Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 42
Filtrar
1.
Artigo em Inglês | MEDLINE | ID: mdl-33601062

RESUMO

BACKGROUND & AIMS: The association of genetic variation with tissue-specific gene expression and alternative splicing guides functional characterization of complex trait associated loci and may suggest novel genes implicated in disease. Here, we aimed to 1) generate reference profiles of colon mucosa gene expression and alternative splicing and compare them across colon subsites (ascending, transverse and descending), 2) identify expression and splicing quantitative trait loci (QTLs), 3) find traits for which identified QTLs contribute to single nucleotide polymorphism (SNP)-based heritability, 4) propose candidate effector genes, and 5) provide a web-based visualization resource. METHODS: We collected colonic mucosal biopsies from 485 healthy adults and performed bulk RNA sequencing (RNA-Seq). We performed genome-wide SNP genotyping from blood leukocytes. Statistical approaches and bioinformatics software were used for QTL identification and downstream analyses. RESULTS: We provided a complete quantification of gene expression and alternative splicing across colon subsites and described their differences. We identified thousands of expression and splicing QTLs and defined their enrichment at genome-wide regulatory regions. We found that part of the SNP-based heritability of diseases affecting colon tissue, such as colorectal cancer and inflammatory bowel disease, but also of diseases affecting other tissues, such as psychiatric conditions, can be explained by the identified QTLs. We provided candidate effector genes for multiple phenotypes. Finally, we provided the Colon Transcriptome Explorer (CoTrEx). CONCLUSIONS: We provided the largest characterization to date of gene expression and splicing across colon subsites. Our findings provide greater etiological insight into complex traits and diseases influenced by transcriptomic changes in colon tissue.

2.
Gastroenterology ; 2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33058866

RESUMO

BACKGROUND AND AIMS: Susceptibility genes and the underlying mechanisms for the majority of risk loci identified by genome-wide association studies (GWAS) for colorectal cancer (CRC) risk remain largely unknown. We conducted a transcriptome-wide association study (TWAS) to identify putative susceptibility genes. METHODS: Gene-expression prediction models were built using transcriptome and genetic data from the 284 normal transverse colon tissues of European descendants from the Genotype-Tissue Expression (GTEx), and model performance was evaluated using data from The Cancer Genome Atlas (n = 355). We applied the gene-expression prediction models and GWAS data to evaluate associations of genetically predicted gene-expression with CRC risk in 58,131 CRC cases and 67,347 controls of European ancestry. Dual-luciferase reporter assays and knockdown experiments in CRC cells and tumor xenografts were conducted. RESULTS: We identified 25 genes associated with CRC risk at a Bonferroni-corrected threshold of P < 9.1 × 10-6, including genes in 4 novel loci, PYGL (14q22.1), RPL28 (19q13.42), CAPN12 (19q13.2), MYH7B (20q11.22), and MAP1L3CA (20q11.22). In 9 known GWAS-identified loci, we uncovered 9 genes that have not been reported previously, whereas 4 genes remained statistically significant after adjusting for the lead risk variant of the locus. Through colocalization analysis in GWAS loci, we additionally identified 12 putative susceptibility genes that were supported by TWAS analysis at P < .01. We showed that risk allele of the lead risk variant rs1741640 affected the promoter activity of CABLES2. Knockdown experiments confirmed that CABLES2 plays a vital role in colorectal carcinogenesis. CONCLUSIONS: Our study reveals new putative susceptibility genes and provides new insight into the biological mechanisms underlying CRC development.

3.
PLoS Genet ; 16(8): e1008947, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32833970

RESUMO

Genome-wide association studies (GWAS) have successfully identified tens of thousands of genetic variants associated with various phenotypes, but together they explain only a fraction of heritability, suggesting many variants have yet to be discovered. Recently it has been recognized that incorporating functional information of genetic variants can improve power for identifying novel loci. For example, S-PrediXcan and TWAS tested the association of predicted gene expression with phenotypes based on GWAS summary statistics by leveraging the information on genetic regulation of gene expression and found many novel loci. However, as genetic variants may have effects on more than one gene and through different mechanisms, these methods likely only capture part of the total effects of these variants. In this paper, we propose a summary statistics-based mixed effects score test (sMiST) that tests for the total effect of both the effect of the mediator by imputing genetically predicted gene expression, like S-PrediXcan and TWAS, and the direct effects of individual variants. It allows for multiple functional annotations and multiple genetically predicted mediators. It can also perform conditional association analysis while adjusting for other genetic variants (e.g., known loci for the phenotype). Extensive simulation and real data analyses demonstrate that sMiST yields p-values that agree well with those obtained from individual level data but with substantively improved computational speed. Importantly, a broad application of sMiST to GWAS is possible, as only summary statistics of genetic variant associations are required. We apply sMiST to a large-scale GWAS of colorectal cancer using summary statistics from ∼120, 000 study participants and gene expression data from the Genotype-Tissue Expression (GTEx) project. We identify several novel and secondary independent genetic loci.


