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  • Open Access
    Authors: 
    Barry A. Chioza; Jean Aicardi; Harald N. Aschauer; Oebele F. Brouwer; Petra M.C. Callenbach; Athanasios Covanis; Joseph M. Dooley; Olivier Dulac; Martina Durner; Orvar Eeg-Olofsson; +13 more
    Publisher: Elsevier BV
    Countries: Netherlands, United Kingdom, United Kingdom, Denmark
    Project: WT

    Childhood absence epilepsy (CAE) is an idiopathic generalised epilepsy (IGE) characterised by typical absence seizures manifested by transitory loss of awareness with 2.5-4 Hz spike-wave complexes on ictal EEG. A genetic component to the aetiology is wet[ recognised but the mechanism of inheritance and the genes involved are yet to be fully established.A genome wide single nucleotide polymorphism (SNP)-based high density linkage scan was carried out using 41 nuclear pedigrees with at least two affected members. Multipoint parametric and non-parametric linkage analyses were performed using MERLIN 1.1.1 and a susceptibility locus was identified on chromosome 3p23-p14 (Z(mean) = 3.9, p < 0.0001; HLOD = 3.3, alpha = 0.7). The (inked region harbours the functional candidate genes TRAK1 and CACNA2D2. Fine-mapping using a tagSNP approach demonstrated disease association with variants in TRAK1. (C) 2009 Elsevier B.V. All rights reserved.

  • Publication . Article . Conference object . Preprint . 2019
    Open Access English
    Authors: 
    Rianne de Heide; Alisa Kirichenko; Nishant Mehta; Peter Grünwald;
    Country: Netherlands

    We study generalized Bayesian inference under misspecification, i.e. when the model is 'wrong but useful'. Generalized Bayes equips the likelihood with a learning rate $\eta$. We show that for generalized linear models (GLMs), $\eta$-generalized Bayes concentrates around the best approximation of the truth within the model for specific $\eta \neq 1$, even under severely misspecified noise, as long as the tails of the true distribution are exponential. We derive MCMC samplers for generalized Bayesian lasso and logistic regression and give examples of both simulated and real-world data in which generalized Bayes substantially outperforms standard Bayes. Comment: Final version. Accepted to AISTATS 2020

  • Publication . Article . Preprint . Other literature type . 2013
    Open Access English
    Authors: 
    Sarah E. Medland; Jaime Derringer; Jian Yang; Tõnu Esko; Nicolas W. Martin; Konstantin Shakhbazov; Abdel Abdellaoui; Arpana Agrawal; Eva Albrecht; Behrooz Z. Alizadeh; +173 more
    Countries: Netherlands, United States, United Kingdom, Croatia, Australia
    Project: WT , NIH | FINANCIAL STATUS--RETIREM... (2P01AG005842-04), NIH | ECONOMICS OF AGING TRAINI... (5T32AG000186-10), EC | DEVHEALTH (269874), NSF | EAGER Proposal: Workshop ... (1064089), EC | GMI (230374), NIH | NBER Center for Aging and... (5P30AG012810-15)

    A genome-wide association study (GWAS) of educational attainment was conducted in a discovery sample of 101,069 individuals and a replication sample of 25,490. Three independent single-nucleotide polymorphisms (SNPs) are genome-wide significant (rs9320913, rs11584700, rs4851266), and all three replicate. Estimated effects sizes are small (coefficient of determination R2 ≈ 0.02%), approximately 1 month of schooling per allele. A linear polygenic score from all measured SNPs accounts for ≈2% of the variance in both educational attainment and cognitive function. Genes in the region of the loci have previously been associated with health, cognitive, and central nervous system phenotypes, and bioinformatics analyses suggest the involvement of the anterior caudate nucleus. These findings provide promising candidate SNPs for follow-up work, and our effect size estimates can anchor power analyses in social-science genetics. Economics

  • Open Access English
    Authors: 
    Sanaz Yahyanejad; Henry King; Venus Sosa Iglesias; Patrick V. Granton; Lydie M. O. Barbeau; Stefan J. van Hoof; Arjan J. Groot; Roger Habets; Jos Prickaerts; Anthony J. Chalmers; +5 more
    Countries: Netherlands, United Kingdom, United Kingdom
    Project: EC | DIRECT (617060)

    Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults. The current standard of care includes surgery followed by radiotherapy (RT) and chemotherapy with temozolomide (TMZ). Treatment often fails due to the radiation resistance and intrinsic or acquired TMZ resistance of a small percentage of cells with stem cell-like behavior (CSC). The NOTCH signaling pathway is expressed and active in human glioblastoma and NOTCH inhibitors attenuate tumor growth in vivo in xenograft models. Here we show using an image guided micro-CT and precision radiotherapy platform that a combination of the clinically approved NOTCH/γ-secretase inhibitor (GSI) RO4929097 with standard of care (TMZ + RT) reduces tumor growth and prolongs survival compared to dual combinations. We show that GSI in combination with RT and TMZ attenuates proliferation, decreases 3D spheroid growth and results into a marked reduction in clonogenic survival in primary and established glioma cell lines. We found that the glioma stem cell marker CD133, SOX2 and Nestin were reduced following combination treatments and NOTCH inhibitors albeit in a different manner. These findings indicate that NOTCH inhibition combined with standard of care treatment has an anti-glioma stem cell effect which provides an improved survival benefit for GBM and encourages further translational and clinical studies.

  • Open Access
    Authors: 
    Hatef Darabi; Karen McCue; Jonathan Beesley; Kyriaki Michailidou; Silje Nord; Siddhartha Kar; Keith Humphreys; Deborah J. Thompson; Maya Ghoussaini; Manjeet K. Bolla; +119 more
    Countries: Netherlands, United Kingdom

    Genome-wide association studies have identified SNPs near ZNF365 at 10q21.2 that are associated with both breast cancer risk and mammographic density. To identify the most likely causal SNPs, we fine mapped the association signal by genotyping 428 SNPs across the region in 89,050 European and 12,893 Asian case and control subjects from the Breast Cancer Association Consortium. We identified four independent sets of correlated, highly trait-associated variants (iCHAVs), three of which were located within ZNF365. The most strongly risk-associated SNP, rs10995201 in iCHAV1, showed clear evidence of association with both estrogen receptor (ER)-positive (OR = 0.85 [0.82-0.88]) and ER-negative (OR = 0.87 [0.82-0.91]) disease, and was also the SNP most strongly associated with percent mammographic density. iCHAV2 (lead SNP, chr10: 64,258,684:D) and iCHAV3 (lead SNP, rs7922449) were also associated with ER-positive (OR = 0.93 [0.91-0.95] and OR = 1.06 [1.03-1.09]) and ER-negative (OR = 0.95 [0.91-0.98] and OR = 1.08 [1.04-1.13]) disease. There was weaker evidence for iCHAV4, located 5' of ADO, associated only with ER-positive breast cancer (OR = 0.93 [0.90-0.96]). We found 12, 17, 18, and 2 candidate causal SNPs for breast cancer in iCHAVs 1-4, respectively. Chromosome conformation capture analysis showed that iCHAV2 interacts with the ZNF365 and NRBF2 (more than 600 kb away) promoters in normal and cancerous breast epithelial cells. Luciferase assays did not identify SNPs that affect transactivation of ZNF365, but identified a protective haplotype in iCHAV2, associated with silencing of the NRBF2 promoter, implicating this gene in the etiology of breast cancer. This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.ajhg.2015.05.002.

  • Open Access
    Authors: 
    Suhua Wei; Chuixiang Yi; George R. Hendrey; Timothy T. Eaton; G. T. Rustic; Shaoqiang Wang; Heping Liu; Nir Y. Krakauer; Weiguo Wang; Ankur R. Desai; +11 more
    Publisher: IOP Publishing
    Country: Netherlands
    Project: NSF | Climate control of terres... (0949637)

