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Posts Tagged ‘Nature Genetics’


Reporter: Aviva Lev-Ari, PhD, RN

International Consortium Finds 15 Novel Risk Loci for Coronary Artery Disease

“lipid metabolism and inflammation as key biological pathways involved in the genetic pathogenesis of CAD”

Themistocles Assimes from Stanford University Medical Center said in a statement that these findings begin to clear up its role. “Our network analysis of the top approximately 240 genetic signals in this study seems to provide evidence that genetic defects in some pathways related to inflammation are a cause,” he said.

On this Open Access Online Scientific Journal, lipid metabolism and inflammation were researched and exposed in the following entries.

However, it is ONLY,  these 15 Novel Risk Loci for Coronary Artery Disease published on 12/3/2012 that provides the genomics loci and the genetic explanation for the following empirical results obtained in the recent research on Cardiovascular diseases, as present in the second half of this post, below.

Special Considerations in Blood Lipoproteins, Viscosity, Assessment and Treatment

https://pharmaceuticalintelligence.com/2012/11/28/special-considerations-in-blood-lipoproteins-viscosity-assessment-and-treatment/

What is the role of plasma viscosity in hemostasis and vascular disease risk?

https://pharmaceuticalintelligence.com/2012/11/28/what-is-the-role-of-plasma-viscosity-in-hemostasis-and-vascular-disease-risk/

PIK3CA mutation in Colorectal Cancer may serve as a Predictive Molecular Biomarker for adjuvant Aspirin therapy

https://pharmaceuticalintelligence.com/2012/11/28/pik3ca-mutation-in-colorectal-cancer-may-serve-as-a-predictive-molecular-biomarker-for-adjuvant-aspirin-therapy/

Peroxisome proliferator-activated receptor (PPAR-gamma) Receptors Activation: PPARγ transrepression for Angiogenesis in Cardiovascular Disease and PPARγ transactivation for Treatment of Diabetes

https://pharmaceuticalintelligence.com/2012/11/13/peroxisome-proliferator-activated-receptor-ppar-gamma-receptors-activation-pparγ-transrepression-for-angiogenesis-in-cardiovascular-disease-and-pparγ-transactivation-for-treatment-of-dia/

Positioning a Therapeutic Concept for Endogenous Augmentation of cEPCs — Therapeutic Indications for Macrovascular Disease: Coronary, Cerebrovascular and Peripheral

https://pharmaceuticalintelligence.com/2012/08/29/positioning-a-therapeutic-concept-for-endogenous-augmentation-of-cepcs-therapeutic-indications-for-macrovascular-disease-coronary-cerebrovascular-and-peripheral/

Cardiovascular Risk Inflammatory Marker: Risk Assessment for Coronary Heart Disease and Ischemic Stroke – Atherosclerosis.

https://pharmaceuticalintelligence.com/2012/10/30/cardiovascular-risk-inflammatory-marker-risk-assessment-for-coronary-heart-disease-and-ischemic-stroke-atherosclerosis/

The Essential Role of Nitric Oxide and Therapeutic NO Donor Targets in Renal Pharmacotherapy

https://pharmaceuticalintelligence.com/2012/11/26/the-essential-role-of-nitric-oxide-and-therapeutic-no-donor-targets-in-renal-pharmacotherapy/

Nitric Oxide Function in Coagulation

https://pharmaceuticalintelligence.com/2012/11/26/nitric-oxide-function-in-coagulation/Nitric Oxide Function in Coagulation

15 Novel Risk Loci for Coronary Artery Disease

December 03, 2012

NEW YORK (GenomeWeb News) – A large-scale association analysis of coronary artery disease has detected 15 new loci associated with risk of the disease, bringing the total number of known risk alleles to 46. As the international CARDIoGRAMplusC4D Consortium reported in Nature Genetics yesterday, the study also found that lipid metabolism and inflammation pathways may play a part in coronary artery disease pathogenesis.

“The number of genetic variations that contribute to heart disease continues to grow with the publication of each new study,” Peter Weissberg from the British Heart Foundation, a co-sponsor of the study, said in a statement. “This latest research further confirms that blood lipids and inflammation are at the heart of the development of atherosclerosis, the process that leads to heart attacks and strokes.”

For its study, the consortium, which was comprised of more than 180 researchers, performed a meta-analysis of data from the 22,233 cases and 64,762 controls of the CARDIoGRAM genome-wide association study and of the 41,513 cases and 65,919 controls from 34 additional studies of people of European and South Asian descent. Using the custom Metabochip array from Illumina, the team tested SNPs for disease association in those populations. The SNPs that reached significance in that stage of the study were then replicated using data from a further four studies.

From this, the team identified 15 new loci with genome-wide significance for risk of coronary artery disease, in addition to known risk loci.

The consortium also reported an additional 104 SNPs that appeared to be associated with coronary artery disease but did not meet the cut-off for genome-wide significance.

Then looking to other known risk factors for coronary artery disease, like blood pressure and diabetes, the researchers assessed whether any of those risk factors were associated with the risk loci. Of the 45 known risk loci, 12 were associated with blood lipid content and five with blood pressure. And while people with type 2 diabetes have a higher risk of developing coronary artery disease, none of the known risk loci were linked to diabetic traits.

An analysis of the pathways that SNPs linked to coronary artery disease fall in revealed that many of them are involved in lipid metabolism and inflammation pathways — 10 risk loci were found to be involved in lipid metabolism. “Our network analysis identified lipid metabolism and inflammation as key biological pathways involved in the genetic pathogenesis of CAD,” the researchers wrote in the paper. “Indeed, there was significant crosstalk between the lipid metabolism and inflammation pathways identified.”

The role of inflammation in coronary artery disease has been up for debate — a debate centering on whether it is a cause or a consequence of the disease — and study author Themistocles Assimes from Stanford University Medical Center said in a statement that these findings begin to clear up its role. “Our network analysis of the top approximately 240 genetic signals in this study seems to provide evidence that genetic defects in some pathways related to inflammation are a cause,” he said.

Related Stories

SOURCE:

http://www.genomeweb.com//node/1159041?hq_e=el&hq_m=1424172&hq_l=3&hq_v=09187c3305

 

GWAS, Meta-Analyses Uncover New Coronary Artery Disease Risk Loci

March 07, 2011

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – Three new studies — including the largest meta-analysis yet of coronary artery disease — have identified dozens of coronary artery disease risk loci in European, South Asian, and Han Chinese populations. All three papers appeared online yesterday in Nature Genetics.

For the first meta-analysis, members of a large international consortium known as the Coronary Artery Disease Genome-wide Replication and Meta-Analysis study, or CARDIoGRAM, sifted through data on more than 135,000 individuals from the UK, US, Europe, Iceland, and Canada. In so doing, they tracked down nearly two-dozen new and previously reported coronary artery disease risk loci.

Because only a few of these loci have been linked to other heart disease-related risk factors such as high blood pressure, those involved say the work points to yet unexplored heart disease pathways.

