Enriched Basaltic Andesites from Mid-crustal Fractional Crystallization, Recharge, and Assimilation (Pilavo Volcano, Western Cordillera of Ecuador)

The origin of andesite is an important issue in petrology because andesite is the main eruptive product at convergent margins, corresponds to the average crustal composition and is often associated with major Cu-Au mineralization. In this study we present petrographic, mineralogical, geochemical and isotopic data for basaltic andesites of the latest Pleistocene Pilavo volcano, one of the most frontal volcanoes of the Ecuadorian Quaternary arc, situated upon thick (30-50 km) mafic crust composed of accreted Cretaceous oceanic plateau rocks and overlying mafic to intermediate Late Cretaceous-Late Tertiary magmatic arcs. The Pilavo rocks are basaltic andesites (54-57·5 wt % SiO2) with a tholeiitic affinity as opposed to the typical calc-alkaline high-silica andesites and dacites (SiO2 59-66 wt %) of other frontal arc volcanoes of Ecuador (e.g. Pichincha, Pululahua). They have much higher incompatible element contents (e.g. Sr 650-1350 ppm, Ba 650-1800 ppm, Zr 100-225 ppm, Th 5-25 ppm, La 15-65 ppm) and Th/La ratios (0·28-0·36) than Pichincha and Pululahua, and more primitive Sr (87Sr/86Sr ∼0·7038-0·7039) and Nd (εNd ∼ +5·5 to +6·1) isotopic signatures. Pilavo andesites have geochemical affinities with modern and recent high-MgO andesites (e.g. low-silica adakites, Setouchi sanukites) and, especially, with Archean sanukitoids, for both of which incompatible element enrichments are believed to result from interactions of slab melts with peridotitic mantle. Petrographic, mineral chemistry, bulk-rock geochemical and isotopic data indicate that the Pilavo magmatic rocks have evolved through three main stages: (1) generation of a basaltic magma in the mantle wedge region by flux melting induced by slab-derived fluids (aqueous, supercritical or melts); (2) high-pressure differentiation of the basaltic melt (at the mantle-crust boundary or at lower crustal levels) through sustained fractionation of olivine and clinopyroxene, leading to hydrous, high-alumina basaltic andesite melts with a tholeiitic affinity, enriched in incompatible elements and strongly impoverished in Ni and Cr; (3) establishment of one or more mid-crustal magma storage reservoirs in which the magmas evolved through dominant amphibole and clinopyroxene (but no plagioclase) fractionation accompanied by assimilation of the modified plutonic roots of the arc and recharge by incoming batches of more primitive magma from depth. The latter process has resulted in strongly increasing incompatible element concentrations in the Pilavo basaltic andesites, coupled with slightly increasing crustal isotopic signatures and a shift towards a more calc-alkaline affinity. Our data show that, although ultimately originating from the slab, incompatible element abundances in arc andesites with primitive isotopic signatures can be significantly enhanced by intra-crustal processes within a thick juvenile mafic crust, thus providing an additional process for the generation of enriched andesite

Quaternary Sanukitoid-like Andesites Generated by Intracrustal Processes (Chacana Caldera Complex, Ecuador): Implications for Archean Sanukitoids

High-Mg diorites enriched in incompatible elements and their extrusive equivalents are rare subduction-related rock types that have been found in modern arc settings and in Late Archean sequences, where they are associated with trondhjemite-tonalite-granodiorite (TTG) suites. Archean rocks with these geochemical features are known as sanukitoids and, despite their limited abundance, are considered to be the indicators of the onset of modern plate tectonics because of their similarities to modern subduction-related high-Mg andesites and diorites. Understanding the genesis of sanukitoid rocks is thus an essential step towards understanding crustal growth processes. The accepted petrogenetic models for modern, enriched, high-Mg andesites and their Archean equivalents, the sanukitoids, consist of metasomatic enrichment of the mantle wedge by slab components and its subsequent partial melting, or the modification of siliceous slab components through continuous reaction with mantle peridotite during their ascent through the mantle wedge. We present new data on the petrography, mineral chemistry and whole-rock geochemistry (major and trace elements and Sr-Nd-Pb isotopes) of andesitic rocks from an ∼30 ka lava flow (Yuyos flow) from the Chacana Caldera Complex, Eastern Cordillera of Ecuador. These rocks show a remarkable geochemical affinity with Archean sanukitoids, including high magnesium numbers (0·58-0·63) accompanied by high contents of incompatible elements (e.g. Th 17-23 ppm, U 6-7·5 ppm, Ba 1600-1800 ppm, Sr 1430-1565 ppm, La 74-94 ppm). Additionally, the sanukitoid-like andesites of Yuyos are associated with predominant silica-rich (adakite-like) andesites, which are widespread throughout the Quaternary arc of Ecuador. This makes the Quaternary Ecuadorian magmatic province a close equivalent of the Archean TTG-sanukitoid association. The bulk-rock geochemistry, petrography and mineral chemistry data indicate that the sanukitoid-like features of the andesites of the Yuyos flow derive from intracrustal recycling of the felsic-intermediate to mafic-ultramafic roots of the Quaternary volcanic arc of Ecuador by ‘normal' mantle-derived basaltic magmas with the geochemical characteristics of continental arc basalts or high-alumina basalts. In view of the similarities between the Yuyos andesites and Archean sanukitoids in terms of geochemistry and lithological association, we suggest that genetic models should consider the possibility of intracrustal recycling as a process responsible for the peculiar signatures of both Archean sanukitoids and modern enriched high-Mg andesite

