The etiology of colorectal cancer is not fully understood.
Using genetic variants and metabolomics data including 217 metabolites from the Framingham Heart Study (n = 1,357), we built genetic ...prediction models for circulating metabolites. Models with prediction R2 > 0.01 (Nmetabolite = 58) were applied to predict levels of metabolites in two large consortia with a combined sample size of approximately 46,300 cases and 59,200 controls of European and approximately 21,700 cases and 47,400 controls of East Asian (EA) descent. Genetically predicted levels of metabolites were evaluated for their associations with colorectal cancer risk in logistic regressions within each racial group, after which the results were combined by meta-analysis.
Of the 58 metabolites tested, 24 metabolites were significantly associated with colorectal cancer risk Benjamini-Hochberg FDR (BH-FDR) < 0.05 in the European population (ORs ranged from 0.91 to 1.06; P values ranged from 0.02 to 6.4 × 10-8). Twenty one of the 24 associations were replicated in the EA population (ORs ranged from 0.26 to 1.69, BH-FDR < 0.05). In addition, the genetically predicted levels of C16:0 cholesteryl ester was significantly associated with colorectal cancer risk in the EA population only (OREA: 1.94, 95% CI, 1.60-2.36, P = 2.6 × 10-11; OREUR: 1.01, 95% CI, 0.99-1.04, P = 0.3). Nineteen of the 25 metabolites were glycerophospholipids and triacylglycerols (TAG). Eighteen associations exhibited significant heterogeneity between the two racial groups (PEUR-EA-Het < 0.005), which were more strongly associated in the EA population. This integrative study suggested a potential role of lipids, especially certain glycerophospholipids and TAGs, in the etiology of colorectal cancer.
This study identified potential novel risk biomarkers for colorectal cancer by integrating genetics and circulating metabolomics data.
The identified metabolites could be developed into new tools for risk assessment of colorectal cancer in both European and EA populations.
Insulin secretion has a crucial role in glucose homeostasis, and failure to secrete sufficient insulin is a hallmark of type 2 diabetes. Genome-wide association studies (GWAS) have identified loci ...contributing to insulin processing and secretion; however, a substantial fraction of the genetic contribution remains undefined. To examine low-frequency (minor allele frequency (MAF) 0.5-5%) and rare (MAF < 0.5%) nonsynonymous variants, we analyzed exome array data in 8,229 nondiabetic Finnish males using the Illumina HumanExome Beadchip. We identified low-frequency coding variants associated with fasting proinsulin concentrations at the SGSM2 and MADD GWAS loci and three new genes with low-frequency variants associated with fasting proinsulin or insulinogenic index: TBC1D30, KANK1 and PAM. We also show that the interpretation of single-variant and gene-based tests needs to consider the effects of noncoding SNPs both nearby and megabases away. This study demonstrates that exome array genotyping is a valuable approach to identify low-frequency variants that contribute to complex traits.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Recognizing the early signs of cancer risk is vital for informing prevention, early detection, and survival.
To investigate whether changes in circulating metabolites characterize the early stages of ...colorectal cancer (CRC) development, we examined the associations between a genetic risk score (GRS) associated with CRC liability (72 single-nucleotide polymorphisms) and 231 circulating metabolites measured by nuclear magnetic resonance spectroscopy in the Avon Longitudinal Study of Parents and Children (N = 6221). Linear regression models were applied to examine the associations between genetic liability to CRC and circulating metabolites measured in the same individuals at age 8 y, 16 y, 18 y, and 25 y.
The GRS for CRC was associated with up to 28% of the circulating metabolites at FDR-P < 0.05 across all time points, particularly with higher fatty acids and very-low- and low-density lipoprotein subclass lipids. Two-sample reverse Mendelian randomization (MR) analyses investigating CRC liability (52,775 cases, 45,940 controls) and metabolites measured in a random subset of UK Biobank participants (N = 118,466, median age 58 y) revealed broadly consistent effect estimates with the GRS analysis. In conventional (forward) MR analyses, genetically predicted polyunsaturated fatty acid concentrations were most strongly associated with higher CRC risk.
These analyses suggest that higher genetic liability to CRC can cause early alterations in systemic metabolism and suggest that fatty acids may play an important role in CRC development.
This work was supported by the Elizabeth Blackwell Institute for Health Research, University of Bristol, the Wellcome Trust, the Medical Research Council, Diabetes UK, the University of Bristol NIHR Biomedical Research Centre, and Cancer Research UK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This work used the computational facilities of the Advanced Computing Research Centre, University of Bristol - http://www.bristol.ac.uk/acrc/.