“[W]e have discovered several new genes not previously known to be involved in the development of coronary heart disease, which is the main cause of heart attacks,” co-corresponding author Nilesh Samani, a cardiology researcher affiliated with the University of Leicester and Glenfield Hospital, said in a statement. “Understanding how these genes work, which is the next step, will vastly improve our knowledge of how the disease develops, and could ultimately help to develop new treatments.”

Samani and his co-workers identified the loci by bringing together data on 22,233 individuals with coronary artery disease and 64,762 unaffected controls. The participants, all of European descent, had been sampled through 14 previous genome-wide association studies and genotyped at an average of about 2.5 million SNPs each. The team then assessed the top candidate SNPs found in this initial analysis in another 56,582 individuals (roughly half of whom had coronary artery disease).

The search not only confirmed associations between coronary artery disease and 10 known loci, but also uncovered associations with 13 other loci. All but three of these were distinct from loci previously implicated in other heart disease risk factors such as hypertension or cholesterol levels, researchers noted.

Consequently, those involved in the study say that exploring the biological functions of the newly detected genes could offer biological clues about how heart disease develops — along with strategies for preventing and treating it.

The genetic complexity of coronary artery disease being revealed by such studies has diagnostic implications as well, according to some.

“Each new gene identified brings us a small step closer to understanding the biological mechanisms of cardiovascular disease development and potential new treatments,” British Heart Foundation Medical Director Peter Weissberg, who was not directly involved in the new studies, said in a statement. “However, as the number of genes grows, it takes us further away from the likelihood that a simple genetic test will identify those most of risk of suffering a heart attack or a stroke.”

Meanwhile, researchers involved with Coronary Artery Disease Genetics Consortium did their own meta-analysis using data collected from four GWAS to find five coronary artery-associated loci in European and South Asian populations.

The group initially looked at 15,420 individuals with coronary artery disease — including 6,996 individuals from South Asia and 8,424 from Europe — and 15,062 unaffected controls. Participants were genotyped at nearly 575,000 SNPs using Illumina BeadChips. Most South Asian individuals tested came from India and Pakistan, researchers noted, while European samples came from the UK, Italy, Sweden, and Germany.

For the validation phase of the study, the team focused in on 59 SNPs at 50 loci from the discovery group that seemed most likely to yield authentic new disease associations. These variants were assessed in 10 replication groups comprised of 21,408 individuals with coronary artery disease and 19,185 individuals without coronary artery disease.

All told, researchers found five loci that seem to influence coronary artery disease risk in the European and South Asian populations: one locus each on chromosomes 7, 11, and 15, along with a pair of loci on chromosome 10.

The team didn’t see significant differences in the frequency or effect sizes of these newly identified variants between the European and South Asian populations, though they emphasized that their approach may have missed some potential risk variants, particularly in those of South Asian descent.

“[C]urrent genome-wide arrays may not capture all important variants in South Asians,” they explained, “Nevertheless, all of the known and new variants were significantly associated with [coronary artery disease] risk in both the European and South Asian populations in the current study, indicating the importance of genes associated with [coronary artery disease] beyond the European ancestry groups in which they were first defined.”

Finally, using a three-stage discovery, validation, and replication GWAS approach, Chinese researchers identified a single coronary artery disease risk variant in the Han Chinese population.

In this first phase of that study, researchers tested samples from 230 cases and 230 controls from populations in Beijing and in China’s Hubei province that were genotyped at Genentech and CapitalBio using Affymetrix Human SNP5.0 arrays.

From the nearly three-dozen SNPs identified in the first stage of the study, they narrowed in on nine suspect variants. After finding linkage disequilibrium between two of the variants, they did validation testing on eight of these in 572 individuals with coronary artery disease and 436 unaffected controls, all from Hubei province.

That analysis implicated a single chromosome 6 SNP called rs6903956 in coronary artery disease — a finding the team ultimately replicated in another group of 2,668 coronary artery disease cases and 3,917 controls from three independent populations in Hubei, Shandong province, and northern China.

The team’s subsequent experiments suggest that the newly detected polymorphism, which falls within a putative gene called C6orf105 on chromosome 6, curbs the expression of this gene. The functional consequences of this shift in expression, if any, are yet to be determined.

Because C6orf105 shares some identity and homology with an androgen hormone inducible gene known as AIG1, those involved in the study argue that it may be worthwhile to investigate possible ties between C6orf105 expression, androgen signaling, and coronary artery disease.

“Androgen has previously been reported to be associated the pathogenesis of atherosclerosis,” they wrote. “Future studies are needed to explore whether C6orf105 expression can be induced by androgen and to further determine the potential mechanism of [coronary artery disease] associated with decreased C6orf105 expression.”

 SOURCE:

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Reporter: Aviva Lev-Ari, PhD, RN

What is the Human Variome Project?

Abstract

The successor to the Human Genome Project intends to establish, by international cooperation, an encyclopedic catalog of sequence variants indexed to the human genome sequence.

Introduction

Genomics is not just for rich countries any more. Anyone can contribute to the Human Variome Project (HVP; see Commentary,page 433). Indeed, the project might just be ambitious enough that everyone really will need to contribute. By stating that all human genetics and genomics contributes to a single aim, the HVP essentially reduces duplication of effort while increasing credit for participation.

However, it will have to find ways to coordinate the disparate activities of clinicians, researchers, database curators and bioinformaticians by providing the means and incentives to lodge the variants they have found in public databases. Variome aims to get all to use compatible nomenclature and phenotype reporting systems and to index variant and phenotype data to gene models in the coordinate system generated by the Human Genome Project. Automation and expert curation, and open comment and expert review, will all have a place in this endeavor. How will we do this without creating more than a necessary minimum of new databases, procedures and bureaucracy?

A very important point, but a tough one to get across, is that much of the necessary work is currently happening across the globe—but is just insufficiently coordinated. The individuals already hard at work aren’t getting the credit they deserve. In a sense, the rest of the world’s geneticists deserve the kind of service that US researchers receive from the excellent coordinating work of the National Human Genome Research Institute and the repositories of the National Center for Biotechnology Information (NCBI), together with the kind of attention afforded by international journals. If only these kinds of coordination, recording and attention could be brought to bear, however briefly, on publication units as small as single instances of a variant gene! Thus, Variome aims to add value to databases such as OMIM, GenBank, dbSNP, dbGAP and the HapMap and organizations including NCBI and the European Bioinformatics Institute (EBI) by working with them all. It will start gene by gene, evaluating variants already found and curated for mendelian diseases, and will add rare and common variants in common diseases as they are reported. As it does so, HVP participants will develop mechanisms to expedite and automate reporting of variants and their occurrence.

In the consensus-building exercise of the first Human Variome meeting (page 433), delegates constructed a wish list of recommendations that numerically exceeded the number of participants at the meeting. We think that two points emerge as particularly important to the success of the project: publication and credit.