Cenozoic continental arc magmatism and associated mineralization in Ecuador

Most of the economic ore deposits of Ecuador are porphyry-Cu and epithermal style gold deposits associated with Tertiary continental arc magmatism. This study presents major and trace element geochemistry, as well as radiogenic isotope (Pb, Sr) signatures, of continental arc magmatic rocks of Ecuador of Eocene to Late Miocene (~50-9Ma, ELM) and Late Miocene to Recent (~8-0Ma, LMR) ages. The most primitive ELM and LMR rocks analyzed consistently display similar trace element and isotopic signatures suggesting a common origin, most likely an enriched MORB-type mantle. In contrast, major and trace element geochemistry, as well as radiogenic isotope systematics of the whole sets of ELM and LMR samples, indicate strikingly different evolutions between ELM and LMR rocks. The ELM rocks have consistently low Sr/Y, increasing Rb/Sr, and decreasing Eu/Gd with SiO2, suggesting an evolution through plagioclase-dominated fractional crystallization at shallow crustal levels (20km), and most likely at sub-crustal levels (>40-50km). The change in geochemical signatures of Tertiary magmatic rocks of Ecuador from the ELM- to the LMR-type coincides chronologically with the transition from a transpressional to a compressional regime that occurred at ~9Ma and has been attributed by other investigations to the onset of subduction of the aseismic Carnegie ridge. The major districts of porphyry-Cu and epithermal deposits of Ecuador (which have a small size, <<200Mt, when compared to their Central Andean counterparts) are spatially and temporally associated with ELM magmatic rocks. No significant porphyry-Cu and epithermal deposits (except the epithermal high-sulfidation mineralization of Quimsacocha) appear to be associated with Late Miocene-Recent (LMR, ~8-0Ma) magmatic rocks. The apparent "infertility” of LMR magmas seems to be at odds with the association of major porphyry-Cu/epithermal deposits of the Central Andes with magmatic rocks having adakite-type geochemical signatures similar to LMR rocks. The paucity of porphyry-Cu/epithermal deposits associated with LMR rocks might be only apparent and bound to exposure level, or real and bound (among other possibilities) to the lack of development of shallow crustal magmatic chambers since ~9Ma as a result of a prolonged compressional regime in the Ecuadorian crust. More work is needed to understand the actual metallogenic potential of LMR rocks in Ecuado