    Several lines of evidence suggest that the warming climate plays a vital role in driving certain types of extreme weather. The impact of this warming and extreme weather on forest carbon assimilation capacity is poorly known. Filling this knowledge gap is critical towards understanding changing the amount of carbon that forests can hold. Here, we used a perfect-deficit approach to identify forest canopy photosynthetic capacity (CPC) deficits and analyze how they correlate to climate extremes, based on data measured by the eddy covariance method at 26 forest sites integrating 146 site-years. We found that droughts severely affect the carbon assimilation capacities of evergreen broadleaf forest and deciduous broadleaf forest. In addition, the carbon assimilation capacities of Mediterranean forests are highly sensitive to climate extremes, while marine forest climates tend to be insensitive to climate extremes. Our estimates suggest an average global reduction of forest canopy photosynthetic capacity of 6.3petagramsof carbon per growing season over 2001-2010, with evergreen broadleaf forests contributing 51.7% of the total reduction. JRC.H.7-Climate Risk Management

  • Open Access English
    Authors: 
    Adriaan A. Voors; Hillary Mulder; Eugene B. Reyes; Martin R. Cowie; Johan Lassus; Adrian F. Hernandez; Justin A. Ezekowitz; Javed Butler; Christopher M. O'Connor; Joerg Koglin; +6 more
    Countries: Netherlands, Finland, Netherlands, United Kingdom

    Abstract Aims Vericiguat reduced the primary composite outcome of cardiovascular death or heart failure (HF) hospitalization in patients with worsening HF with reduced ejection fraction (HFrEF) and a lower limit of baseline estimated glomerular filtration rate (eGFR) of 15 mL/min/1.73 m2. We evaluated the relationship between the efficacy of vericiguat and baseline and subsequent changes in renal function. Methods and results In VICTORIA, core laboratory serum creatinine was measured at baseline (n = 4956) and weeks 16, 32, and 48. Worsening renal function (WRF), defined as an increase ≥0.3 mg/dL in creatinine from baseline to week 16, was assessed via a Cox model with respect to subsequent primary events. Mean age was 69 years, 24% were female, and mean baseline eGFR was 61 mL/min/1.73 m2. During 48 weeks of treatment, the trajectories in eGFR and creatinine with vericiguat were similar to placebo (P = 0.50 and 0.18). The beneficial effects of vericiguat on the primary outcome were not influenced by baseline eGFR (interaction P = 0.48). WRF occurred in 15% of patients and was associated with worse outcomes (adjusted hazard ratio 1.28, 95% confidence interval 1.11–1.47; P < 0.001), but the beneficial effects of vericiguat on the primary outcome were similar in patients with or without WRF (interaction P = 0.76). Conclusion Renal function trajectories were similar between vericiguat‐ and placebo‐treated patients and the beneficial effects of vericiguat on the primary outcome were consistent across the full range of eGFR and irrespective of WRF. The left panel shows no differences in the change in creatinine (P = 0.18) between the vericiguat and placebo groups, as evaluated by the interaction between treatment and study visit in the model. The right panel shows a natural cubic spline plot showing that the treatment effect of vericiguat on the primary outcome was similar across the full range of estimated glomerular filtration rate (eGFR) (P = 0.23).

  • Open Access English
    Authors: 
    Fergus J. Couch; Karoline Kuchenbaecker; Kyriaki Michailidou; Janna Lilyquist; Curtis Olswold; Emily Hallberg; Simona Agata; Habibul Ahsan; Christine B. Ambrosone; Irene L. Andrulis; +206 more
    Publisher: Nature Publishing Group
    Countries: United Kingdom, Finland, United Kingdom, Belgium, Belgium, Iceland, Spain, Spain, Norway, Germany ...
    Project: NWO | Secure and gentle grip of... (2300183393), NIH | A genome-wide association... (5R01CA128978-02), WT , EC | COGS (223175), NIH | Elucidating Loci Involved... (5U19CA148537-02), CIHR , NIH | Discovery Expansion and R... (5U19CA148065-04), NIH | Follow-up of Ovarian Canc... (3U19CA148112-04S1)

    Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 × 10(-8)) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for ∼11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction. B.C.A.C. was funded through a European Community Seventh Framework Programme under grant agreement no 223175 (HEALTH-F2-2009-223175; COGS); Cancer Research UK (C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692); the National Institutes of Health Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), R01 grants (CA128978, CA176785, CA192393), and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative); the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, the Breast Cancer Res. Foundation, and the Ovarian Cancer Research Fund. CIMBA genotyping was supported by National Institutes of Health grant (CA128978); the Department of Defence (W81XWH-10-1-0341); and the Breast Cancer Res. Foundation. CIMBA data management and data analysis were supported by Cancer Research UK grants C12292/A11174 and C1287/A10118. This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/ncomms11375

  • Open Access
    Authors: 
    Montserrat Garcia-Closas; Kyriaki Michailidou; Marjanka K. Schmidt; Mark N. Brook; Suhn K. Rhie; Elio Riboli; Julie E. Buring; Diana Eccles; Penelope Miron; Peter A. Fasching; +203 more
    Publisher: Springer Nature
    Countries: United Kingdom, Ireland, Netherlands, United Kingdom
    Project: WT , NIH | Breast &Prostate Cancer &... (1U01CA098758-01), NIH | Characterizing Genetic Su... (5U01CA098233-06), NIH | Genetic epidemiology of c... (3R01CA122340-03S1), NIH | Characterizing Genetic Su... (5U01CA098710-06), CIHR , NIH | Breast &prostate cancer &... (1U01CA098216-01), EC | COGS (223175), NIH | Discovery Expansion and R... (5U19CA148065-04)

    Estrogen receptor (ER)-negative tumors represent 20-30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry. The etiology and clinical behavior of ER-negative tumors are different from those of tumors expressing ER (ER positive), including differences in genetic predisposition. To identify susceptibility loci specific to ER-negative disease, we combined in a metaanalysis 3 genome-wide association studies of 4,193 ER-negative breast cancer cases and 35,194 controls with a series of 40 follow-up studies (6,514 cases and 41,455 controls), genotyped using a custom Illumina array, iCOGS, developed by the Collaborative Oncological Gene-environment Study (COGS). SNPs at four loci, 1q32.1 (MDM4, P= 2.1 x 10(-12) and LGR6, P = 1.4 x 10(-8)), 2p24.1 (P = 4.6 x 10(-8)) and 16q12.2 (FTO, P = 4.0 x 10(-8)), were associated with ER-negative but not ER-positive breast cancer (P&gt; 0.05). These findings provide further evidence for distinct etiological pathways associated with invasive ER-positive and ER-negative breast cancers.

  • Open Access
    Authors: 
    R. Thomas Lumbers; Sonia Shah; Honghuang Lin; Tomasz Czuba; Albert Henry; Daniel I. Swerdlow; Anders Mälarstig; Charlotte Andersson; Niek Verweij; Michael V. Holmes; +156 more
    Publisher: Wiley
    Countries: France, France, United Kingdom, Sweden, Sweden, Denmark, Denmark, United Kingdom, United Kingdom, Netherlands
    Project: EC | BigData Heart (116074), EC | inHForm (679242)

    Abstract: Aims: The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure. Methods and results: The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome‐wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow‐up following heart failure diagnosis ranged from 2 to 116 months. Forty‐nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34–90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low‐frequency variants (allele frequency 0.01–0.05) at P < 5 × 10−8 under an additive genetic model. Conclusions: HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction. Funder: Department of Medicine, Boston University School of Medicine; Id: http://dx.doi.org/10.13039/100008748 Funder: National Heart, Lung, and Blood Institute; Id: http://dx.doi.org/10.13039/100000050 Funder: Knut and Alice Wallenberg Foundation; Id: http://dx.doi.org/10.13039/501100004063 Funder: NIHR UCLH Biomedical Research Centre; Id: http://dx.doi.org/10.13039/501100012317 Funder: Skåne University Hospital; Id: http://dx.doi.org/10.13039/501100011077 Funder: Evans Medical Foundation; Id: http://dx.doi.org/10.13039/100015927 Funder: Crafoord Foundation; Id: http://dx.doi.org/10.13039/501100003173 Funder: British Heart Foundation Cardiovascular Biomedicine Funder: Swedish National Health Service

search
Include:
The following results are related to Canada. Are you interested to view more results? Visit OpenAIRE - Explore.
2,087 Research products, page 1 of 209
  • Open Access
    Authors: 
    Barry A. Chioza; Jean Aicardi; Harald N. Aschauer; Oebele F. Brouwer; Petra M.C. Callenbach; Athanasios Covanis; Joseph M. Dooley; Olivier Dulac; Martina Durner; Orvar Eeg-Olofsson; +13 more
    Publisher: Elsevier BV
    Countries: Netherlands, United Kingdom, United Kingdom, Denmark
    Project: WT