To be successful in persuading clinical and diagnostic laboratories to contribute variations and persuading researchers to evaluate the pathogenic potential of each variant, the HVP will need to introduce publishing innovations at both ends of the citation spectrum. It will need to track the citation of each variant’s accession code in papers, database entries and across the web. This closing of the online publication loop might be termed microattribution. Perhaps existing journals could be persuaded to take responsibility for monitoring and highlighting the citation of database entries in their papers, so that the HVP can readily aggregate this information. A journal devoted to the human variome could commission peer-reviewed, gene-based synopses of mendelian mutations based on information in locus-specific databases (see pages 425 and 427), meta-analyses of association studies and resequencing data such as those reported by Jonathan Cohen and colleagues in this issue (page 513, with News and Views on page 439). Phenotypic and diagnostic information might be linked to these synopses from existing databases such as the dysmorphology databases, PharmGKB (page 426) and GeneTests (http://www.genetests.org). Genome browsers including Ensembl and UCSC might then be persuaded to display a Variome track. We envisage such synopses to be a gene-based extension of the disease-based annual synopses for association studies we proposed last year (Nat. Genet. 38, 1; 2006). The first of these, on Alzheimer disease, was published by Lars Bertram and colleagues (Nat. Genet. 39, 17–23; 2007) using their newly created AlzGene database.

Which genes should the HVP annotate first to demonstrate the utility and impact of its coordinating activities? Perhaps we can learn from one of the most impressive recent exercises in evidence-based medicine: namely, the American College of Medical Genetics‘ systematic prioritization of genes for newborn screening (http://mchb.hrsa.gov/screening/). Variome synopses would take into account the prevalence, seriousness and treatability of the clinical condition(s), the value added by combining all three types of genetic study listed above and the availability of all three kinds of evidence in existing laboratories, databases and publications.

There are, inevitably, limits to what can be achieved by a gene-based view of human variation. Gene models are revised and re-annotated, and structural genomic variation plays havoc with reference genome builds and the context within which point variants and haplotypes are found. Physicians and the general public will want a disease-based view—and the associated diagnostic genetic tests, rather than genome annotation. Delaying the appearance of such alternative views, there is often a many-to-many correspondence between genes and disease phenotypes. On the brighter side, this complexity should provide good business for database designers and review journals.

As the participants of the Variome meeting note in their Commentary, the effort to index and evaluate all of human variation will provide many new opportunities in genomics for researchers whose home countries did not participate in the initial human genome sequencing project. They are right that this is both the project and the time to achieve the globalization of genomics.

SOURCE:

Nature Genetics 39, 423 (2007)
doi:10.1038/ng0407-423

Our Vision for the Future

E-mail

Imagine you are sick. For many, this is not a difficult task. Now imagine you are sick and none of your doctors know why. Your symptoms suggest that you have a rare genetic disease, and you’ve been tested for a mutation in the gene responsible, but the results are inconclusive. The laboratory found a change in your genetic sequence, but is unable to definitively state that it’s what’s causing your symptoms. And with no definitive result from the test, your doctor—and your insurance company—are unwilling to prescribe the expensive course of drugs needed to control your symptoms.While many people might be willing to dismiss the chances of this happening to them, when you start to look at the facts, things start to get a little frightening. There are over 6,000 diseases that can be caused by a mutation in a single gene and it is estimated that 1 child in every 200 born will suffer from one of these diseases. Add to that the number of cancers that have an inherited genetic component and the chances of you, or someone you know being in this position is quite high.

Now imagine that the information the laboratory and your doctor needed to make an accurate diagnosis was out there, but it wasn’t accessible to them: it was hidden away in an obscure academic paper, or in some researcher’s forgotten notes.

Unfortunately, this is the situation that is currently facing thousands of people across the globe who are suffering the devastating effects of genetic illnesses.

The role that our genes play in our health and well-being is well known. The genetic makeup of an individual can cause a host of genetic disorders that can manifest from early childhood (cystic fibrosis, Prader-Willi Syndrome, Fragile X Syndrome) to adulthood (Alzheimer’s disease, polycystic kidney disease, Huntington’s disease) as well as significantly increase the risk of contracting more common diseases such as schizophrenia, diabetes, depression and cancer.

The world is rapidly moving towards an era where it is both economically and scientifically feasible to sequence the genome of every patient presenting with a chronic condition; already in the past decade the cost of a whole-genome sequence has dropped from several billion dollars to a few thousand.

But being able to sequence the genome of a patient cheaply and easily will be useless if we are unable to determine if the variations present in a sequence have an effect on human health. We are suffering from a critical lack of information about the consequences of the vast majority of the mutations possible within the human genome. And, even more concerning, is the fact that even when that information exists, it is not being shared and captured by the global medical research community in a manner that guarantees widespread dissemination and long-term preservation.

The Human Variome Project is trying to change this. We strongly believe in the free and open sharing of information on genetic variation and its consequences and are dedicated to developing and maintaining the standards, systems and infrastructure that will embed information sharing into routine clinical practice. We envision a world where the availability of, and access to, genetic variation information is not an impediment to diagnosis and treatment; where the burden of genetic disease on the human population is significantly decreased; where never again will a doctor have to look at a genetic sequence and ask, “What does this change mean for my patient?”

The Human Variome Project is motivated by the knowledge that by working together, we will be able to significantly reduce the needless physical, psychological, emotional and economic suffering of millions of people.

SOURCE:

http://www.humanvariomeproject.org/index.php/about/our-vision-for-the-future

Human Variome Project International Limited is a not-for-profit Australian public company limited by guarantee that was founded in 2010 to provide central coordination efforts to the global Human Variome Project effort and run the International Coordinating Office. The company has no shareholders and is endorsed by the Australian Tax Office as a deductible gift recipient as a Health Project Charity.

Human Variome Project International Limited, as a company limited by guarantee, is a public unlisted company. It must file accounts annually with the Australian Securities and Investment Commission, it must be audited and, as a public company, the directors and officers of the company must comply with all the duties and responsibilities set out in the Australian Corporations Act. UNESCO also stipulates strict conditions for compliance with its functions and operation as a non-government and non-profit making organisation.

Human Variome Project International’s objects and powers include:

  • to promote the prevention or the control of diseases in human beings
  • to develop and provide educational programs, training and courses in public administration, public sector management, public policy, public affairs and any other related fields
  • to alleviate human suffering by collecting, organising and sharing data on genetic variation;
  • to further the Human Variome Project
  • to act as the co-ordinating office for the Human Variome Project
  • to attract and employ academics, researchers, practitioners and other staff as required to provide and support the services to further the objects of the Company
  • to provide facilities for research, study and education related to the Human Variome Project
  • to carry out and conduct the business of provider of administrative and consulting services;
  • to seek, encourage and accept gifts, grants, donations or endorsements
  • to affiliate with and enter into co-operative agreements with research educational institutions, government, local governments, practitioner bodies, non-government organisations, commercial, cultural and any other institutions or bodies

Company Members

  • Mr David Abraham
  • Professor Richard Cotton
  • Sir John Burn
  • Dr David Rimoin
  • Dr Eric Haan
  • Professor Jean-Jacques Cassiman
  • (representative of) National Institute of Gene Science and Technology Development (China)

SOURCE:
http://www.humanvariomeproject.org/index.php?option=com_content&view=article&id=164&Itemid=152

Scientific Advisory Committee E-mail
The Board of Directors is advised by the Scientific Advisory Committee in matters of strategic scientific direction for current and future projects. The Scientific Advisory Committee has a variety of {ln:roles and responsibilities}, as wells as the delegated authority of the Board of Directors on the publication of all HVP Standards and Guidelines, and the arbitration of any dispute resolution processes in the generation of HVP Standards and Guidelines.The Scientific Advisory Committee consists of twelve members including one Chair. The Scientific Advisory Committee members are elected by the two Advisory Councils every two years, with half the positions on the Committee becoming vacant every two years. The Chair of the Scientific Advisory Committee is appointed by the Coordinating Office from among the members of the Scientific Advisory Committee. Membership of the Committee, in an ex-officio capacity, is also extended to:

  • the Scientific Director of the Human Variome Project Coordinating Office;
  • the President of the Human Genome Variation Society;
  • the President of the International Federation of Human Genetics Societies; and
  • a representative from the central genetic databases, chosen from amongst themselves.