Adakite-like volcanism of Ecuador: lower crust magmatic evolution and recycling

In the Northern Andes of Ecuador, a broad Quaternary volcanic arc with significant across-arc geochemical changes sits upon continental crust consisting of accreted oceanic and continental terranes. Quaternary volcanic centers occur, from west to east, along the Western Cordillera (frontal arc), in the Inter-Andean Depression and along the Eastern Cordillera (main arc), and in the Sub-Andean Zone (back-arc). The adakite-like signatures of the frontal and main arc volcanoes have been interpreted either as the result of slab melting plus subsequent slab melt-mantle interactions or of lower crustal melting, fractional crystallization, and assimilation processes. In this paper, we present petrographic, geochemical, and isotopic (Sr, Nd, Pb) data on dominantly andesitic to dacitic volcanic rocks as well as crustal xenolith and cumulate samples from five volcanic centers (Pululagua, Pichincha, Ilalo, Chacana, Sumaco) forming a NW-SE transect at about 0° latitude and encompassing the frontal (Pululagua, Pichincha), main (Ilalo, Chacana), and back-arc (Sumaco) chains. All rocks display typical subduction-related geochemical signatures, such as Nb and Ta negative anomalies and LILE enrichment. They show a relative depletion of fluid-mobile elements and a general increase in incompatible elements from the front to the back-arc suggesting derivation from progressively lower degrees of partial melting of the mantle wedge induced by decreasing amounts of fluids released from the slab. We observe widespread petrographic evidence of interaction of primary melts with mafic xenoliths as well as with clinopyroxene- and/or amphibole-bearing cumulates and of magma mixing at all frontal and main arc volcanic centers. Within each volcanic center, rocks display correlations between evolution indices and radiogenic isotopes, although absolute variations of radiogenic isotopes are small and their values are overall rather primitive (e.g., εNd=+1.5 to +6, 87Sr/86Sr=0.7040-0.70435). Rare earth element patterns are characterized by variably fractionated light to heavy REE (La/YbN=5.7-34) and by the absence of Eu negative anomalies suggesting evolution of these rocks with limited plagioclase fractionation. We interpret the petrographic, geochemical, and isotopic data as indicating open-system evolution at all volcanic centers characterized by fractional crystallization and magma mixing processes at different lower- to mid-crustal levels as well as by assimilation of mafic lower crust and/or its partial melts. Thus, we propose that the adakite-like signatures of Ecuadorian rocks (e.g., high Sr/Y and La/Yb values) are primarily the result of lower- to mid-crustal processing of mantle-derived melts, rather than of slab melts and slab melt-mantle interactions. The isotopic signatures of the least evolved adakite-like rocks of the active and recent volcanoes are the same as those of Tertiary ”normal” calc-alkaline magmatic rocks of Ecuador suggesting that the source of the magma did not change through time. What changed was the depth of magmatic evolution, probably as a consequence of increased compression induced by the stronger coupling between the subducting and overriding plates associated with subduction of the aseismic Carnegie Ridg

Metallogenic features of Miocene porphyry Cu and porphyry-related mineral deposits in Ecuador revealed by Re-Os, 40Ar/39Ar, and U-Pb geochronology

Mineralization and alteration events at ten Miocene porphyry Cu and porphyry-related epithermal mineral deposits in southern, central, and northern Ecuador were dated by means of molybdenite Re-Os, biotite and alunite 40Ar/39Ar, and titanite U-Pb geochronology. Most of these hydrothermal events show a spatio-temporal correlation with porphyry intrusion emplacement as constrained by zircon U-Pb ages. The total age range for these events spans the 23.5-6.1Ma period, without displaying systematic along- or across-arc age distribution trends. While epithermal deposits tend to be spatially associated with volcanic rocks of a similar age, porphyry Cu deposits in Ecuador are frequently spatially associated with deeper-seated basement units and batholith-scale precursor intrusive systems assembled over ≥5m.y. time periods. In most cases, formation of the porphyry Cu deposits is related to the youngest magmatic (-hydrothermal) event in a given area, postdating batholith construction at a regional scale. The majority of Miocene deposits occurs in southern Ecuador where areally extensive, post-mineralization (late Miocene to recent) volcanic sequences with the potential to conceal mineralization at depth are lacking. Only few Miocene deposits occur in northern-central Ecuador, where they mainly crop out in the Western Cordillera, west of the productive present-day volcanic arc. The surface distribution of post-mineralization arc volcanism reflects along-arc variations in subducting slab geometry. Porphyry Cu and epithermal deposits in Ecuador define a Miocene metallogenic belt broadly continuous with its coeval counterpart in northern-central Peru. Although both belt segments were formed in an overall similar tectonomagmatic and metallogenic setting, their respective metal endowments differ significantl

Los peligros volcánicos asociados con el Atacazo-Ninahuilca y Pululahua

Dos volcanes poco conocidos por la sociedad ecuatoriana se presentan en esta quinta entrega de Los peligros volcánicos en Ecuador. El Atacazo-Ninahuilca y el Pululahua han sido desde siempre opacados por la presencia de volcanes más imponentes y con erupciones registradas por la historia, como el Cotopaxi, el Guagua Pichincha o el Tungurahua. Sin embargo, tanto el Atacazo-Ninahuilca como el Pululahua han presentado erupciones de gran magnitud en los últimos miles de años, por lo que se les califica como “potencialmente activos”. El objetivo de este trabajo es dar a conocer la historia de su formación, su tipo de actividad y sus peligros potenciales