Habitat fragmentation can restrict geneflow, reduce neighbourhood effective population size, and increase genetic drift and inbreeding in small, isolated habitat remnants. The extent to which habitat ...fragmentation leads to population fragmentation, however, differs among landscapes and taxa. Commonly, researchers use information on the current status of a species to predict population effects of habitat fragmentation. Such methods, however, do not convey information on species-specific responses to fragmentation. Here, we compare levels of past population differentiation, estimated from microsatellite genotypes, with contemporary dispersal rates, estimated from multi-strata capture-recapture models, to infer changes in mobility over time in seven sympatric, forest-dependent bird species of a Kenyan cloud forest archipelago. Overall, populations of sedentary species were more strongly differentiated and clustered compared to those of vagile ones, while geographical patterning suggested an important role of landscape structure in shaping genetic variation. However, five of seven species with broadly similar levels of genetic differentiation nevertheless differed substantially in their current dispersal rates. We conclude that post-fragmentation levels of vagility, without reference to past population connectivity, may not be the best predictor of how forest fragmentation affects the life history of forest-dependent species. As effective conservation strategies often hinge on accurate prediction of shifts in ecological and genetic relationships among populations, conservation practices based solely upon current population abundances or movements may, in the long term, prove to be inadequate.
Genome-wide association studies (GWASs) and functional genomics approaches implicate enhancer disruption in islet dysfunction and type 2 diabetes (T2D) risk. We applied genetic fine-mapping and ...functional (epi)genomic approaches to a T2D- and proinsulin-associated 15q22.2 locus to identify a most likely causal variant, determine its direction of effect, and elucidate plausible target genes. Fine-mapping and conditional analyses of proinsulin levels of 8,635 non-diabetic individuals from the METSIM study support a single association signal represented by a cluster of 16 strongly associated (p < 10−17) variants in high linkage disequilibrium (r2 > 0.8) with the GWAS index SNP rs7172432. These variants reside in an evolutionarily and functionally conserved islet and β cell stretch or super enhancer; the most strongly associated variant (rs7163757, p = 3 × 10−19) overlaps a conserved islet open chromatin site. DNA sequence containing the rs7163757 risk allele displayed 2-fold higher enhancer activity than the non-risk allele in reporter assays (p < 0.01) and was differentially bound by β cell nuclear extract proteins. Transcription factor NFAT specifically potentiated risk-allele enhancer activity and altered patterns of nuclear protein binding to the risk allele in vitro, suggesting that it could be a factor mediating risk-allele effects. Finally, the rs7163757 proinsulin-raising and T2D risk allele (C) was associated with increased expression of C2CD4B, and possibly C2CD4A, both of which were induced by inflammatory cytokines, in human islets. Together, these data suggest that rs7163757 contributes to genetic risk of islet dysfunction and T2D by increasing NFAT-mediated islet enhancer activity and modulating C2CD4B, and possibly C2CD4A, expression in (patho)physiologic states.
Transcriptome-wide association studies have been successful in identifying candidate susceptibility genes for colorectal cancer (CRC). To strengthen susceptibility gene discovery, we conducted a ...large transcriptome-wide association study and an alternative splicing transcriptome-wide association study in CRC using improved genetic prediction models and performed in-depth functional investigations.
We analyzed RNA-sequencing data from normal colon tissues and genotype data from 423 European descendants to build genetic prediction models of gene expression and alternative splicing and evaluated model performance using independent RNA-sequencing data from normal colon tissues of the Genotype-Tissue Expression Project. We applied the verified models to genome-wide association studies (GWAS) summary statistics among 58 131 CRC cases and 67 347 controls of European ancestry to evaluate associations of genetically predicted gene expression and alternative splicing with CRC risk. We performed in vitro functional assays for 3 selected genes in multiple CRC cell lines.
We identified 57 putative CRC susceptibility genes, which included the 48 genes from transcriptome-wide association studies and 15 genes from splicing transcriptome-wide association studies, at a Bonferroni-corrected P value less than .05. Of these, 16 genes were not previously implicated in CRC susceptibility, including a gene PDE7B (6q23.3) at locus previously not reported by CRC GWAS. Gene knockdown experiments confirmed the oncogenic roles for 2 unreported genes, TRPS1 and METRNL, and a recently reported gene, C14orf166.
This study discovered new putative susceptibility genes of CRC and provided novel insights into the biological mechanisms underlying CRC development.