Any Individual Member of the Human Variome Project Consortium is eligible to stand for election to the Scientific Advisory Committee. Candidates must be nominated and seconded by a member of either of the Advisory Councils.

The Scientific Advisory Committee meets on a face–to–face basis once per year, usually in conjunction with the HVP Fora series. The Scientific Advisory Committee also regularly meets via telephone/video–conference.

Current Committee

Arleen Auerbach The Rockefeller University USA
Mireille Claustres IURC, Institut Universitaire Clinical Research France
Richard Cotton Human Variome Project Australia
Garry Cutting Johns Hopkins School of Medicine USA
Johan T. den Dunnen Leiden University Medical Center The Netherlands
Mona El Ruby National Research Centre Egypt
Aida Falcón de Vargas Venezuelan Central University Venezuela
Marc Greenblatt University of Vermont USA
Stephen Lam Hong Kong Department of Health Hong Kong
Finlay Macrae The Royal Melbourne Hospital Australia
Yoichi Matsubara Tohoku University School of Medicine Japan
Gert-Jan B. van Ommen Leiden University Medical Center The Netherlands
Mauno Vihinen Lund University Sweden
Non-Voting Members
Professor Sir John Burn National Institute of Health Research  UK
Ming Qi Zhejiang University Medical School and James Watson Institute of Genome Sciences China
Richard Gibbs Baylor College of Medicine USA

Document Repository

Documents (minutes, etc.) relating to the International Scientific Adviosry Committee can be found here.

SOURCE:

http://www.humanvariomeproject.org/index.php/about/scientific-advisory-committee

Nature Genetics Journal

Table of contents

November 2012, Volume 44 No11 pp1171-1285

  • Credit for clinical trial data –p1171
topof page

News and Views

Tracking the evolution of cancer methylomes –pp1173 – 1174

Arnaud R Krebs & Dirk Schübeler

doi:10.1038/ng.2451

Cellular transformation in cancer has long been associated with aberrant DNA methylation, most notably, hypermethylation of promoter sequences. A new study uses a clever approach of selective high-resolution profiling to follow DNA methylation over a time course of cellular transformation and challenges the notion that hypermethylation in cancer arises in an orchestrated fashion.

Full Text- Tracking the evolution of cancer methylomes | PDF (2,267 KB)- Tracking the evolution of cancer methylomes

See also: Article by Landan et al.

Older males beget more mutations –pp1174 – 1176

Matthew Hurles

doi:10.1038/ng.2448

Three papers characterizing human germline mutation rates bolster evidence for a relatively low rate of base substitution in modern humans and highlight a central role for paternal age in determining rates of mutation. These studies represent the advent of a transformation in our understanding of mutation rates and processes, which may ultimately have public health implications.

Full Text- Older males beget more mutations | PDF (2,319 KB)- Older males beget more mutations

See also: Letter by Campbell et al.

FOXA1 and breast cancer risk –pp1176 – 1177

Kerstin B Meyer & Jason S Carroll

doi:10.1038/ng.2449

Many SNPs associated with human disease are located in non-coding regions of the genome. A new study shows that SNPs associated with breast cancer risk are located in enhancer regions and alter binding affinity for the pioneer factor FOXA1.

Full Text- FOXA1 and breast cancer risk | PDF (254 KB)- FOXA1 and breast cancer risk

See also: Article by Cowper-Sal·lari et al.

Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis –pp1179 – 1181

Lambert Busque, Jay P Patel, Maria E Figueroa, Aparna Vasanthakumar, Sylvie Provost, Zineb Hamilou, Luigina Mollica, Juan Li, Agnes Viale, Adriana Heguy, Maryam Hassimi, Nicholas Socci, Parva K Bhatt, Mithat Gonen, Christopher E Mason, Ari Melnick, Lucy A Godley, Cameron W Brennan, Omar Abdel-Wahab & Ross L Levine

doi:10.1038/ng.2413

Ross Levine, Lambert Busque and colleagues report the identification of recurrent somatic mutations in TET2 in elderly female individuals with clonal hematopoiesis. The mutations were identified in individuals without clinically apparent hematological malignancies.

Abstract- Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis | Full Text- Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis | PDF (324 KB)- Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis | Supplementary information

Genome-wide association study identifies a common variant in RAD51B associated with male breast cancer risk –pp1182 – 1184

Nick Orr, Alina Lemnrau, Rosie Cooke, Olivia Fletcher, Katarzyna Tomczyk, Michael Jones, Nichola Johnson, Christopher J Lord, Costas Mitsopoulos, Marketa Zvelebil, Simon S McDade, Gemma Buck, Christine Blancher, KConFab Consortium, Alison H Trainer, Paul A James, Stig E Bojesen, Susanne Bokmand, Heli Nevanlinna, Johanna Mattson, Eitan Friedman, Yael Laitman, Domenico Palli, Giovanna Masala, Ines Zanna, Laura Ottini, Giuseppe Giannini, Antoinette Hollestelle, Ans M W van den Ouweland, Srdjan Novaković, Mateja Krajc, Manuela Gago-Dominguez, Jose Esteban Castelao, Håkan Olsson, Ingrid Hedenfalk, Douglas F Easton, Paul D P Pharoah, Alison M Dunning, D Timothy Bishop, Susan L Neuhausen, Linda Steele, Richard S Houlston, Montserrat Garcia-Closas, Alan Ashworth & Anthony J Swerdlow

doi:10.1038/ng.2417

Nick Orr and colleagues report a genome-wide association study for male breast cancer. They identify a new susceptibility locus atRAD51B and examine association evidence for known female breast cancer loci in these cohorts.

Abstract- Genome-wide association study identifies a common variant in RAD51B associated with male breast cancer risk | Full Text- Genome-wide association study identifies a common variant in RAD51B associated with male breast cancer risk | PDF (301 KB)- Genome-wide association study identifies a common variant in RAD51B associated with male breast cancer risk | Supplementary information

A common single-nucleotide variant in T is strongly associated with chordoma –pp1185 – 1187

Nischalan Pillay, Vincent Plagnol, Patrick S Tarpey, Samira B Lobo, Nadège Presneau, Karoly Szuhai, Dina Halai, Fitim Berisha, Stephen R Cannon, Simon Mead, Dalia Kasperaviciute, Jutta Palmen, Philippa J Talmud, Lars-Gunnar Kindblom, M Fernanda Amary, Roberto Tirabosco & Adrienne M Flanagan

doi:10.1038/ng.2419

Adrienne Flanagan and colleagues identify a common variant in the T gene associated with strong risk of chordoma, a rare malignant bone tumor. The risk variant alters an amino acid in the DNA-binding domain of the T transcription factor and is associated with differential expression of T and its downstream targets.

