HIV replication and infectivity: a genome-wide association study.

PLoS One 2015 18;10(3):e0118149. Epub 2015 Mar 18.

RTI International, Research Triangle Park, NC, Atlanta, GA, San Francisco, CA, United States of America.

Fifty percent of variability in HIV-1 susceptibility is attributable to host genetics. Thus identifying genetic associations is essential to understanding pathogenesis of HIV-1 and important for targeting drug development. To date, however, CCR5 remains the only gene conclusively associated with HIV acquisition. To identify novel host genetic determinants of HIV-1 acquisition, we conducted a genome-wide association study among a high-risk sample of 3,136 injection drug users (IDUs) from the Urban Health Study (UHS). In addition to being IDUs, HIV-controls were frequency-matched to cases on environmental exposures to enhance detection of genetic effects. We tested independent replication in the Women's Interagency HIV Study (N=2,533). We also examined publicly available gene expression data to link SNPs associated with HIV acquisition to known mechanisms affecting HIV replication/infectivity. Analysis of the UHS nominated eight genetic regions for replication testing. SNP rs4878712 in FRMPD1 met multiple testing correction for independent replication (P=1.38x10(-4)), although the UHS-WIHS meta-analysis p-value did not reach genome-wide significance (P=4.47x10(-7) vs. P<5.0x10(-8)) Gene expression analyses provided promising biological support for the protective G allele at rs4878712 lowering risk of HIV: (1) the G allele was associated with reduced expression of FBXO10 (r=-0.49, P=6.9x10(-5)); (2) FBXO10 is a component of the Skp1-Cul1-F-box protein E3 ubiquitin ligase complex that targets Bcl-2 protein for degradation; (3) lower FBXO10 expression was associated with higher BCL2 expression (r=-0.49, P=8x10(-5)); (4) higher basal levels of Bcl-2 are known to reduce HIV replication and infectivity in human and animal in vitro studies. These results suggest new potential biological pathways by which host genetics affect susceptibility to HIV upon exposure for follow-up in subsequent studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0118149PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4364715PMC
February 2016

Characterization of large structural genetic mosaicism in human autosomes.

Am J Hum Genet 2015 Mar;96(3):487-97

Department of Thoracic and Cardiovascular Surgery, Cancer Research Institute, College of Medicine, Seoul National University, Seoul 151-742, Republic of Korea.

Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 × 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2015.01.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4375431PMC
March 2015

Novel Deletion of SERPINF1 Causes Autosomal Recessive Osteogenesis Imperfecta Type VI in Two Brazilian Families.

Mol Syndromol 2014 Dec 25;5(6):268-75. Epub 2014 Nov 25.

Center of Medical Genetics, Federal University of São Paulo (UNIFESP), São Paulo, Brazil.

Autosomal recessive osteogenesis imperfecta (OI) accounts for 10% of all OI cases, and, currently, mutations in 10 genes (CRTAP, LEPRE1, PPIB, SERPINH1, FKBP10, SERPINF1, SP7, BMP1, TMEM38B, and WNT1) are known to be responsible for this form of the disease. PEDF is a secreted glycoprotein of the serpin superfamily that maintains bone homeostasis and regulates osteoid mineralization, and it is encoded by SERPINF1, currently associated with OI type VI (MIM 172860). Here, we report a consanguineous Brazilian family in which multiple individuals from at least 4 generations are affected with a severe form of OI, and we also report an unrelated individual from the same small city in Brazil with a similar but more severe phenotype. In both families the same homozygous SERPINF1 19-bp deletion was identified which is not known in the literature yet. We described intra- and interfamilial clinical and radiological phenotypic variability of OI type VI caused by the same homozygous SERPINF1 19-bp deletion and suggest a founder effect. Furthermore, the SERPINF1 genotypes/phenotypes reported so far in the literature are reviewed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000369108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4281578PMC
December 2014

Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome.

Am J Med Genet A 2015 Feb 13;167A(2):271-81. Epub 2014 Nov 13.

Division of Medical Genetics, A.I. duPont Hospital for Children, Wilmington, Delaware, and Sidney Kimmel Medical School at T. Jefferson University, Philadelphia, Pennsylvania.

