Genome-wide meta-analysis of common variant differences between men and women

The male-to-female sex ratio at birth is constant across world populations with an average of 1.06 (106 male to 100 female live births) for populations of European descent. The sex ratio is considered to be affected by numerous biological and environmental factors and to have a heritable component. The aim of this study was to investigate the presence of common allele modest effects at autosomal and chromosome X variants that could explain the observed sex ratio at birth. We conducted a large-scale genome-wide association scan (GWAS) meta-analysis across 51 studies, comprising overall 114 863 individuals (61 094 women and 53 769 men) of European ancestry and 2 623 828 common (minor allele frequency >0.05) single-nucleotide polymorphisms (SNPs). Allele frequencies were compared between men and women for directly-typed and imputed variants within each study. Forward-time simulations for unlinked, neutral, autosomal, common loci were performed under the demographic model for European populations with a fixed sex ratio and a random mating scheme to assess the probability of detecting significant allele frequency differences. We do not detect any genome-wide significant (P < 5 × 10−8) common SNP differences between men and women in this well-powered meta-analysis. The simulated data provided results entirely consistent with these findings. This large-scale investigation across ∼115 000 individuals shows no detectable contribution from common genetic variants to the observed skew in the sex ratio. The absence of sex-specific differences is useful in guiding genetic association study design, for example when using mixed controls for sex-biased trait

Genome-Wide Diet-Gene Interaction Analyses for Risk of Colorectal Cancer

Dietary factors, including meat, fruits, vegetables and fiber, are associated with colorectal cancer; however, there is limited information as to whether these dietary factors interact with genetic variants to modify risk of colorectal cancer. We tested interactions between these dietary factors and approximately 2.7 million genetic variants for colorectal cancer risk among 9,287 cases and 9,117 controls from ten studies. We used logistic regression to investigate multiplicative gene-diet interactions, as well as our recently developed Cocktail method that involves a screening step based on marginal associations and gene-diet correlations and a testing step for multiplicative interactions, while correcting for multiple testing using weighted hypothesis testing. Per quartile increment in the intake of red and processed meat were associated with statistically significant increased risks of colorectal cancer and vegetable, fruit and fiber intake with lower risks. From the case-control analysis, we detected a significant interaction between rs4143094 (10p14/near GATA3) and processed meat consumption (OR = 1.17; p = 8.7E-09), which was consistently observed across studies (p heterogeneity = 0.78). The risk of colorectal cancer associated with processed meat was increased among individuals with the rs4143094-TG and -TT genotypes (OR = 1.20 and OR = 1.39, respectively) and null among those with the GG genotype (OR = 1.03). Our results identify a novel gene-diet interaction with processed meat for colorectal cancer, highlighting that diet may modify the effect of genetic variants on disease risk, which may have important implications for prevention. © 2014