Colorectal cancer (CRC) is a heterogeneous disease with evidence of distinct tumor types that develop through different somatically altered pathways. To better understand the impact of the host ...genome on somatically mutated genes and pathways, we assessed associations of germline variations with somatic events via two complementary approaches. We first analyzed the association between individual germline genetic variants and the presence of non-silent somatic mutations in genes in 1375 CRC cases with genome-wide SNPs data and a tumor sequencing panel targeting 205 genes. In the second analysis, we tested if germline variants located within previously identified regions of somatic allelic imbalance were associated with overall CRC risk using summary statistics from a recent large scale GWAS (n≃125 k CRC cases and controls). The first analysis revealed that a variant (rs78963230) located within a CNA region associated with TLR3 was also associated with a non-silent mutation within gene FBXW7. In the secondary analysis, the variant rs2302274 located in CDX1/PDGFRB frequently gained/lost in colorectal tumors was associated with overall CRC risk (OR = 0.96, p = 7.50e-7). In summary, we demonstrate that an integrative analysis of somatic and germline variation can lead to new insights about CRC.
A multicenter study was set up to elucidate the environmental and medical risk factors contributing to age-related hearing impairment (ARHI). Nine subsamples, collected by nine audiological centers ...across Europe, added up to a total of 4,083 subjects between 53 and 67 years. Audiometric data (pure-tone average PTA) were collected and the participants filled out a questionnaire on environmental risk factors and medical history. People with a history of disease that could affect hearing were excluded. PTAs were adjusted for age and sex and tested for association with exposure to risk factors. Noise exposure was associated with a significant loss of hearing at high sound frequencies (>1 kHz). Smoking significantly increased high-frequency hearing loss, and the effect was dose-dependent. The effect of smoking remained significant when accounting for cardiovascular disease events. Taller people had better hearing on average with a more pronounced effect at low sound frequencies (<2 kHz). A high body mass index (BMI) correlated with hearing loss across the frequency range tested. Moderate alcohol consumption was inversely correlated with hearing loss. Significant associations were found in the high as well as in the low frequencies. The results suggest that a healthy lifestyle can protect against age-related hearing impairment.
Observational studies have suggested a protective role for eosinophils in colorectal cancer (CRC) development and implicated neutrophils, but the causal relationships remain unclear. Here, we aimed ...to estimate the causal effect of circulating white blood cell (WBC) counts (N = ~550 000) for basophils, eosinophils, monocytes, lymphocytes and neutrophils on CRC risk (N = 52 775 cases and 45 940 controls) using Mendelian randomisation (MR). For comparison, we also examined this relationship using individual-level data from UK Biobank (4043 incident CRC cases and 332 773 controls) in a longitudinal cohort analysis. The inverse-variance weighted (IVW) MR analysis suggested a protective effect of increased basophil count and eosinophil count on CRC risk OR per 1-SD increase: 0.88, 95% CI: 0.78-0.99, P = .04; OR: 0.93, 95% CI: 0.88-0.98, P = .01. The protective effect of eosinophils remained OR per 1-SD increase: 0.88, 95% CI: 0.80-0.97, P = .01 following adjustments for all other WBC subtypes, to account for genetic correlation between the traits, using multivariable MR. A protective effect of increased lymphocyte count on CRC risk was also found OR: 0.84, 95% CI: 0.76-0.93, P = 6.70e-4 following adjustment. Consistent with MR results, a protective effect for eosinophils in the cohort analysis in the fully adjusted model RR per 1-SD increase: 0.96, 95% CI: 0.93-0.99, P = .02 and following adjustment for the other WBC subtypes RR: 0.96, 95% CI: 0.93-0.99, P = .001 was observed. Our study implicates peripheral blood immune cells, in particular eosinophils and lymphocytes, in CRC development, highlighting a need for mechanistic studies to interrogate these relationships.
This study aimed at contributing to the elucidation of the genetic basis of age-related hearing impairment (ARHI), a common multifactorial disease with an important genetic contribution as ...demonstrated by heritability studies. We conducted a genome-wide association study (GWAS) in the Finnish Saami, a small, ancient, genetically isolated population without evidence of demographic expansion. The choice of this study population was motivated by its anticipated higher extent of LD, potentially offering a substantial power advantage for association mapping. DNA samples and audiometric measurements were collected from 352 Finnish Saami individuals, aged between 50 and 75 years. To reduce the burden of multiple testing, we applied principal component (PC) analysis to the multivariate audiometric phenotype. The first three PCs captured 80% of the variation in hearing thresholds, while maintaining biologically important audiometric features. All subjects were genotyped with the Affymetrix 100 K chip. To account for multiple levels of relatedness among subjects, as well as for population stratification, association testing was performed using a mixed model. We summarised the top-ranking association signals for the three traits under study. The top-ranked SNP, rs457717 (P-value 3.55 x 10(-7)), was associated with PC3 and was localised in an intron of the IQ motif-containing GTPase-activating-like protein (IQGAP2). Intriguingly, the SNP rs161927 (P-value 0.000149), seventh-ranked for PC1, was positioned immediately downstream from the metabotropic glutamate receptor-7 gene (GRM7). As a previous GWAS of a European and Finnish sample set already suggested a role for GRM7 in ARHI, this study provides further evidence for the involvement of this gene.
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