Modeling spatial effects of PM₂.₅ on term low birth weight in Los Angeles County

Air pollution epidemiological studies suggest that elevated exposure to fine particulate matter (PM₂.₅) is associated with higher prevalence of term low birth weight (TLBW). Previous studies have generally assumed the exposure–response of PM₂.₅ on TLBW to be the same throughout a large geographical area. Health effects related to PM₂.₅ exposures, however, may not be uniformly distributed spatially, creating a need for studies that explicitly investigate the spatial distribution of the exposure–response relationship between individual-level exposure to PM₂.₅ and TLBW. Here, we examine the overall and spatially varying exposure–response relationship between PM₂.₅ and TLBW throughout urban Los Angeles (LA) County, California. We estimated PM₂.₅ from a combination of land use regression (LUR), aerosol optical depth from remote sensing, and atmospheric modeling techniques. Exposures were assigned to LA County individual pregnancies identified from electronic birth certificates between the years 1995-2006 (N=1,359,284) provided by the California Department of Public Health. We used a single pollutant multivariate logistic regression model, with multilevel spatially structured and unstructured random effects set in a Bayesian framework to estimate global and spatially varying pollutant effects on TLBW at the census tract level. Overall, increased PM₂.₅ level was associated with higher prevalence of TLBW county-wide. The spatial random effects model, however, demonstrated that the exposure–response for PM₂.₅ and TLBW was not uniform across urban LA County. Rather, the magnitude and certainty of the exposure–response estimates for PM₂.₅ on log odds of TLBW were greatest in the urban core of Central and Southern LA County census tracts. These results suggest that the effects may be spatially patterned, and that simply estimating global pollutant effects obscures disparities suggested by spatial patterns of effects. Studies that incorporate spatial multilevel modeling with random coefficients allow us to identify areas where air pollutant effects on adverse birth outcomes may be most severe and policies to further reduce air pollution might be most effectiveKEYWORDS: Multilevel modeling, Term low birth weight, Air pollution, PM2.5, Spatial effects, PM₂.₅This is the publisher’s final pdf. The published article is copyrighted by the author(s) and published by Elsevier. The published article can be found at: http://www.journals.elsevier.com/environmental-research

Multi-pollutant exposure profiles associated with term low birth weight in Los Angeles County

Research indicates that multiple outdoor air pollutants and adverse neighborhood conditions are spatially correlated. Yet health risks associated with concurrent exposure to air pollution mixtures and clustered neighborhood factors remain underexplored. Statistical models to assess the health effects from pollutant mixtures remain limited, due to problems of collinearity between pollutants and area-level covariates, and increases in covariate dimensionality. Here we identify pollutant exposure profiles and neighborhood contextual profiles within Los Angeles (LA) County. We then relate these profiles with term low birth weight (TLBW). We used land use regression to estimate NO2, NO, and PM2.5 concentrations averaged over census block groups to generate pollutant exposure profile clusters and census block group-level contextual profile clusters, using a Bayesian profile regression method. Pollutant profile cluster risk estimation was implemented using a multilevel hierarchical model, adjusting for individual-level covariates, contextual profile cluster random effects, and modeling of spatially structured and unstructured residual error. Our analysis found 13 clusters of pollutant exposure profiles. Correlations between study pollutants varied widely across the 13 pollutant clusters. Pollutant clusters with elevated NO2, NO, and PM2.5 concentrations exhibited increased log odds of TLBW, and those with low PM2.5, NO2, and NO concentrations showed lower log odds of TLBW. The spatial patterning of pollutant cluster effects on TLBW, combined with between-pollutant correlations within pollutant clusters, imply that traffic-related primary pollutants influence pollutant cluster TLBW risks. Furthermore, contextual clusters with the greatest log odds of TLBW had more adverse neighborhood socioeconomic, demographic, and housing conditions. Our data indicate that, while the spatial patterning of high-risk multiple pollutant clusters largely overlaps with adverse contextual neighborhood cluster, both contribute to TLBW while controlling for the other.Health Effects Institute (HEI), an organization jointly funded by the United States Environmental Protection Agency (EPA) (Assistance Award No. R-82811201

Common non-synonymous SNPs associated with breast cancer susceptibility: findings from the Breast Cancer Association Consortium.

Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility variants, although most studies have been underpowered to detect associations of a realistic magnitude. We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsSNPs) for which evidence of association with breast cancer risk had been previously reported. Case-control data were combined from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21 [rs1053338, per allele OR = 1.07, 95% confidence interval (CI) = 1.04-1.10, P = 2.9 × 10(-6)], AKAP9-M463I at 7q21 (rs6964587, OR = 1.05, 95% CI = 1.03-1.07, P = 1.7 × 10(-6)) and NEK10-L513S at 3p24 (rs10510592, OR = 1.10, 95% CI = 1.07-1.12, P = 5.1 × 10(-17)). The first two associations reached genome-wide statistical significance in a combined analysis of available data, including independent data from nine genome-wide association studies (GWASs): for ATXN7-K264R, OR = 1.07 (95% CI = 1.05-1.10, P = 1.0 × 10(-8)); for AKAP9-M463I, OR = 1.05 (95% CI = 1.04-1.07, P = 2.0 × 10(-10)). Further analysis of other common variants in these two regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility region; the association was substantially attenuated after adjustment for the known GWAS hit. Thus, each of the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying variants and the genes through which they act.BCAC is funded by Cancer Research UK (C1287/A10118, C1287/A12014) and by the European Community’s Seventh Framework Programme under grant agreement n8 223175 (HEALTH-F2–2009-223175) (COGS). Meetings of the BCAC have been funded by the European Union COST programme (BM0606). Genotyping of the iCOGS array was funded by the European Union (HEALTH-F2-2009-223175), Cancer Research UK (C1287/A10710), the Canadian Institutes of Health Research for the ‘CIHR Team in Familial Risks of Breast Cancer’ program and the Ministry of Economic Development, Innovation and Export Trade of Quebec (PSR-SIIRI-701). Additional support for the iCOGS infrastructure was provided by the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112—the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. The ABCFS and OFBCR work was supported by grant UM1 CA164920 from the National Cancer Institute (USA). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products or organizations imply endorsement t by the US Government or the BCFR. The ABCFS was also supported by the National Health and Medical Research Council of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia) and the Victorian Breast Cancer Research Consortium. J.L.H. is a National Health and Medical Research Council (NHMRC) Senior Principal Research Fellow and M.C.S. is a NHMRC Senior Research Fellow. The OFBCR work was also supported by the Canadian Institutes of Health Research ‘CIHR Team in Familial Risks of Breast Cancer’ program. The ABCS was funded by the Dutch Cancer Society Grant no. NKI2007-3839 and NKI2009-4363. The ACP study is funded by the Breast Cancer Research Trust, UK. The work of the BBCC was partly funded by ELAN-Programme of the University Hospital of Erlangen. The BBCS is funded by Cancer Research UK and Breakthrough Breast Cancer and acknowledges NHS funding to the NIHR Biomedical Research Centre, and the National Cancer Research Network (NCRN). E.S. is supported by NIHR Comprehensive Biomedical Research Centre, Guy’s & St. Thomas’ NHS Foundation Trust in partnership with King’s College London, UK. Core funding to the Wellcome Trust Centre for Human Genetics was provided by the Wellcome Trust (090532/Z/09/Z). I.T. is supported by the Oxford Biomedical Research Centre. The BSUCH study was supported by the Dietmar-Hopp Foundation, the Helmholtz Society and the German Cancer Research Center (DKFZ). The CECILE study was funded by the Fondation de France, the French National Institute of Cancer (INCa), The National League against Cancer, the National Agency for Environmental l and Occupational Health and Food Safety (ANSES), the National Agency for Research (ANR), and the Association for Research against Cancer (ARC). The CGPS was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council and Herlev Hospital.The CNIO-BCS was supported by the Genome Spain Foundation the Red Temática de Investigación Cooperativa en Cáncer and grants from the Asociación Española Contra el Cáncer and the Fondo de Investigación Sanitario PI11/00923 and PI081120). The Human Genotyping-CEGEN Unit, CNIO is supported by the Instituto de Salud Carlos III. D.A. was supported by a Fellowship from the Michael Manzella Foundation (MMF) and was a participant in the CNIO Summer Training Program. The CTS was initially supported by the California Breast Cancer Act of 1993 and the California Breast Cancer Research Fund (contract 97-10500) and is currently funded through the National Institutes of Health (R01 CA77398). Collection of cancer incidence e data was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885. HAC