Lateral meningocele syndrome (LMS, OMIM%130720), also known as Lehman syndrome, is a very rare skeletal disorder with facial anomalies, hypotonia and meningocele-related neurologic dysfunction. The characteristic lateral meningoceles represent the severe end of the dural ectasia spectrum and are typically most severe in the lower spine. Facial features of LMS include hypertelorism and telecanthus, high arched eyebrows, ptosis, midfacial hypoplasia, micrognathia, high and narrow palate, low-set ears and a hypotonic appearance. Hyperextensibility, hernias and scoliosis reflect a connective tissue abnormality, and aortic dilation, a high-pitched nasal voice, wormian bones and osteolysis may be present. Lateral meningocele syndrome has phenotypic overlap with Hajdu-Cheney syndrome. We performed exome resequencing in five unrelated individuals with LMS and identified heterozygous truncating NOTCH3 mutations. In an additional unrelated individual Sanger sequencing revealed a deleterious variant in the same exon 33. In total, five novel de novo NOTCH3 mutations were identified in six unrelated patients. One had a 26 bp deletion (c.6461_6486del, p.G2154fsTer78), two carried the same single base pair insertion (c.6692_93insC, p.P2231fsTer11), and three individuals had a nonsense point mutation at c.6247A > T (pK2083*), c.6663C > G (p.Y2221*) or c.6732C > A, (p.Y2244*). All mutations cluster into the last coding exon, resulting in premature termination of the protein and truncation of the negative regulatory proline-glutamate-serine-threonine rich PEST domain. Our results suggest that mutant mRNA products escape nonsense mediated decay. The truncated NOTCH3 may cause gain-of-function through decreased clearance of the active intracellular product, resembling NOTCH2 mutations in the clinically related Hajdu-Cheney syndrome and contrasting the NOTCH3 missense mutations causing CADASIL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.36863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5589071PMC
February 2015

Genetic Associations with Plasma B12, B6, and Folate Levels in an Ischemic Stroke Population from the Vitamin Intervention for Stroke Prevention (VISP) Trial.

Front Public Health 2014 6;2:112. Epub 2014 Aug 6.

Center for Public Health Genomics, University of Virginia , Charlottesville, VA , USA ; Department of Public Health Sciences, University of Virginia , Charlottesville, VA , USA ; Department of Biochemistry & Molecular Genetics, University of Virginia , Charlottesville, VA , USA.

Background: B vitamins play an important role in homocysteine metabolism, with vitamin deficiencies resulting in increased levels of homocysteine and increased risk for stroke. We performed a genome-wide association study (GWAS) in 2,100 stroke patients from the Vitamin Intervention for Stroke Prevention (VISP) trial, a clinical trial designed to determine whether the daily intake of high-dose folic acid, vitamins B6, and B12 reduce recurrent cerebral infarction.

Methods: Extensive quality control (QC) measures resulted in a total of 737,081 SNPs for analysis. Genome-wide association analyses for baseline quantitative measures of folate, Vitamins B12, and B6 were completed using linear regression approaches, implemented in PLINK.

Results: Six associations met or exceeded genome-wide significance (P ≤ 5 × 10(-08)). For baseline Vitamin B12, the strongest association was observed with a non-synonymous SNP (nsSNP) located in the CUBN gene (P = 1.76 × 10(-13)). Two additional CUBN intronic SNPs demonstrated strong associations with B12 (P = 2.92 × 10(-10) and 4.11 × 10(-10)), while a second nsSNP, located in the TCN1 gene, also reached genome-wide significance (P = 5.14 × 10(-11)). For baseline measures of Vitamin B6, we identified genome-wide significant associations for SNPs at the ALPL locus (rs1697421; P = 7.06 × 10(-10) and rs1780316; P = 2.25 × 10(-08)). In addition to the six genome-wide significant associations, nine SNPs (two for Vitamin B6, six for Vitamin B12, and one for folate measures) provided suggestive evidence for association (P ≤ 10(-07)).

Conclusion: Our GWAS study has identified six genome-wide significant associations, nine suggestive associations, and successfully replicated 5 of 16 SNPs previously reported to be associated with measures of B vitamins. The six genome-wide significant associations are located in gene regions that have shown previous associations with measures of B vitamins; however, four of the nine suggestive associations represent novel finding and warrant further investigation in additional populations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fpubh.2014.00112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4123605PMC
August 2014

Identification of an HMGB3 frameshift mutation in a family with an X-linked colobomatous microphthalmia syndrome using whole-genome and X-exome sequencing.

JAMA Ophthalmol 2014 Oct;132(10):1215-20

McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland4Icahn School of Medicine at Mount Sinai, New York, New York.

Importance: Microphthalmias are rare disorders whose genetic bases are not fully understood. HMGB3 is a new candidate gene for X-linked forms of this disease.

Objective: To identify the causative gene in a pedigree with an X-linked colobomatous microphthalmos phenotype.

Design, Setting, And Participants: Whole-genome sequencing and chromosome X-exome-targeted sequencing were performed at the High Throughput Sequencing Laboratory of the Genetic Resources Core Facility at the Johns Hopkins University School of Medicine on the DNA of the male proband and informatically filtered to identify rare variants. Polymerase chain reaction and Sanger sequencing were used to confirm the variant in the proband and the carrier status of his mother. Thirteen unrelated male patients with a similar phenotype were also screened.

Main Outcomes And Measures: Whole-genome and X-exome sequencing to identify a frameshift variant in HMGB3.