    Childhood absence epilepsy (CAE) is an idiopathic generalised epilepsy (IGE) characterised by typical absence seizures manifested by transitory loss of awareness with 2.5-4 Hz spike-wave complexes on ictal EEG. A genetic component to the aetiology is wet[ recognised but the mechanism of inheritance and the genes involved are yet to be fully established.A genome wide single nucleotide polymorphism (SNP)-based high density linkage scan was carried out using 41 nuclear pedigrees with at least two affected members. Multipoint parametric and non-parametric linkage analyses were performed using MERLIN 1.1.1 and a susceptibility locus was identified on chromosome 3p23-p14 (Z(mean) = 3.9, p < 0.0001; HLOD = 3.3, alpha = 0.7). The (inked region harbours the functional candidate genes TRAK1 and CACNA2D2. Fine-mapping using a tagSNP approach demonstrated disease association with variants in TRAK1. (C) 2009 Elsevier B.V. All rights reserved.

  • Publication . Article . Conference object . Preprint . 2019
    Open Access English
    Authors: 
    Rianne de Heide; Alisa Kirichenko; Nishant Mehta; Peter Grünwald;
    Country: Netherlands

    We study generalized Bayesian inference under misspecification, i.e. when the model is 'wrong but useful'. Generalized Bayes equips the likelihood with a learning rate $\eta$. We show that for generalized linear models (GLMs), $\eta$-generalized Bayes concentrates around the best approximation of the truth within the model for specific $\eta \neq 1$, even under severely misspecified noise, as long as the tails of the true distribution are exponential. We derive MCMC samplers for generalized Bayesian lasso and logistic regression and give examples of both simulated and real-world data in which generalized Bayes substantially outperforms standard Bayes. Comment: Final version. Accepted to AISTATS 2020

  • Publication . Article . Preprint . Other literature type . 2013
    Open Access English
    Authors: 
    Sarah E. Medland; Jaime Derringer; Jian Yang; Tõnu Esko; Nicolas W. Martin; Konstantin Shakhbazov; Abdel Abdellaoui; Arpana Agrawal; Eva Albrecht; Behrooz Z. Alizadeh; +173 more
    Countries: Netherlands, United States, United Kingdom, Croatia, Australia
    Project: WT , NIH | FINANCIAL STATUS--RETIREM... (2P01AG005842-04), NIH | ECONOMICS OF AGING TRAINI... (5T32AG000186-10), EC | DEVHEALTH (269874), NSF | EAGER Proposal: Workshop ... (1064089), EC | GMI (230374), NIH | NBER Center for Aging and... (5P30AG012810-15)

    A genome-wide association study (GWAS) of educational attainment was conducted in a discovery sample of 101,069 individuals and a replication sample of 25,490. Three independent single-nucleotide polymorphisms (SNPs) are genome-wide significant (rs9320913, rs11584700, rs4851266), and all three replicate. Estimated effects sizes are small (coefficient of determination R2 ≈ 0.02%), approximately 1 month of schooling per allele. A linear polygenic score from all measured SNPs accounts for ≈2% of the variance in both educational attainment and cognitive function. Genes in the region of the loci have previously been associated with health, cognitive, and central nervous system phenotypes, and bioinformatics analyses suggest the involvement of the anterior caudate nucleus. These findings provide promising candidate SNPs for follow-up work, and our effect size estimates can anchor power analyses in social-science genetics. Economics

