Functional Mechanisms Underlying Pleiotropic Risk Alleles at the 19p13.1 Breast–Ovarian Cancer Susceptibility Locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P = 9.2 X 10-20), ER-negative BC (P = 1.1 X 10-13), BRCA1 -associated BC (P = 7.7 X 10-16) and triple negative BC (P-diff = 2 X 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P = 2 X 10-3) and ABHD8 (P \u3c 2 X 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8 , and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3\u27-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

Associations between sociodemographic characteristics and receipt of professional diagnosis in Common Mental Disorder: Results from the Adult Psychiatric Morbidity Survey 2014

BACKGROUND: Many people with Common Mental Disorders (CMDs), especially men, people from older age groups, and ethnic minority backgrounds, receive no treatment. Self-acknowledgement of mental illness symptoms, and a professional diagnosis are usually required to access treatment. To understand barriers, we therefore tested whether these groups were relatively less likely to self-diagnose a CMD, or to receive a professional diagnosis. METHODS: We analysed data from the 2014 English Adult Psychiatric Morbidity Survey (APMS). We used regression models to examine whether gender, age, and minority ethnic status were associated with professional and self-diagnosis, after controlling for CMD symptoms. RESULTS: 27.3 % of the population reported a professional and self-diagnosis of CMD, 15.9 % a self- diagnosis only, and the remainder no diagnosis. Odds of professional diagnosis were lower for men compared with women (adjusted odds ratio [AOR] 0.54, 95 % confidence intervals [CI] 0.47–0.62). People from White Other (0.49, 0.36–0.67), Black (0.31, 0.18–0.51), and Asian (0.22, 0.15–0.33) groups were less likely than the White British group to receive a professional diagnosis. The least likely age group to have a professional CMD diagnosis (relative to adults aged 16–34) were people aged over 75 (0.52, 0.39–0.69). Patterns were similar for self-diagnosis. LIMITATIONS: Ethnicity categories were heterogeneous. Data are cross-sectional, and selection and response bias are possible. CONCLUSIONS: For every three people who self-diagnose CMD, two have a professional diagnosis. Men, ethnic minority, and older age groups are less likely to receive a diagnosis or self-diagnose after adjustment for presence of symptoms

Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer

Abstract Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer

Measurement of pseudorapidity distributions of charged particles in proton-proton collisions at sqrt(s) = 8 TeV by the CMS and TOTEM experiments

Pseudorapidity ( $\eta$ ) distributions of charged particles produced in proton–proton collisions at a centre-of-mass energy of 8 $~\text {TeV}$ are measured in the ranges $|\eta | < 2.2$ and $5.3 < |\eta | < 6.4$ covered by the CMS and TOTEM detectors, respectively. The data correspond to an integrated luminosity of $\mathcal {L} = 45 \mu {\mathrm {b}}^{-1}$ . Measurements are presented for three event categories. The most inclusive category is sensitive to 91–96 % of the total inelastic proton–proton cross section. The other two categories are disjoint subsets of the inclusive sample that are either enhanced or depleted in single diffractive dissociation events. The data are compared to models used to describe high-energy hadronic interactions. None of the models considered provide a consistent description of the measured distributions