Abstract- A common single-nucleotide variant in T is strongly associated with chordoma | Full Text- A common single-nucleotide variant in T is strongly associated with chordoma | PDF (317 KB)- A common single-nucleotide variant in T is strongly associated with chordoma | Supplementary information

Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy –pp1188 – 1190

Sarah E Heron, Katherine R Smith, Melanie Bahlo, Lino Nobili, Esther Kahana, Laura Licchetta, Karen L Oliver, Aziz Mazarib, Zaid Afawi, Amos Korczyn, Giuseppe Plazzi, Steven Petrou, Samuel F Berkovic, Ingrid E Scheffer & Leanne M Dibbens

doi:10.1038/ng.2440

Samuel Berkovic and colleagues report the identification of missense mutations in KCNT1, which encodes a sodium-gated potassium channel, that cause severe autosomal dominant nocturnal frontal lobe epilepsy.

Abstract- Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy | Full Text- Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy | PDF (294 KB)- Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy | Supplementary information


Articles

Breast cancer risk–associated SNPs modulate the affinity of chromatin for FOXA1 and alter gene expression –pp1191 – 1198

Richard Cowper-Sal·lari, Xiaoyang Zhang, Jason B Wright, Swneke D Bailey, Michael D Cole, Jerome Eeckhoute, Jason H Moore & Mathieu Lupien

doi:10.1038/ng.2416

Mathieu Lupien, Jason Moore and colleagues show that breast cancer risk–associated SNPs commonly disrupt the binding of FOXA1 to chromatin, thereby directly affecting gene expression.

Abstract- Breast cancer risk-associated SNPs modulate the affinity of chromatin for FOXA1 and alter gene expression | Full Text- Breast cancer risk–associated SNPs modulate the affinity of chromatin for FOXA1 and alter gene expression | PDF (1,353 KB)- Breast cancer risk–associated SNPs modulate the affinity of chromatin for FOXA1 and alter gene expression | Supplementary information

See also: News and Views by Meyer & Carroll

LIN28B induces neuroblastoma and enhances MYCN levels via let-7 suppression –pp1199 – 1206

Jan J Molenaar, Raquel Domingo-Fernández, Marli E Ebus, Sven Lindner, Jan Koster, Ksenija Drabek, Pieter Mestdagh, Peter van Sluis, Linda J Valentijn, Johan van Nes, Marloes Broekmans, Franciska Haneveld, Richard Volckmann, Isabella Bray, Lukas Heukamp, Annika Sprüssel, Theresa Thor, Kristina Kieckbusch, Ludger Klein-Hitpass, Matthias Fischer, Jo Vandesompele, Alexander Schramm, Max M van Noesel, Luigi Varesio, Frank Speleman, Angelika Eggert, Raymond L Stallings, Huib N Caron, Rogier Versteeg & Johannes H Schulte

doi:10.1038/ng.2436

Jan Molenaar and colleagues show that LIN28B is overexpressed and amplified in human neuroblastomas and that LIN28B regulates let-7 family miRNAs and MYCN. They create a transgenic mouse model of LIN28B overexpression and show that these mice develop neuroblastoma tumors.

Abstract- LIN28B induces neuroblastoma and enhances MYCN levels via let-7 suppression | Full Text- LIN28B induces neuroblastoma and enhances MYCN levels via let-7 suppression | PDF (1,453 KB)- LIN28B induces neuroblastoma and enhances MYCN levels via let-7 suppression | Supplementary information

Epigenetic polymorphism and the stochastic formation of differentially methylated regions in normal and cancerous tissues –pp1207 – 1214

Gilad Landan, Netta Mendelson Cohen, Zohar Mukamel, Amir Bar, Alina Molchadsky, Ran Brosh, Shirley Horn-Saban, Daniela Amann Zalcenstein, Naomi Goldfinger, Adi Zundelevich, Einav Nili Gal-Yam, Varda Rotter & Amos Tanay

doi:10.1038/ng.2442

Amos Tanay and colleagues characterize DNA methylation polymorphism within cell populations and track immortalized fibroblasts in culture for over 300 generations to show that formation of differentially methylated regions occurs through a stochastic process and nearly deterministic epigenetic remodeling.

Abstract- Epigenetic polymorphism and the stochastic formation of differentially methylated regions in normal and cancerous tissues | Full Text- Epigenetic polymorphism and the stochastic formation of differentially methylated regions in normal and cancerous tissues | PDF (1,518 KB)- Epigenetic polymorphism and the stochastic formation of differentially methylated regions in normal and cancerous tissues | Supplementary information

See also: News and Views by Krebs & Schübeler

Intracontinental spread of human invasive SalmonellaTyphimurium pathovariants in sub-Saharan Africa-pp1215 – 1221

Chinyere K Okoro, Robert A Kingsley, Thomas R Connor, Simon R Harris, Christopher M Parry, Manar N Al-Mashhadani, Samuel Kariuki, Chisomo L Msefula, Melita A Gordon, Elizabeth de Pinna, John Wain, Robert S Heyderman, Stephen Obaro, Pedro L Alonso, Inacio Mandomando, Calman A MacLennan, Milagritos D Tapia, Myron M Levine, Sharon M Tennant, Julian Parkhill & Gordon Dougan

doi:10.1038/ng.2423

Gordon Dougan and colleagues report whole-genome sequencing of a global collection of 179 Salmonella Typhimurium isolates, including 129 diverse sub-Saharan African isolates associated with invasive disease. They determine the phylogenetic structure of invasive Salmonella Typhimurium in sub-Saharan Africa and find that the majority are from two closely related highly conserved lineages, which emerged in the last 60 years in close temporal association with the current HIV epidemic.

Abstract- Intracontinental spread of human invasive Salmonella Typhimurium pathovariants in sub-Saharan Africa | Full Text- Intracontinental spread of human invasive Salmonella Typhimurium pathovariants in sub-Saharan Africa | PDF (1,126 KB)- Intracontinental spread of human invasive Salmonella Typhimurium pathovariants in sub-Saharan Africa | Supplementary information


Letters

Genome-wide association study identifies eight new susceptibility loci for atopic dermatitis in the Japanese population –pp1222 – 1226

Tomomitsu Hirota, Atsushi Takahashi, Michiaki Kubo, Tatsuhiko Tsunoda, Kaori Tomita, Masafumi Sakashita, Takechiyo Yamada, Shigeharu Fujieda, Shota Tanaka, Satoru Doi, Akihiko Miyatake, Tadao Enomoto, Chiharu Nishiyama, Nobuhiro Nakano, Keiko Maeda, Ko Okumura, Hideoki Ogawa, Shigaku Ikeda, Emiko Noguchi, Tohru Sakamoto, Nobuyuki Hizawa, Koji Ebe, Hidehisa Saeki, Takashi Sasaki, Tamotsu Ebihara, Masayuki Amagai, Satoshi Takeuchi, Masutaka Furue, Yusuke Nakamura & Mayumi Tamari

doi:10.1038/ng.2438

Mayumi Tamari and colleagues report a genome-wide association study for atopic dermatitis, a chronic inflammatory skin disease, in a Japanese population. They identify eight new susceptibility loci for atopic dermatitis and compare their results to those of previous studies in European and Chinese populations.