  • Open Access English
    Authors: 
    Sanaz Yahyanejad; Henry King; Venus Sosa Iglesias; Patrick V. Granton; Lydie M. O. Barbeau; Stefan J. van Hoof; Arjan J. Groot; Roger Habets; Jos Prickaerts; Anthony J. Chalmers; +5 more
    Countries: Netherlands, United Kingdom, United Kingdom
    Project: EC | DIRECT (617060)

    Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults. The current standard of care includes surgery followed by radiotherapy (RT) and chemotherapy with temozolomide (TMZ). Treatment often fails due to the radiation resistance and intrinsic or acquired TMZ resistance of a small percentage of cells with stem cell-like behavior (CSC). The NOTCH signaling pathway is expressed and active in human glioblastoma and NOTCH inhibitors attenuate tumor growth in vivo in xenograft models. Here we show using an image guided micro-CT and precision radiotherapy platform that a combination of the clinically approved NOTCH/γ-secretase inhibitor (GSI) RO4929097 with standard of care (TMZ + RT) reduces tumor growth and prolongs survival compared to dual combinations. We show that GSI in combination with RT and TMZ attenuates proliferation, decreases 3D spheroid growth and results into a marked reduction in clonogenic survival in primary and established glioma cell lines. We found that the glioma stem cell marker CD133, SOX2 and Nestin were reduced following combination treatments and NOTCH inhibitors albeit in a different manner. These findings indicate that NOTCH inhibition combined with standard of care treatment has an anti-glioma stem cell effect which provides an improved survival benefit for GBM and encourages further translational and clinical studies.

  • Open Access
    Authors: 
    Hatef Darabi; Karen McCue; Jonathan Beesley; Kyriaki Michailidou; Silje Nord; Siddhartha Kar; Keith Humphreys; Deborah J. Thompson; Maya Ghoussaini; Manjeet K. Bolla; +119 more
    Countries: Netherlands, United Kingdom

    Genome-wide association studies have identified SNPs near ZNF365 at 10q21.2 that are associated with both breast cancer risk and mammographic density. To identify the most likely causal SNPs, we fine mapped the association signal by genotyping 428 SNPs across the region in 89,050 European and 12,893 Asian case and control subjects from the Breast Cancer Association Consortium. We identified four independent sets of correlated, highly trait-associated variants (iCHAVs), three of which were located within ZNF365. The most strongly risk-associated SNP, rs10995201 in iCHAV1, showed clear evidence of association with both estrogen receptor (ER)-positive (OR = 0.85 [0.82-0.88]) and ER-negative (OR = 0.87 [0.82-0.91]) disease, and was also the SNP most strongly associated with percent mammographic density. iCHAV2 (lead SNP, chr10: 64,258,684:D) and iCHAV3 (lead SNP, rs7922449) were also associated with ER-positive (OR = 0.93 [0.91-0.95] and OR = 1.06 [1.03-1.09]) and ER-negative (OR = 0.95 [0.91-0.98] and OR = 1.08 [1.04-1.13]) disease. There was weaker evidence for iCHAV4, located 5' of ADO, associated only with ER-positive breast cancer (OR = 0.93 [0.90-0.96]). We found 12, 17, 18, and 2 candidate causal SNPs for breast cancer in iCHAVs 1-4, respectively. Chromosome conformation capture analysis showed that iCHAV2 interacts with the ZNF365 and NRBF2 (more than 600 kb away) promoters in normal and cancerous breast epithelial cells. Luciferase assays did not identify SNPs that affect transactivation of ZNF365, but identified a protective haplotype in iCHAV2, associated with silencing of the NRBF2 promoter, implicating this gene in the etiology of breast cancer. This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.ajhg.2015.05.002.