Results: A 2-base pair frameshift insertion (c.477_478insTA, coding for p.Lys161Ilefs*54) in the HGMB3 gene was found in the proband and his carrier mother but not in the unrelated patients. The mutation, confirmed by 3 orthogonal methods, alters an evolutionarily conserved region of the HMGB3 protein from a negatively charged polyglutamic acid tract to a positively charged arginine-rich motif that is likely to interfere with normal protein function.

Conclusions And Relevance: In this family, microphthalmia, microcephaly, intellectual disability, and short stature are associated with a mutation on the X chromosome in the HMGB3 gene. HMGB3 should be considered when performing genetic studies of patients with similar phenotypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaophthalmol.2014.1731DOI Listing
October 2014

Whole exome sequencing of distant relatives in multiplex families implicates rare variants in candidate genes for oral clefts.

Genetics 2014 Jul 2;197(3):1039-44. Epub 2014 May 2.

Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205

A dozen genes/regions have been confirmed as genetic risk factors for oral clefts in human association and linkage studies, and animal models argue even more genes may be involved. Genomic sequencing studies should identify specific causal variants and may reveal additional genes as influencing risk to oral clefts, which have a complex and heterogeneous etiology. We conducted a whole exome sequencing (WES) study to search for potentially causal variants using affected relatives drawn from multiplex cleft families. Two or three affected second, third, and higher degree relatives from 55 multiplex families were sequenced. We examined rare single nucleotide variants (SNVs) shared by affected relatives in 348 recognized candidate genes. Exact probabilities that affected relatives would share these rare variants were calculated, given pedigree structures, and corrected for the number of variants tested. Five novel and potentially damaging SNVs shared by affected distant relatives were found and confirmed by Sanger sequencing. One damaging SNV in CDH1, shared by three affected second cousins from a single family, attained statistical significance (P = 0.02 after correcting for multiple tests). Family-based designs such as the one used in this WES study offer important advantages for identifying genes likely to be causing complex and heterogeneous disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1534/genetics.114.165225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4096358PMC
July 2014

Genome-wide meta-analysis of homocysteine and methionine metabolism identifies five one carbon metabolism loci and a novel association of ALDH1L1 with ischemic stroke.

PLoS Genet 2014 Mar 20;10(3):e1004214. Epub 2014 Mar 20.

Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, United States of America; Department of Medicine, University of Virginia, Charlottesville, Virginia, United States of America; Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia, United States of America.

Circulating homocysteine levels (tHcy), a product of the folate one carbon metabolism pathway (FOCM) through the demethylation of methionine, are heritable and are associated with an increased risk of common diseases such as stroke, cardiovascular disease (CVD), cancer and dementia. The FOCM is the sole source of de novo methyl group synthesis, impacting many biological and epigenetic pathways. However, the genetic determinants of elevated tHcy (hyperhomocysteinemia), dysregulation of methionine metabolism and the underlying biological processes remain unclear. We conducted independent genome-wide association studies and a meta-analysis of methionine metabolism, characterized by post-methionine load test tHcy, in 2,710 participants from the Framingham Heart Study (FHS) and 2,100 participants from the Vitamin Intervention for Stroke Prevention (VISP) clinical trial, and then examined the association of the identified loci with incident stroke in FHS. Five genes in the FOCM pathway (GNMT [p = 1.60 × 10(-63)], CBS [p = 3.15 × 10(-26)], CPS1 [p = 9.10 × 10(-13)], ALDH1L1 [p = 7.3 × 10(-13)] and PSPH [p = 1.17 × 10(-16)]) were strongly associated with the difference between pre- and post-methionine load test tHcy levels (ΔPOST). Of these, one variant in the ALDH1L1 locus, rs2364368, was associated with incident ischemic stroke. Promoter analyses reveal genetic and epigenetic differences that may explain a direct effect on GNMT transcription and a downstream affect on methionine metabolism. Additionally, a genetic-score consisting of the five significant loci explains 13% of the variance of ΔPOST in FHS and 6% of the variance in VISP. Association between variants in FOCM genes with ΔPOST suggest novel mechanisms that lead to differences in methionine metabolism, and possibly the epigenome, impacting disease risk. These data emphasize the importance of a concerted effort to understand regulators of one carbon metabolism as potential therapeutic targets.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pgen.1004214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3961178PMC
March 2014

Mutations in Alström protein impair terminal differentiation of cardiomyocytes.

Nat Commun 2014 Mar 4;5:3416. Epub 2014 Mar 4.

Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.