First Paragraph- Genome-wide association study identifies eight new susceptibility loci for atopic dermatitis in the Japanese population | Full Text- Genome-wide association study identifies eight new susceptibility loci for atopic dermatitis in the Japanese population | PDF (999 KB)- Genome-wide association study identifies eight new susceptibility loci for atopic dermatitis in the Japanese population | Supplementary information

CSK regulatory polymorphism is associated with systemic lupus erythematosus and influences B-cell signaling and activation –pp1227 – 1230

Nataly Manjarrez-Orduño, Emiliano Marasco, Sharon A Chung, Matthew S Katz, Jenna F Kiridly, Kim R Simpfendorfer, Jan Freudenberg, David H Ballard, Emil Nashi, Thomas J Hopkins, Deborah S Cunninghame Graham, Annette T Lee, Marieke J H Coenen, Barbara Franke, Dorine W Swinkels, Robert R Graham, Robert P Kimberly, Patrick M Gaffney, Timothy J Vyse, Timothy W Behrens, Lindsey A Criswell, Betty Diamond & Peter K Gregersen

doi:10.1038/ng.2439

Peter Gregersen and colleagues identify a regulatory variant inCSK, coding for an intracellular kinase that physically interacts with Lyp (PTPN22), associated with systemic lupus erythematosus (SLE). Their work suggests that the Lyp-Csk complex influences susceptibility to SLE through regulation of B-cell signaling, maturation and activation.

First Paragraph- CSK regulatory polymorphism is associated with systemic lupus erythematosus and influences B-cell signaling and activation | Full Text- CSK regulatory polymorphism is associated with systemic lupus erythematosus and influences B-cell signaling and activation | PDF (747 KB)- CSK regulatory polymorphism is associated with systemic lupus erythematosus and influences B-cell signaling and activation | Supplementary information

Genome-wide association study in Chinese men identifies two new prostate cancer risk loci at 9q31.2 and 19q13.4 –pp1231 – 1235

Jianfeng Xu, Zengnan Mo, Dingwei Ye, Meilin Wang, Fang Liu, Guangfu Jin, Chuanliang Xu, Xiang Wang, Qiang Shao, Zhiwen Chen, Zhihua Tao, Jun Qi, Fangjian Zhou, Zhong Wang, Yaowen Fu, Dalin He, Qiang Wei, Jianming Guo, Denglong Wu, Xin Gao, Jianlin Yuan, Gongxian Wang, Yong Xu, Guozeng Wang, Haijun Yao, Pei Dong, Yang Jiao, Mo Shen, Jin Yang, Jun Ou-Yang, Haowen Jiang, Yao Zhu, Shancheng Ren, Zhengdong Zhang, Changjun Yin, Xu Gao, Bo Dai, Zhibin Hu, Yajun Yang, Qijun Wu, Hongyan Chen, Peng Peng, Ying Zheng, Xiaodong Zheng, Yongbing Xiang, Jirong Long, Jian Gong, Rong Na, Xiaoling Lin, Hongjie Yu, Zhong Wang, Sha Tao, Junjie Feng, Jishan Sun, Wennuan Liu, Ann Hsing, Jianyu Rao, Qiang Ding, Fredirik Wiklund, Henrik Gronberg, Xiao-Ou Shu, Wei Zheng, Hongbing Shen, Li Jin, Rong Shi, Daru Lu, Xuejun Zhang, Jielin Sun, S Lilly Zheng & Yinghao Sun

doi:10.1038/ng.2424

Yinghao Sun and colleagues report a genome-wide association study for prostate cancer in Han Chinese men. They identify two new risk-associated loci at chromosomes 9q31 and 19q13.

First Paragraph- Genome-wide association study in Chinese men identifies two new prostate cancer risk loci at 9q31.2 and 19q13.4 | Full Text- Genome-wide association study in Chinese men identifies two new prostate cancer risk loci at 9q31.2 and 19q13.4 | PDF (686 KB)- Genome-wide association study in Chinese men identifies two new prostate cancer risk loci at 9q31.2 and 19q13.4 | Supplementary information

Epigenomic analysis detects widespread gene-body DNA hypomethylation in chronic lymphocytic leukemia-pp1236 – 1242

Marta Kulis, Simon Heath, Marina Bibikova, Ana C Queirós, Alba Navarro, Guillem Clot, Alejandra Martínez-Trillos, Giancarlo Castellano, Isabelle Brun-Heath, Magda Pinyol, Sergio Barberán-Soler, Panagiotis Papasaikas, Pedro Jares, Sílvia Beà, Daniel Rico, Simone Ecker, Miriam Rubio, Romina Royo, Vincent Ho, Brandy Klotzle, Lluis Hernández, Laura Conde, Mónica López-Guerra, Dolors Colomer, Neus Villamor, Marta Aymerich, María Rozman, Mónica Bayes, Marta Gut, Josep L Gelpí, Modesto Orozco, Jian-Bing Fan, Víctor Quesada, Xose S Puente, David G Pisano, Alfonso Valencia, Armando López-Guillermo, Ivo Gut, Carlos López-Otín, Elías Campo & José I Martín-Subero

doi:10.1038/ng.2443

José Martin-Subero and colleagues report whole-genome bisulfite sequencing and methylome analysis of two CLLs and three B-cell subpopulations using high-density microarrays on 139 CLLs. They identify widespread hypomethylation in the gene body that is largely associated with intragenic enhancer elements.

First Paragraph- Epigenomic analysis detects widespread gene-body DNA hypomethylation in chronic lymphocytic leukemia | Full Text- Epigenomic analysis detects widespread gene-body DNA hypomethylation in chronic lymphocytic leukemia | PDF (2,067 KB)- Epigenomic analysis detects widespread gene-body DNA hypomethylation in chronic lymphocytic leukemia | Supplementary information

Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature –pp1243 – 1248

Gillian I Rice, Paul R Kasher, Gabriella M A Forte, Niamh M Mannion, Sam M Greenwood, Marcin Szynkiewicz, Jonathan E Dickerson, Sanjeev S Bhaskar, Massimiliano Zampini, Tracy A Briggs, Emma M Jenkinson, Carlos A Bacino, Roberta Battini, Enrico Bertini, Paul A Brogan, Louise A Brueton, Marialuisa Carpanelli, Corinne De Laet, Pascale de Lonlay, Mireia del Toro, Isabelle Desguerre, Elisa Fazzi, Àngels Garcia-Cazorla, Arvid Heiberg, Masakazu Kawaguchi, Ram Kumar, Jean-Pierre S-M Lin, Charles M Lourenco, Alison M Male, Wilson Marques Jr, Cyril Mignot, Ivana Olivieri, Simona Orcesi, Prab Prabhakar, Magnhild Rasmussen, Robert A Robinson, Flore Rozenberg, Johanna L Schmidt, Katharina Steindl, Tiong Y Tan, William G van der Merwe, Adeline Vanderver, Grace Vassallo, Emma L Wakeling, Evangeline Wassmer, Elizabeth Whittaker, John H Livingston, Pierre Lebon, Tamio Suzuki, Paul J McLaughlin, Liam P Keegan, Mary A O’Connell, Simon C Lovell & Yanick J Crow

doi:10.1038/ng.2414

Yanick Crow and colleagues show that mutations in ADAR1 cause the autoimmune disorder Aicardi-Goutières syndrome, accompanied by upregulation of interferon-stimulated genes.ADAR1 encodes an enzyme that catalyzes the deamination of adeonosine to inosine in double-stranded RNA, and the findings suggest a possible role for RNA editing in limiting the accumulation of repeat-derived RNA species.

First Paragraph- Mutations in ADAR1 cause Aicardi-Goutieres syndrome associated with a type I interferon signature | Full Text- Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature | PDF (844 KB)- Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature | Supplementary information

Mutations in the TGF-β repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm-pp1249 – 1254

Alexander J Doyle, Jefferson J Doyle, Seneca L Bessling, Samantha Maragh, Mark E Lindsay, Dorien Schepers, Elisabeth Gillis, Geert Mortier, Tessa Homfray, Kimberly Sauls, Russell A Norris, Nicholas D Huso, Dan Leahy, David W Mohr, Mark J Caulfield, Alan F Scott, Anne Destrée, Raoul C Hennekam, Pamela H Arn, Cynthia J Curry, Lut Van Laer, Andrew S McCallion, Bart L Loeys & Harry C Dietz

doi:10.1038/ng.2421

Harry Dietz and colleagues report the identification of mutations in SKI in Shprintzen-Goldberg syndrome, which shares features with Marfan syndrome and Loeys-Dietz syndrome. SKI encodes a known repressor of TGF-β activity, and this work provides evidence for paradoxical increased TGF-β signaling as the mechanism underlying these related syndromes.

First Paragraph- Mutations in the TGF-[beta] repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm | Full Text- Mutations in the TGF-β repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm | PDF (1,158 KB)- Mutations in the TGF-β repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm | Supplementary information

De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy-pp1255 – 1259

Giulia Barcia, Matthew R Fleming, Aline Deligniere, Valeswara-Rao Gazula, Maile R Brown, Maeva Langouet, Haijun Chen, Jack Kronengold, Avinash Abhyankar, Roberta Cilio, Patrick Nitschke, Anna Kaminska, Nathalie Boddaert, Jean-Laurent Casanova, Isabelle Desguerre, Arnold Munnich, Olivier Dulac, Leonard K Kaczmarek, Laurence Colleaux & Rima Nabbout

doi:10.1038/ng.2441

Rima Nabbout and colleagues report the identification of de novomutations in the KCNT1 potassium channel gene in individuals with malignant migrating partial seizures of infancy, a rare epileptic encephalopathy with pharmacoresistant seizures and developmental delay. The authors show that the mutations have a gain-of-function effect on KCNT1 channel activity.

First Paragraph- De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy | Full Text- De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy | PDF (745 KB)- De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy | Supplementary information

CHMP1A encodes an essential regulator of BMI1-INK4A in cerebellar development –pp1260 – 1264

Ganeshwaran H Mochida, Vijay S Ganesh, Maria I de Michelena, Hugo Dias, Kutay D Atabay, Katie L Kathrein, Hsuan-Ting Huang, R Sean Hill, Jillian M Felie, Daniel Rakiec, Danielle Gleason, Anthony D Hill, Athar N Malik, Brenda J Barry, Jennifer N Partlow, Wen-Hann Tan, Laurie J Glader, A James Barkovich, William B Dobyns, Leonard I Zon & Christopher A Walsh

doi:10.1038/ng.2425

Christopher Walsh and colleagues identify mutations in CHMP1Ain human cerebellar hypoplasia and microcephaly. Cells lackingCHMP1A show decreased cell proliferation and decreased expression of BMI1, a negative regulator of stem cell proliferation.

First Paragraph- CHMP1A encodes an essential regulator of BMI1-INK4A in cerebellar development | Full Text- CHMP1A encodes an essential regulator of BMI1-INK4A in cerebellar development | PDF (1,449 KB)- CHMP1A encodes an essential regulator of BMI1-INK4A in cerebellar development | Supplementary information

Alterations of the CIB2 calcium- and integrin-binding protein cause Usher syndrome type 1J and nonsyndromic deafness DFNB48 –pp1265 – 1271

Saima Riazuddin, Inna A Belyantseva, Arnaud P J Giese, Kwanghyuk Lee, Artur A Indzhykulian, Sri Pratima Nandamuri, Rizwan Yousaf, Ghanshyam P Sinha, Sue Lee, David Terrell, Rashmi S Hegde, Rana A Ali, Saima Anwar, Paula B Andrade-Elizondo, Asli Sirmaci, Leslie V Parise, Sulman Basit, Abdul Wali, Muhammad Ayub, Muhammad Ansar, Wasim Ahmad, Shaheen N Khan, Javed Akram, Mustafa Tekin, Sheikh Riazuddin, Tiffany Cook, Elke K Buschbeck, Gregory I Frolenkov, Suzanne M Leal, Thomas B Friedman & Zubair M Ahmed

doi:10.1038/ng.2426

Zubair Ahmed and colleagues identify homozygous mutations inCIB2, a gene that encodes a calcium- and integrin-binding protein, that cause Usher syndrome type 1J and nonsyndromic deafness DFNB48. CIB2 is required for hair cell development and retinal photoreceptor cells in zebrafish and Drosophila melanogaster.

First Paragraph- Alterations of the CIB2 calcium- and integrin-binding protein cause Usher syndrome type 1J and nonsyndromic deafness DFNB48 | Full Text- Alterations of the CIB2 calcium- and integrin-binding protein cause Usher syndrome type 1J and nonsyndromic deafness DFNB48 | PDF (1,380 KB)- Alterations of the CIB2 calcium- and integrin-binding protein cause Usher syndrome type 1J and nonsyndromic deafness DFNB48 | Supplementary information

Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma –pp1272 – 1276

Elizabeth Pohler, Ons Mamai, Jennifer Hirst, Mozheh Zamiri, Helen Horn, Toshifumi Nomura, Alan D Irvine, Benvon Moran, Neil J Wilson, Frances J D Smith, Christabelle S M Goh, Aileen Sandilands, Christian Cole, Geoffrey J Barton, Alan T Evans, Hiroshi Shimizu, Masashi Akiyama, Mitsuhiro Suehiro, Izumi Konohana, Mohammad Shboul, Sebastien Teissier, Lobna Boussofara, Mohamed Denguezli, Ali Saad, Moez Gribaa, Patricia J Dopping-Hepenstal, John A McGrath, Sara J Brown, David R Goudie, Bruno Reversade, Colin S Munro & W H Irwin McLean

doi:10.1038/ng.2444

Irwin McLean and colleagues report that heterozygous loss-of-function mutations in AAGAB, which encodes a cytosolic protein implicated in vesicular trafficking, cause punctate palmoplantar keratoderma. They further show that knockdown of AAGAB in keratinocytes leads to increased cell proliferation accompanied by highly elevated levels of epidermal growth factor receptor.