  • Open Access
    Authors: 
    Suhua Wei; Chuixiang Yi; George R. Hendrey; Timothy T. Eaton; G. T. Rustic; Shaoqiang Wang; Heping Liu; Nir Y. Krakauer; Weiguo Wang; Ankur R. Desai; +11 more
    Publisher: IOP Publishing
    Country: Netherlands
    Project: NSF | Climate control of terres... (0949637)

    Several lines of evidence suggest that the warming climate plays a vital role in driving certain types of extreme weather. The impact of this warming and extreme weather on forest carbon assimilation capacity is poorly known. Filling this knowledge gap is critical towards understanding changing the amount of carbon that forests can hold. Here, we used a perfect-deficit approach to identify forest canopy photosynthetic capacity (CPC) deficits and analyze how they correlate to climate extremes, based on data measured by the eddy covariance method at 26 forest sites integrating 146 site-years. We found that droughts severely affect the carbon assimilation capacities of evergreen broadleaf forest and deciduous broadleaf forest. In addition, the carbon assimilation capacities of Mediterranean forests are highly sensitive to climate extremes, while marine forest climates tend to be insensitive to climate extremes. Our estimates suggest an average global reduction of forest canopy photosynthetic capacity of 6.3petagramsof carbon per growing season over 2001-2010, with evergreen broadleaf forests contributing 51.7% of the total reduction. JRC.H.7-Climate Risk Management

  • Open Access English
    Authors: 
    Adriaan A. Voors; Hillary Mulder; Eugene B. Reyes; Martin R. Cowie; Johan Lassus; Adrian F. Hernandez; Justin A. Ezekowitz; Javed Butler; Christopher M. O'Connor; Joerg Koglin; +6 more
    Countries: Netherlands, Finland, Netherlands, United Kingdom

    Abstract Aims Vericiguat reduced the primary composite outcome of cardiovascular death or heart failure (HF) hospitalization in patients with worsening HF with reduced ejection fraction (HFrEF) and a lower limit of baseline estimated glomerular filtration rate (eGFR) of 15 mL/min/1.73 m2. We evaluated the relationship between the efficacy of vericiguat and baseline and subsequent changes in renal function. Methods and results In VICTORIA, core laboratory serum creatinine was measured at baseline (n = 4956) and weeks 16, 32, and 48. Worsening renal function (WRF), defined as an increase ≥0.3 mg/dL in creatinine from baseline to week 16, was assessed via a Cox model with respect to subsequent primary events. Mean age was 69 years, 24% were female, and mean baseline eGFR was 61 mL/min/1.73 m2. During 48 weeks of treatment, the trajectories in eGFR and creatinine with vericiguat were similar to placebo (P = 0.50 and 0.18). The beneficial effects of vericiguat on the primary outcome were not influenced by baseline eGFR (interaction P = 0.48). WRF occurred in 15% of patients and was associated with worse outcomes (adjusted hazard ratio 1.28, 95% confidence interval 1.11–1.47; P < 0.001), but the beneficial effects of vericiguat on the primary outcome were similar in patients with or without WRF (interaction P = 0.76). Conclusion Renal function trajectories were similar between vericiguat‐ and placebo‐treated patients and the beneficial effects of vericiguat on the primary outcome were consistent across the full range of eGFR and irrespective of WRF. The left panel shows no differences in the change in creatinine (P = 0.18) between the vericiguat and placebo groups, as evaluated by the interaction between treatment and study visit in the model. The right panel shows a natural cubic spline plot showing that the treatment effect of vericiguat on the primary outcome was similar across the full range of estimated glomerular filtration rate (eGFR) (P = 0.23).

  • Open Access English
    Authors: 
    Fergus J. Couch; Karoline Kuchenbaecker; Kyriaki Michailidou; Janna Lilyquist; Curtis Olswold; Emily Hallberg; Simona Agata; Habibul Ahsan; Christine B. Ambrosone; Irene L. Andrulis; +206 more
    Publisher: Nature Publishing Group
    Countries: United Kingdom, Finland, United Kingdom, Belgium, Belgium, Iceland, Spain, Spain, Norway, Germany ...
    Project: NWO | Secure and gentle grip of... (2300183393), NIH | A genome-wide association... (5R01CA128978-02), WT , EC | COGS (223175), NIH | Elucidating Loci Involved... (5U19CA148537-02), CIHR , NIH | Discovery Expansion and R... (5U19CA148065-04), NIH | Follow-up of Ovarian Canc... (3U19CA148112-04S1)

    Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 × 10(-8)) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for ∼11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction. B.C.A.C. was funded through a European Community Seventh Framework Programme under grant agreement no 223175 (HEALTH-F2-2009-223175; COGS); Cancer Research UK (C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692); the National Institutes of Health Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), R01 grants (CA128978, CA176785, CA192393), and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative); the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, the Breast Cancer Res. Foundation, and the Ovarian Cancer Research Fund. CIMBA genotyping was supported by National Institutes of Health grant (CA128978); the Department of Defence (W81XWH-10-1-0341); and the Breast Cancer Res. Foundation. CIMBA data management and data analysis were supported by Cancer Research UK grants C12292/A11174 and C1287/A10118. This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/ncomms11375

  • Open Access
    Authors: 
    Montserrat Garcia-Closas; Kyriaki Michailidou; Marjanka K. Schmidt; Mark N. Brook; Suhn K. Rhie; Elio Riboli; Julie E. Buring; Diana Eccles; Penelope Miron; Peter A. Fasching; +203 more
    Publisher: Springer Nature
    Countries: United Kingdom, Ireland, Netherlands, United Kingdom
    Project: WT , NIH | Breast &Prostate Cancer &... (1U01CA098758-01), NIH | Characterizing Genetic Su... (5U01CA098233-06), NIH | Genetic epidemiology of c... (3R01CA122340-03S1), NIH | Characterizing Genetic Su... (5U01CA098710-06), CIHR , NIH | Breast &prostate cancer &... (1U01CA098216-01), EC | COGS (223175), NIH | Discovery Expansion and R... (5U19CA148065-04)

    Estrogen receptor (ER)-negative tumors represent 20-30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry. The etiology and clinical behavior of ER-negative tumors are different from those of tumors expressing ER (ER positive), including differences in genetic predisposition. To identify susceptibility loci specific to ER-negative disease, we combined in a metaanalysis 3 genome-wide association studies of 4,193 ER-negative breast cancer cases and 35,194 controls with a series of 40 follow-up studies (6,514 cases and 41,455 controls), genotyped using a custom Illumina array, iCOGS, developed by the Collaborative Oncological Gene-environment Study (COGS). SNPs at four loci, 1q32.1 (MDM4, P= 2.1 x 10(-12) and LGR6, P = 1.4 x 10(-8)), 2p24.1 (P = 4.6 x 10(-8)) and 16q12.2 (FTO, P = 4.0 x 10(-8)), were associated with ER-negative but not ER-positive breast cancer (P&gt; 0.05). These findings provide further evidence for distinct etiological pathways associated with invasive ER-positive and ER-negative breast cancers.

  • Open Access
    Authors: 
    R. Thomas Lumbers; Sonia Shah; Honghuang Lin; Tomasz Czuba; Albert Henry; Daniel I. Swerdlow; Anders Mälarstig; Charlotte Andersson; Niek Verweij; Michael V. Holmes; +156 more
    Publisher: Wiley
    Countries: France, France, United Kingdom, Sweden, Sweden, Denmark, Denmark, United Kingdom, United Kingdom, Netherlands
    Project: EC | BigData Heart (116074), EC | inHForm (679242)

    Abstract: Aims: The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure. Methods and results: The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome‐wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow‐up following heart failure diagnosis ranged from 2 to 116 months. Forty‐nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34–90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low‐frequency variants (allele frequency 0.01–0.05) at P < 5 × 10−8 under an additive genetic model. Conclusions: HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction. Funder: Department of Medicine, Boston University School of Medicine; Id: http://dx.doi.org/10.13039/100008748 Funder: National Heart, Lung, and Blood Institute; Id: http://dx.doi.org/10.13039/100000050 Funder: Knut and Alice Wallenberg Foundation; Id: http://dx.doi.org/10.13039/501100004063 Funder: NIHR UCLH Biomedical Research Centre; Id: http://dx.doi.org/10.13039/501100012317 Funder: Skåne University Hospital; Id: http://dx.doi.org/10.13039/501100011077 Funder: Evans Medical Foundation; Id: http://dx.doi.org/10.13039/100015927 Funder: Crafoord Foundation; Id: http://dx.doi.org/10.13039/501100003173 Funder: British Heart Foundation Cardiovascular Biomedicine Funder: Swedish National Health Service