Cardiomyocyte cell division and replication in mammals proceed through embryonic development and abruptly decline soon after birth. The process governing cardiomyocyte cell cycle arrest is poorly understood. Here we carry out whole-exome sequencing in an infant with evidence of persistent postnatal cardiomyocyte replication to determine the genetic risk factors. We identify compound heterozygous ALMS1 mutations in the proband, and confirm their presence in her affected sibling, one copy inherited from each heterozygous parent. Next, we recognize homozygous or compound heterozygous truncating mutations in ALMS1 in four other children with high levels of postnatal cardiomyocyte proliferation. Alms1 mRNA knockdown increases multiple markers of proliferation in cardiomyocytes, the percentage of cardiomyocytes in G2/M phases, and the number of cardiomyocytes by 10% in cultured cells. Homozygous Alms1-mutant mice have increased cardiomyocyte proliferation at 2 weeks postnatal compared with wild-type littermates. We conclude that deficiency of Alström protein impairs postnatal cardiomyocyte cell cycle arrest.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ncomms4416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3992616PMC
March 2014

Stroke Genetics Network (SiGN) study: design and rationale for a genome-wide association study of ischemic stroke subtypes.

Stroke 2013 Oct 10;44(10):2694-702. Epub 2013 Sep 10.

From the Mayo Clinic Jacksonville, FL (J.F.M.); University of Alabama at Birmingham (D.K.A., L.A.M.); Mayo Clinic Rochester, MN (R.D.B.); Massachusetts General Hospital, Boston, MA (H.A., J.R., O.W.); University of British Columbia, Vancouver, British Columbia, Canada (O.R.B.); University of Maryland School of Medicine and Veterans Administration Medical Center, Baltimore, MD (J.W.C., P.F.M., B.D.M., A.R.S., S.J.K.); University Medical Center Utrecht, Utrecht, The Netherlands (P.I.W.d.B.); Brigham and Women's Hospital, Harvard Medical School, Boston, MA (P.I.W.d.B.); Broad Institute of Harvard, MIT, Cambridge, MA (P.I.W.d.B.); Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (M.D.); Johns Hopkins University, Baltimore, MD (K.F.D.); University of Texas Health Science Center at Houston (M.F.); Saint Francis Medical Center, Lynwood, CA (R.P.G.); NINDS Neurogenetics Cluster, Bethesda, MD (K.G.); IMIM-Hospital Universitari del Mar, Barcelona, Spain (J.J.C.); University of Florida, College of Pharmacy, Gainesville, FL (J.A.J.); Institute of Neuroscience and Physiology, the Sahlgrenska Academy at University of Gothenburg, Sweden (K.J., C.J.); University of Washington, Seattle, WA (C.C.L.); Washington University School of Medicine, St. Louis, MO (J.-M.L.); Lund University, Lund, Sweden (A.L.); St. George's University of London, London, United Kingdom (H.S.M.); Medical University Graz, Graz, Austria (R.S.); Brigham and Women's Hospital, Boston, MA (K.M.R.); University of Virginia, Charlottesville, VA (S.S.R., B.B.W.); Radcliffe Infirmary, Oxford, England (P.M.R.); University of Miami, Coral Gables, FL (T.R., R.L.S.); Imperial College London, London, United Kingdom (P.S.); Jagiellonian University, Krakow, Poland (A.S.); Albert Einstein College of Medicine, Bronx, NY (S.W.-S.); University of Edinburgh, Edinburgh, United Kingdom (C.S.); Universitaire Ziekenhuizen Leuven, Leuven, Belgium (V.N.S.T.); and University of Cincinnati, Cincinnati, OH (

Background And Purpose: Meta-analyses of extant genome-wide data illustrate the need to focus on subtypes of ischemic stroke for gene discovery. The National Institute of Neurological Disorders and Stroke SiGN (Stroke Genetics Network) contributes substantially to meta-analyses that focus on specific subtypes of stroke.

Methods: The National Institute of Neurological Disorders and Stroke SiGN includes ischemic stroke cases from 24 genetic research centers: 13 from the United States and 11 from Europe. Investigators harmonize ischemic stroke phenotyping using the Web-based causative classification of stroke system, with data entered by trained and certified adjudicators at participating genetic research centers. Through the Center for Inherited Diseases Research, the Network plans to genotype 10,296 carefully phenotyped stroke cases using genome-wide single nucleotide polymorphism arrays and adds to these another 4253 previously genotyped cases, for a total of 14,549 cases. To maximize power for subtype analyses, the study allocates genotyping resources almost exclusively to cases. Publicly available studies provide most of the control genotypes. Center for Inherited Diseases Research-generated genotypes and corresponding phenotypes will be shared with the scientific community through the US National Center for Biotechnology Information database of Genotypes and Phenotypes, and brain MRI studies will be centrally archived.

Conclusions: The Stroke Genetics Network, with its emphasis on careful and standardized phenotyping of ischemic stroke and stroke subtypes, provides an unprecedented opportunity to uncover genetic determinants of ischemic stroke.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/STROKEAHA.113.001857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4056331PMC
October 2013
-->