receives support from the Lon V Smith Foundation (LVS39420). The ESTHER study was supported by a grant from the Baden Württemberg Ministry of Science, Research and Arts. Additional cases were recruited in the context of the VERDI study, which was supported by a grant from the German Cancer Aid (Deutsche Krebshilfe). The GENICA was funded by the Federal Ministry of Education and Research (BMBF) Germany grants 01KW9975/5, 01KW9976/8, 01KW9977/0 and 01KW0114, the Robert Bosch Foundation, Stuttgart, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), as well as the Department of Internal Medicine , Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus Bonn, Germany. The HEBCS was supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (132473), the Finnish Cancer Society, The Nordic Cancer Union and the Sigrid Juselius Foundation. The HERPACC was supported by a Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Science, Sports, Culture and Technology of Japan, by a Grant-in-Aid for the Third Term Comprehensive 10-Year strategy for Cancer Control from Ministry Health, Labour and Welfare of Japan, by a research grant from Takeda Science Foundation , by Health and Labour Sciences Research Grants for Research on Applying Health Technology from Ministry Health, Labour and Welfare of Japan and by National Cancer Center Research and Development Fund. The HMBCS was supported by short-term fellowships from the German Academic Exchange Program (to N.B), and the Friends of Hannover Medical School (to N.B.). Financial support for KARBAC was provided through the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet, the Stockholm Cancer Foundation and the Swedish Cancer Society. The KBCP was financially supported by the special Government Funding (EVO) of Kuopio University Hospital grants, Cancer Fund of North Savo, the Finnish Cancer Organizations, the Academy of Finland and by the strategic funding of the University of Eastern Finland. kConFab is supported by grants from the National Breast Cancer Foundation , the NHMRC, the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia and the Cancer Foundation of Western Australia. The kConFab Clinical Follow Up Study was funded by the NHMRC (145684, 288704, 454508). Financial support for the AOCS was provided by the United States Army Medical Research and Materiel Command (DAMD17-01-1-0729), the Cancer Council of Tasmania and Cancer Foundation of Western Australia and the NHMRC (199600). G.C.T. and P.W. are supported by the NHMRC. LAABC is supported by grants (1RB-0287, 3PB-0102, 5PB-0018 and 10PB-0098) from the California Breast Cancer Research Program. Incident breast cancer cases were collected by the USC Cancer Surveillance Program (CSP) which is supported under subcontract by the California Department of Health. The CSP is also part of the National Cancer Institute’s Division of Cancer Prevention and Control Surveillance, Epidemiology, and End Results Program, under contract number N01CN25403. LMBC is supported by the ‘Stichting tegen Kanker’ (232-2008 and 196-2010). The MARIE study was supported by the Deutsche Krebshilfe e.V. (70-2892-BR I), the Federal Ministry of Education Research (BMBF) Germany (01KH0402), the Hamburg Cancer Society and the German Cancer Research Center (DKFZ). MBCSG is supported by grants from the Italian Association ciation for Cancer Research (AIRC) and by funds from the Italian citizens who allocated a 5/1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects ‘5 × 1000’). The MCBCS was supported by the NIH grants (CA122340, CA128978) and a Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), the Breast Cancer Research Foundation and a generous gift from the David F. and Margaret T. Grohne Family Foundation and the Ting Tsung and Wei Fong Chao Foundation. MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057, 251553 and 504711 and by infrastructure provided by Cancer Council Victoria. The MEC was supported by NIH grants CA63464, CA54281, CA098758 and CA132839. The work of MTLGEBCS was supported by the Quebec Breast Cancer Foundation, the Canadian Institutes of Health Research (grant CRN-87521) and the Ministry of Economic Development, Innovation and Export Trade (grant PSR-SIIRI-701). MYBRCA is funded by research grants from the Malaysian Ministry of Science, Technology and Innovation (MOSTI), Malaysian Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Initiatives Foundation (CARIF). Additional controls were recruited by the Singapore Eye Research Institute, which was supported by a grant from the Biomedical Research Council (BMRC08/1/35/19,tel:08/1/35/19./550), Singapore and the National medical Research Council, Singapore (NMRC/CG/SERI/2010). The NBCS was supported by grants from the Norwegian Research council (155218/V40, 175240/S10 to A.L.B.D., FUGE-NFR 181600/ V11 to V.N.K. and a Swizz Bridge Award to A.L.B.D.). The NBHS was supported by