Association studies on 11 published colorectal cancer risk loci

Colorectal cancer (CRC) is the third most common cancer type in the Western world. Over one million patients are diagnosed worldwide yearly. A family history of CRC is a major risk factor for CRC. The total genetic contribution to disease development is estimated to be 35%. High-risk syndromes caused by known genes such as familial adenomatous polyposis (FAP) and Lynch Syndrome (LS) explain less than 5% of that number. Recently, several genome-wide association studies (GWAS) have independently found numerous loci at which common single-nucleotide polymorphisms (SNPs) modestly influence the risk of developing colorectal cancer. In total, germline mutations in known genes and moderate- and low risk variants are today suggested to explain 10-15% of the total genetic burden. Hence, predisposed genetic factor are still left to be found. The aim of paper I was to investigate if 11 published loci reported to be associated with an increased or decreased risk of colorectal cancer could be confirmed in a Swedish-based cohort. The cohort was composed of 1786 cases and 1749 controls that were genotyped and analyzed statistically. Genotype– phenotype analysis, for all 11 SNPs and sex, age of onset, family history of CRC and tumor location, was performed. Of 11 loci, 5 showed statistically significant odds ratios similar to previously published findings. Most of the remaining loci showed similar OR to previous publications. Four statistically significant genotype–phenotype associations were reported. The aim of paper II was to further study these 11 SNPs and their possible correlation with morphological features in tumors. We analyzed 15 histological features in 1572 CRC cases. Five SNPs showed statistically significant associations with morphological parameters. The parameters were poor differentiation, mucin production, decreased frequency of Crohn-like peritumoral reaction and desmoplastic response. The aim of paper III was to identify new CRC loci using a genome wide linkage analysis. We used 121 non-FAP/LS colorectal cancer families and genotyped 600 subjects using SNP array chips. No statistically significant result was found. However, suggestive linkage was found in the parametric analysis. This was observed in a recessive model for high-risk families, at locus 9q31.1 (HLOD=2.2) and for moderate-risk families, at locus Xp22.33 (LOD=2.2 and HLOD=2.5). Using families with early-onset, recessive analysis suggested one locus on 4p16.3 (LOD=2.2) and one on 17p13.2 (LOD/HLOD=2.0). Our linkage study adds support for the previously suggested region on chromosome 9 and suggests three additional loci to be involved in colorectal cancer risk. It is debated whether CRC is a single entity or two different entities, colon- and rectal cancer. Studies have recognized their molecular differences. The aim of paper IV was to identify novel colon- and rectal loci. We performed a genome wide linkage analysis using 32 colon- and 56 rectal cancer families. No LOD or HLOD score above three was observed. However, results close to three could be demonstrated. A maximum HLOD= 2.49 at locus 6p21.1-p12.1 and HLOD= 2.55 at locus 18p11.2 was observed for the colon- and rectal cancer families respectively. Exome sequencing was done, on colon and rectal patients, in these regions of interest. We report 25 variants mutated in family members on chromosome 6 and 27 variants on chromosome 18. Further studies are ongoing to elucidate the importance of these variants

Evaluation of Allele-Specific Somatic Changes of Genome-Wide Association Study Susceptibility Alleles in Human Colorectal Cancers

Tumors frequently exhibit loss of tumor suppressor genes or allelic gains of activated oncogenes. A significant proportion of cancer susceptibility loci in the mouse show somatic losses or gains consistent with the presence of a tumor susceptibility or resistance allele. Thus, allele-specific somatic gains or losses at loci may demarcate the presence of resistance or susceptibility alleles. The goal of this study was to determine if previously mapped susceptibility loci for colorectal cancer show evidence of allele-specific somatic events in colon tumors.We performed quantitative genotyping of 16 single nucleotide polymorphisms (SNPs) showing statistically significant association with colorectal cancer in published genome-wide association studies (GWAS). We genotyped 194 paired normal and colorectal tumor DNA samples and 296 paired validation samples to investigate these SNPs for allele-specific somatic gains and losses. We combined analysis of our data with published data for seven of these SNPs.No statistically significant evidence for allele-specific somatic selection was observed for the tested polymorphisms in the discovery set. The rs6983267 variant, which has shown preferential loss of the non-risk T allele and relative gain of the risk G allele in previous studies, favored relative gain of the G allele in the combined discovery and validation samples (corrected p-value = 0.03). When we combined our data with published allele-specific imbalance data for this SNP, the G allele of rs6983267 showed statistically significant evidence of relative retention (p-value = 2.06×10(-4)).Our results suggest that the majority of variants identified as colon cancer susceptibility alleles through GWAS do not exhibit somatic allele-specific imbalance in colon tumors. Our data confirm previously published results showing allele-specific imbalance for rs6983267. These results indicate that allele-specific imbalance of cancer susceptibility alleles may not be a common phenomenon in colon cancer

Inhibition of p38 MAPK Suppresses Inflammatory Cytokine Induction by Etoposide, 5-Fluorouracil, and Doxorubicin without Affecting Tumoricidal Activity

Cancer patients undergoing treatment with systemic cancer chemotherapy drugs often experience debilitating fatigue similar to sickness behavior, a normal response to infection or tissue damage caused by the production of the inflammatory cytokines IL-1β, TNF-α, and IL-6. The p38 mitogen activated protein kinase (p38 MAPK) plays a central role in the production of these cytokines and consequently the development of sickness behavior. Targeted inhibitors of p38 MAPK can reduce systemic inflammatory cytokine production and the development of sickness behavior. Several systemic cancer chemotherapy drugs have been shown to stimulate inflammatory cytokine production, yet whether this response is related to a common ability to activate p38 MAPK is not known and is the focus of this study. This understanding may present the possibility of using p38 MAPK inhibitors to reduce chemotherapy-induced inflammatory cytokine production and consequently treatment-related fatigue. One caveat of this approach is a potential reduction in chemotherapeutic efficacy as some believe that p38 MAPK activity is required for chemotherapy-induced cytotoxicity of tumor cells. The purpose of this study was to demonstrate proof of principal that p38 MAPK inhibition can block chemotherapy- induced inflammatory cytokine production without inhibiting drug-induced cytotoxicity using murine peritoneal macrophages and Lewis Lung Carcinoma (LLC1) cells as model cell systems. Using these cells we assessed the requirement of etoposide, doxorubicin, 5-flourouracil, and docetaxel for p38 MAPK in inflammatory cytokine production and cytotoxicity. Study findings demonstrate that clinically relevant doses of etoposide, doxorubicin, and 5-FU activated p38 MAPK in both macrophages and LLC1 cells. In contrast, docetaxel failed to activate p38 MAPK in either cell type. Activation of p38 MAPK mediated the drug's effects on inflammatory cytokine production in macrophages but not LLC1 cytotoxicity and this was confirmed with inhibitor studies

cis-Expression QTL Analysis of Established Colorectal Cancer Risk Variants in Colon Tumors and Adjacent Normal Tissue

Genome-wide association studies (GWAS) have identified 19 risk variants associated with colorectal cancer. As most of these risk variants reside outside the coding regions of genes, we conducted cis-expression quantitative trait loci (cis-eQTL) analyses to investigate possible regulatory functions on the expression of neighboring genes. Forty microsatellite stable and CpG island methylator phenotype-negative colorectal tumors and paired adjacent normal colon tissues were used for genome-wide SNP and gene expression profiling. We found that three risk variants (rs10795668, rs4444235 and rs9929218, using near perfect proxies rs706771, rs11623717 and rs2059252, respectively) were significantly associated (FDR q-value ≤0.05) with expression levels of nearby genes (<2 Mb up- or down-stream). We observed an association between the low colorectal cancer risk allele (A) for rs10795668 at 10p14 and increased expression of ATP5C1 (q = 0.024) and between the colorectal cancer high risk allele (C) for rs4444235 at 14q22.2 and increased expression of DLGAP5 (q = 0.041), both in tumor samples. The colorectal cancer low risk allele (A) for rs9929218 at 16q22.1 was associated with a significant decrease in expression of both NOL3 (q = 0.017) and DDX28 (q = 0.046) in the adjacent normal colon tissue samples. Of the four genes, DLGAP5 and NOL3 have been previously reported to play a role in colon carcinogenesis and ATP5C1 and DDX28 are mitochondrial proteins involved in cellular metabolism and division, respectively. The combination of GWAS findings, prior functional studies, and the cis-eQTL analyses described here suggest putative functional activities for three of the colorectal cancer GWAS identified risk loci as regulating the expression of neighboring genes

Biological processes, properties and molecular wiring diagrams of candidate low-penetrance breast cancer susceptibility genes

Background: Recent advances in whole-genome association studies (WGASs) for human cancer risk are beginning to provide the part lists of low-penetrance susceptibility genes. However, statistical analysis in these studies is complicated by the vast number of genetic variants examined and the weak effects observed, as a result of which constraints must be incorporated into the study design and analytical approach. In this scenario, biological attributes beyond the adjusted statistics generally receive little attention and, more importantly, the fundamental biological characteristics of low-penetrance susceptibility genes have yet to be determined. Methods: We applied an integrative approach for identifying candidate low-penetrance breast cancer susceptibility genes, their characteristics and molecular networks through the analysis of diverse sources of biological evidence. Results: First, examination of the distribution of Gene Ontology terms in ordered WGAS results identified asymmetrical distribution of Cell Communication and Cell Death processes linked to risk. Second, analysis of 11 different types of molecular or functional relationships in genomic and proteomic data sets defined the 'omic' properties of candidate genes: i/ differential expression in tumors relative to normal tissue; ii/ somatic genomic copy number changes correlating with gene expression levels; iii/ differentially expressed across age at diagnosis; and iv/ expression changes after BRCA1 perturbation. Finally, network modeling of the effects of variants on germline gene expression showed higher connectivity than expected by chance between novel candidates and with known susceptibility genes, which supports functional relationships and provides mechanistic hypotheses of risk. Conclusion: This study proposes that cell communication and cell death are major biological processes perturbed in risk of breast cancer conferred by low-penetrance variants, and defines the common omic properties, molecular interactions and possible functional effects of candidate genes and proteins

The anomalous magnetic moment of the muon in the Standard Model:an update

We present the current Standard Model (SM) prediction for the muon anomalous magnetic moment, aμ, updating the first White Paper (WP20) [1]. The pure QED and electroweak contributions have been further consolidated, while hadronic contributions continue to be responsible for the bulk of the uncertainty of the SM prediction. Significant progress has been achieved in the hadronic light-by-light scattering contribution using both the data-driven dispersive approach as well as lattice-QCD calculations, leading to a reduction of the uncertainty by almost a factor of two. The most important development since WP20 is the change in the estimate of the leading-order hadronic-vacuum-polarization (LO HVP) contribution. A new measurement of the e+e−→π+π− cross section by CMD-3 has increased the tensions among data-driven dispersive evaluations of the LO HVP contribution to a level that makes it impossible to combine the results in a meaningful way. At the same time, the attainable precision of lattice-QCD calculations has increased substantially and allows for a consolidated lattice-QCD average of the LO HVP contribution with a precision of about 0.9%. Adopting the latter in this update has resulted in a major upward shift of the total SM prediction, which now reads aμSM=116592033(62)×10−11 (530ppb). When compared against the current experimental average based on the E821 experiment and runs 1–6 of E989 at Fermilab, one finds aμexp−aμSM=38(63)×10−11, which implies that there is no tension between the SM and experiment at the current level of precision. The final precision of E989 (127 ppb) is the target of future efforts by the Theory Initiative. The resolution of the tensions among data-driven dispersive evaluations of the LO HVP contribution will be a key element in this endeavor.</p

Fine-mapping of common genetic variants associated with colorectal tumor risk identified potential functional variants

Genome-wide association studies (GWAS) have identified many common single nucleotide polymorphisms (SNPs) associated with colorectal cancer risk. These SNPs may tag correlated variants with biological importance. Fine-mapping around GWAS loci can facilitate detection of functional candidates and additional independent risk variants. We analyzed 11,900 cases and 14,311 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. To fine-map genomic regions containing all known common risk variants, we imputed high-density genetic data from the 1000 Genomes Project. We tested single-variant associations with colorectal tumor risk for all variants spanning genomic regions 250-kb upstream or downstream of 31 GWAS-identified SNPs (index SNPs). We queried the University of California, Santa Cruz Genome Browser to examine evidence for biological function. Index SNPs did not show the strongest association signals with colorectal tumor risk in their respective genomic regions. Bioinformatics analysis of SNPs showing smaller P-values in each region revealed 21 functional candidates in 12 loci (5q31.1, 8q24, 11q13.4, 11q23, 12p13.32, 12q24.21, 14q22.2, 15q13, 18q21, 19q13.1, 20p12.3, and 20q13.33). We did not observe evidence of additional independent association signals in GWAS-identified regions. Our results support the utility of integrating data from comprehensive fine-mapping with expanding publicly available genomic databases to help clarify GWAS associations and identify functional candidates that warrant more onerous laboratory follow-up. Such efforts may aid the eventual discovery of disease-causing variant(s).National Institutes of Health; National Cancer Institute; U.S. Department of Health and Human Services