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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> 0.05). These findings provide further evidence for distinct etiological pathways associated with invasive ER-positive and ER-negative breast cancers.

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Abstract The complex nature of human cognition has resulted in cognitive genomics lagging behind many other fields in terms of gene discovery using genome-wide association study (GWAS) methods. In an attempt to overcome these barriers, the current study utilized GWAS meta-analysis to examine the association of common genetic variation (~8M single-nucleotide polymorphisms (SNP) with minor allele frequency ⩾1%) to general cognitive function in a sample of 35 298 healthy individuals of European ancestry across 24 cohorts in the Cognitive Genomics Consortium (COGENT). In addition, we utilized individual SNP lookups and polygenic score analyses to identify genetic overlap with other relevant neurobehavioral phenotypes. Our primary GWAS meta-analysis identified two novel SNP loci (top SNPs: rs76114856 in the CENPO gene on chromosome 2 and rs6669072 near LOC105378853 on chromosome 1) associated with cognitive performance at the genome-wide significance level (P<5 × 10−8). Gene-based analysis identified an additional three Bonferroni-corrected significant loci at chromosomes 17q21.31, 17p13.1 and 1p13.3. Altogether, common variation across the genome resulted in a conservatively estimated SNP heritability of 21.5% (s.e.=0.01%) for general cognitive function. Integration with prior GWAS of cognitive performance and educational attainment yielded several additional significant loci. Finally, we found robust polygenic correlations between cognitive performance and educational attainment, several psychiatric disorders, birth length/weight and smoking behavior, as well as a novel genetic association to the personality trait of openness. These data provide new insight into the genetics of neurocognitive function with relevance to understanding the pathophysiology of neuropsychiatric illness.

While data generation has been, and will remain crucial to making scientific discoveries, our ability to analyze data has not been at par with data generation. Therefore, it is important to direct our efforts towards making sense of the data already produced. In this thesis, the harmonization of single nucleotide polymorphism (SNP) identifiers is investigated. Harmonization of SNP identifiers means having the same identifier for a SNP every time it occurs. Harmonizing SNP identifiers would allow the genetic data from different datasets to become comparable, which would allow re-purposing of existing datasets in public repositories. Genetic data helps in associating genetic alterations with disease and health. Genetic data is being generated at a rate faster than Moore’s law. With the intention of making generated data available to all researchers in the world, public repositories like the UK Biobank, European Genome-phenome archive (EGA), and database of Genotypes and Phenotypes (dbGaP) have been set up to host public data and disseminate it according to protocols established. The data in these repositories is from different time points, is generated using different genotyping arrays, and is submitted by researchers all over the world. This leads to a large degree of heterogeneity in the data. In order to make the most of the data, they need to be harmonized. The greater the overlap between two datasets, the easier it is to harmonize them. Thus, in order to assess the extent to which datasets can be harmonized, it is important to perform an overlap between them. SNPs are of most interest in genetic datasets. Because of the numerous kinds of identifiers a SNP may have, determining the number and identity of overlapping SNPs between datasets is challenging and increases in complexity with the number of comparisons (SNPs and datasets). There is no tool available to perform on-the-fly harmonization of SNP identifiers. The SNP Overlap Tool (SPOT) was designed to harmonize SNP identifiers using the SNP chromosomal locations, and subsequently calculate the overlap of SNPs between two datasets. It is a web-based tool, coded in Java programming language.

© 2014 WILEY PERIODICALS INC. Methylmalonyl CoA mutase (MUT) is an essential enzyme in propionate catabolism that requires adenosylcobalamin as a cofactor. Almost 250 inherited mutations in the MUT gene are known to cause the devastating disorder methylmalonic aciduria; however the mechanism of dysfunction of these mutations more than half of which are missense changes has not been thoroughly investigated. Here we examined 23 patient missense mutations covering a spectrum of exonic/structural regions clinical phenotypes and ethnic populations in order to determine their influence on protein stability using two recombinant expression systems and a thermostability assay and enzymatic function by measuring MUT activity and affinity for its cofactor and substrate. Our data stratify MUT missense mutations into categories of biochemical defects including (1) reduced protein level due to misfolding (2) increased thermolability (3) impaired enzyme activity and (4) reduced cofactor response in substrate turnover. We further demonstrate the stabilization of wild type and thermolabile mutants by chemical chaperones in vitro and in bacterial cells. This in depth mutation study illustrates the tools available for MUT enzyme characterization guides future categorization of further missense mutations and supports the development of alternative chaperone based therapy for patients not responding to current treatment.

Funding: Royal Society - UF150663, RGF\EA\180141; Wellcome Trust - 217065/Z/19/Z; H2020 European Research Council - 694189; NWO - 451-15-017; National Health and Medical Research Council - 1173896; Canadian Institute for Health Research - MOP-133440. Handedness has been studied for association with language-related disorders because of its link with language hemispheric dominance. No clear pattern has emerged, possibly because of small samples, publication bias, and heterogeneous criteria across studies. Non-right-handedness (NRH) frequency was assessed in N = 2503 cases with reading and/or language impairment and N = 4316 sex-matched controls identified from 10 distinct cohorts (age range 6–19 years old; European ethnicity) using a priori set criteria. A meta-analysis (Ncases = 1994) showed elevated NRH % in individuals with language/reading impairment compared with controls (OR = 1.21, CI = 1.06–1.39, p = .01). The association between reading/language impairments and NRH could result from shared pathways underlying brain lateralization, handedness, and cognitive functions. Publisher PDF Peer reviewed