First Paragraph- Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma | Full Text- Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma | PDF (848 KB)- Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma | Supplementary information

Estimating the human mutation rate using autozygosity in a founder population –pp1277 – 1281

Catarina D Campbell, Jessica X Chong, Maika Malig, Arthur Ko, Beth L Dumont, Lide Han, Laura Vives, Brian J O’Roak, Peter H Sudmant, Jay Shendure, Mark Abney, Carole Ober & Evan E Eichler

doi:10.1038/ng.2418

Evan Eichler and colleagues report an estimate of the mutation rate in humans that is based on the whole-genome sequences of five parent-offspring trios from a Hutterite population and genotyping data from an extended pedigree. They use a new approach for estimating the mutation rate over multiple generations that takes into account the extensive autozygosity in this founder population.

First Paragraph- Estimating the human mutation rate using autozygosity in a founder population | Full Text- Estimating the human mutation rate using autozygosity in a founder population | PDF (620 KB)- Estimating the human mutation rate using autozygosity in a founder population | Supplementary information

See also: News and Views by Hurles

Variation in germline mtDNA heteroplasmy is determined prenatally but modified during subsequent transmission –pp1282 – 1285

Christoph Freyer, Lynsey M Cree, Arnaud Mourier, James B Stewart, Camilla Koolmeister, Dusanka Milenkovic, Timothy Wai, Vasileios I Floros, Erik Hagström, Emmanouella E Chatzidaki, Rudolf J Wiesner, David C Samuels, Nils-Göran Larsson & Patrick F Chinnery

doi:10.1038/ng.2427

Patrick Chinnery, Nils-Goran Larsson and colleagues show that mitochondrial heteroplasmy levels are principally determined prenatally within the developing female germline in mice transmitting a heteroplasmic single base-pair deletion in the mitochondrial tRNAMet gene.

First Paragraph- Variation in germline mtDNA heteroplasmy is determined prenatally but modified during subsequent transmission | Full Text- Variation in germline mtDNA heteroplasmy is determined prenatally but modified during subsequent transmission | PDF (523 KB)- Variation in germline mtDNA heteroplasmy is determined prenatally but modified during subsequent transmission | Supplementary information

SOURCE:

http://www.nature.com/ng/journal/v44/n11/index.html 

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Reporter: Aviva Lev-Ari, PhD, RN

Australian-led Team Reports on New Nocturnal Epilepsy Gene

October 22, 2012

NEW YORK (GenomeWeb News) – An international team led by investigators in Australia has linked mutations in a sodium-gated potassium channel subunit gene to a subset of severe nocturnal frontal lobe epilepsy cases.

As they reported online yesterday in Nature Genetics, the researchers began by testing a family with autosomal dominant nocturnal frontal lobe epilepsy, or ADNFLE. Affected members of the family often had not only typical ADNFLE symptoms, but also intellectual and/or psychiatric features that don’t usually characterize the disorder.

After narrowing in on a chromosome 9 region via linkage analyses in the family, the team identified ADNFLE-associated missense mutations in the sodium-gated potassium channel subunit gene KCNT1 by whole-exome sequencing in two affected family members. Follow-up testing on more than 100 other unrelated individuals with nocturnal frontal lobe epilepsy indicated that both inherited and de novo mutations in the gene can cause severe forms of the conditions that tend to include other co-morbidities.

“KCNT1 mutations were identified in two additional families and a sporadic case with severe ADNFLE and psychiatric features,” University of South Australia researcher Leanne Dibbens and the University of Melbourne’s Ingrid Scheffer, the study’s co-corresponding authors, and their colleagues wrote.

“These findings implicate the sodium-gated potassium channel complex in ADNFLE, and, more broadly, in the pathogenesis of focal epilepsies,” they added.

As the name suggests, ADNFLE is inherited in an autosomal dominant manner in affected families. Symptoms of the condition — including seizures that occur while individuals are asleep — generally appear in childhood, the researchers explained. And previous studies have implicated mutations to nicotinic acetylcholine receptor subunit genes in a subset of ADNFLE cases.

For the current study, the team focused on a multi-generational family with an especially severe form of ADNFLE that was accompanied by other symptoms such as intellectual disability and psychiatric disorders.

Genome-wide linkage analyses within the family led to a suspicious 2.36 million base stretch of sequence on chromosome 9, which housed almost 100 genes. Among them: two ion channel-coding genes, KCNT1 and GRIN1.

For two of the affected family members, the team turned to whole-exome sequencing to try to track down the most likely cause of ADNFLE. Indeed, missense mutations in KCNT1 that were predicted to be pathogenic turned up in one of the two exome sequences.

The mutation was not initially identified in the other family member’s exome sequence data, owing to low coverage, researchers explained. But it was subsequently shown to be present in both individuals by Sanger sequencing.

Consistent with the notion that this KCNT1 mutation could be related to ADNFLE pathogenesis, the investigators did not find it when they tested 111 unaffected, ancestry-matched individuals. Nor did it turn up in the dbSNP database, they reported, or in data generated for the 1000 Genomes Project or through the National Heart, Lung, and Blood Institute’s Exome Sequencing Project.

On the other hand, the team did find mutations in KCNT1 when it assessed another 108 unrelated individuals who either had ADNFLE or sporadically occurring nocturnal frontal lobe epilepsy.

That analysis helped the investigators track down two more ADNFLE-affected families with KCNT1 mutations that co-segregated with the disease, along with one case of sporadic nocturnal frontal lobe epilepsy including psychiatric features that seemed to stem from de novo mutations to KCNT1.

“[T]he phenotype associated with KNCT1 mutations is both more severe and more penetrant than that typically found with mutations affecting [nicotinic acetylcholine receptors],” the study’s authors noted.

In addition to showing more pronounced ADNFLE symptoms, they explained, the disease appears to manifest itself at a younger age in the cases linked to KCNT1 mutations.

Moreover, several cases that appear to be caused by alterations to KCNT1 also included intellectual disability, psychiatric, and/or behavioral features. The severity of such symptoms varied from one individual to the next — a pattern that the researchers speculated might be due to differences in the nature and extent of the KCNT1 mutation involved.

In addition to providing clues to help classify ADNFLE cases and offer genetic counseling for families affected by it, those involved in the study say the results should also prove useful for understanding — and potentially targeting — the processes that underlie this type of epilepsy.

“[T]his finding should provide new insights into the biological mechanisms underlying the pathogenesis of ADNFLE,” they concluded, “which may lead to targeted therapies addressing the serious co-morbidities as well as the debilitating seizure disorder.”

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