NIH grant R01CA100374. Biological sample preparation was conducted the Survey and Biospecimen Shared Resource, which is supported by P30 CA68485. The OBCS was supported by research grants from the Finnish Cancer Foundation, the Sigrid Juselius Foundation, the Academy of Finland, the University of Oulu, and the Oulu University Hospital. The ORIGO study was supported by the Dutch Cancer Society (RUL 1997-1505) and the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NLCP16). The PBCS was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. pKARMA is a combination of the KARMA and LIBRO-1 studies. KARMA was supported by Ma¨rit and Hans Rausings Initiative Against Breast Cancer. KARMA and LIBRO-1 were supported the Cancer Risk Prediction Center (CRisP; www.crispcenter.org), a Linnaeus Centre (Contract ID 70867902) financed by the Swedish Research Council. The RBCS was funded by the Dutch Cancer Society (DDHK 2004-3124, DDHK 2009-4318). SASBAC was supported by funding from the Agency for Science, Technology and Research of Singapore (A∗STAR), the US National Institute of Health (NIH) and the Susan G. Komen Breast Cancer Foundation KC was financed by the Swedish Cancer Society (5128-B07-01PAF). The SBCGS was supported primarily by NIH grants R01CA64277, R01CA148667, and R37CA70867. Biological sample preparation was conducted the Survey and Biospecimen Shared Resource, which is supported by P30 CA68485. The SBCS was supported by Yorkshire Cancer Research S305PA, S299 and S295. Funding for the SCCS was provided by NIH grant R01 CA092447. The Arkansas Central Cancer Registry is fully funded by a grant from National Program of Cancer Registries, Centers for Disease Control and Prevention (CDC). Data on SCCS cancer cases from Mississippi were collected by the Mississippi Cancer Registry which participates in the National Program of Cancer Registries (NPCR) of the Centers for Disease Control and Prevention (CDC). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the CDC or the Mississippi Cancer Registry. SEARCH is funded by a programme grant from Cancer Research UK (C490/A10124) and supported by the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge. The SEBCS was supported by the BRL (Basic Research Laboratory) program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (2012-0000347). SGBCC is funded by the National Medical Research Council Start-up Grant and Centre Grant (NMRC/CG/NCIS /2010). The recruitment of controls by the Singapore Consortium of Cohort Studies-Multi-ethnic cohort (SCCS-MEC) was funded by the Biomedical Research Council (grant number: 05/1/21/19/425). SKKDKFZS is supported by the DKFZ. The SZBCS was supported by Grant PBZ_KBN_122/P05/2004. K. J. is a fellow of International PhD program, Postgraduate School of Molecular Medicine, Warsaw Medical University, supported by the Polish Foundation of Science. The TNBCC was supported by the NIH grant (CA128978), the Breast Cancer Research Foundation , Komen Foundation for the Cure, the Ohio State University Comprehensive Cancer Center, the Stefanie Spielman Fund for Breast Cancer Research and a generous gift from the David F. and Margaret T. Grohne Family Foundation and the Ting Tsung and Wei Fong Chao Foundation. Part of the TNBCC (DEMOKRITOS) has been co-financed by the European Union (European Social Fund – ESF) and Greek National Funds through the Operational Program ‘Education and Life-long Learning’ of the National Strategic Reference Framework (NSRF)—Research Funding Program of the General Secretariat for Research & Technology: ARISTEIA. The TWBCS is supported by the Institute of Biomedical Sciences, Academia Sinica and the National Science Council, Taiwan. The UKBGS is funded by Breakthrough Breast Cancer and the Institute of Cancer Research (ICR). ICR acknowledges NHS funding to the NIHR Biomedical Research Centre. Funding to pay the Open Access publication charges for this article was provided by the Wellcome Trust.This is the advanced access published version distributed under a Creative Commons Attribution License 2.0, which can also be viewed on the publisher's webstie at: http://hmg.oxfordjournals.org/content/early/2014/07/04/hmg.ddu311.full.pdf+htm

Fine-Scale Mapping of the 4q24 Locus Identifies Two Independent Loci Associated with Breast Cancer Risk

Background: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. Methods: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium. Results: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10−4; OR, 1.04; 95% confidence interval (CI), 1.02–1.07] and rs77928427 (P = 1.86 × 10−4; OR, 1.04; 95% CI, 1.02–1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r2 ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor–binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue. Conclusion: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2. Impact: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk