Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus.

BACKGROUND: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. METHOD: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/ ), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. RESULTS: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 × 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 × 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 × 10(-4)) identified in the general populations, and rs113824616 (P = 7 × 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05. CONCLUSION: This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.UK funding includes Cancer Research UK and NIH.This is the final version of the article. It first appeared from BioMed Central via http://dx.doi.org/10.1186/s13058-016-0718-

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat

Measurements of integrated water vapor and cloud liquid water from microwave radiometers at the DOE ARM Cloud and Radiation Testbed in the U.S. Southern Great Plains

The operation and calibration of the ARM microwave radiometers is summarized. Measured radiometric brightness temperatures are compared with calculations based on the model using co-located radiosondes. Comparisons of perceptible water vapor retrieved from the radiometer with integrated soundings and co-located GPS retrievals are presented. The three water vapor sensing systems are shown to agree to within about 1 mm

Water vapor from sunradiometry in comparison wit microwave and balloon-sonde measurements at the Southern Great Plains ARM site

Water vapor plays an important role in weather in climate; it is the most important greenhouse gas and the most variable in space and time. The DOE Atmospheric Radiation Measurement (ARM) program is studying the column abundance and distribution of water vapor with altitude. Although the Multi-Filter Rotating Shadowband Radiometer (MFRSR) is mainly for measurements of spectral short-wave radiation and spectral extinction by aerosol, it can also measure total column water vapor. This paper reports a preliminary investigation of MFRSR`s capabilities for total column water vapor under cloudless conditions

Heterogeneous surface fluxes and their effects on the SGP CART site

The treatment of subgrid-scale variations of surface properties and the resultant spatial variations of sensible and latent heat fluxes has received increasing attention in recent years. Mesoscale numerical simulations of highly idealized conditions, in which strong flux contrasts exist between adjacent surfaces, have shown that under some circumstances the secondary circulations induced by land-use differences can significantly affect the properties of the planetary boundary layer (PBL) and the region of the atmosphere above the PBL. At the Southern Great Plains (SGP) Cloud and Radiation Testbed (CART) site, the fluxes from different land-surface types are not expected to differ as dramatically as those found in idealized simulations. Although the corresponding effects on the atmosphere should thus be less dramatic, they are still potentially important. From an ARM perspective, in tests of single column models (SCMs) it would be useful to understand the effects of the lower boundary conditions on model performance. We describe here our initial efforts to characterize the variable surface fluxes over the CART site and to assess their effects on the PBL that are important for the performance of SCMs