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

A model for information retrieval driven by conceptual spaces

A retrieval model describes the transformation of a query into a set of documents. The question is: what drives this transformation? For semantic information retrieval type of models this transformation is driven by the content and structure of the semantic models. In this case, Knowledge Organization Systems (KOSs) are the semantic models that encode the meaning employed for monolingual and cross-language retrieval. The focus of this research is the relationship between these meanings’ representations and their role and potential in augmenting existing retrieval models effectiveness. The proposed approach is unique in explicitly interpreting a semantic reference as a pointer to a concept in the semantic model that activates all its linked neighboring concepts. It is in fact the formalization of the information retrieval model and the integration of knowledge resources from the Linguistic Linked Open Data cloud that is distinctive from other approaches. The preprocessing of the semantic model using Formal Concept Analysis enables the extraction of conceptual spaces (formal contexts)that are based on sub-graphs from the original structure of the semantic model. The types of conceptual spaces built in this case are limited by the KOSs structural relations relevant to retrieval: exact match, broader, narrower, and related. They capture the definitional and relational aspects of the concepts in the semantic model. Also, each formal context is assigned an operational role in the flow of processes of the retrieval system enabling a clear path towards the implementations of monolingual and cross-lingual systems. By following this model’s theoretical description in constructing a retrieval system, evaluation results have shown statistically significant results in both monolingual and bilingual settings when no methods for query expansion were used. The test suite was run on the Cross-Language Evaluation Forum Domain Specific 2004-2006 collection with additional extensions to match the specifics of this model.