Assuntos
Neoplasias Colorretais/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Locos de Características Quantitativas/genética , Neoplasias Colorretais/patologia , Biologia Computacional , Regulação Neoplásica da Expressão Gênica/genética , Variação Genética/genética , Genótipo , Humanos , Modelos Estatísticos , Fenótipo , Polimorfismo de Nucleotídeo Único/genética
4.
Cancer Epidemiol Biomarkers Prev ; 29(9): 1800-1808, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32651213

RESUMO

BACKGROUND: Regular use of nonsteroidal anti-inflammatory drugs (NSAID) is associated with lower risk of colorectal cancer. Genome-wide interaction analysis on single variants (G × E) has identified several SNPs that may interact with NSAIDs to confer colorectal cancer risk, but variations in gene expression levels may also modify the effect of NSAID use. Therefore, we tested interactions between NSAID use and predicted gene expression levels in relation to colorectal cancer risk. METHODS: Genetically predicted gene expressions were tested for interaction with NSAID use on colorectal cancer risk among 19,258 colorectal cancer cases and 18,597 controls from 21 observational studies. A Mixed Score Test for Interactions (MiSTi) approach was used to jointly assess G × E effects which are modeled via fixed interaction effects of the weighted burden within each gene set (burden) and residual G × E effects (variance). A false discovery rate (FDR) at 0.2 was applied to correct for multiple testing. RESULTS: Among the 4,840 genes tested, genetically predicted expression levels of four genes modified the effect of any NSAID use on colorectal cancer risk, including DPP10 (PG×E = 1.96 × 10-4), KRT16 (PG×E = 2.3 × 10-4), CD14 (PG×E = 9.38 × 10-4), and CYP27A1 (PG×E = 1.44 × 10-3). There was a significant interaction between expression level of RP11-89N17 and regular use of aspirin only on colorectal cancer risk (PG×E = 3.23 × 10-5). No interactions were observed between predicted gene expression and nonaspirin NSAID use at FDR < 0.2. CONCLUSIONS: By incorporating functional information, we discovered several novel genes that interacted with NSAID use. IMPACT: These findings provide preliminary support that could help understand the chemopreventive mechanisms of NSAIDs on colorectal cancer.

5.
J Natl Cancer Inst ; 2020 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-32324875

RESUMO

BACKGROUND: Body mass index (BMI) is a complex phenotype that may interact with genetic variants to influence colorectal cancer risk. METHODS: We tested multiplicative statistical interactions between BMI (per 5 kg·m2) and approximately 2.7 million single nucleotide polymorphisms (SNPs) with colorectal cancer risk among 14,059 colorectal cancer case (53.2% women) and 14,416 control (53.8% women) participants. All analyses were stratified by sex a priori. Statistical methods included two-step (i.e., Cocktail method) and single-step (i.e., case-control logistic regression and a joint 2-degree of freedom test) procedures. All statistical tests were two-sided. RESULTS: Each 5 kg·m2 increase in BMI was associated with higher risks of colorectal cancer, less so for women (odds ratio [OR]: 1.14; 95% confidence intervals [CI]: 1.11-1.18; p-value: 9.75 x 10-17) than for men (OR: 1.26; 95% CI: 1.20-1.32; p-value: 2.13 x 10-24). The two-step Cocktail method identified an interaction for women, but not men, between BMI and a SMAD7 intronic variant at 18q21.1 (rs4939827; p-observed: 0.0009; p-threshold: 0.005). A joint 2-degree of freedom test was consistent with this finding for women (joint p-value: 2.43 x 10-10). Each 5 kg·m2 increase in BMI was more strongly associated with colorectal cancer risk for women with the rs4939827-CC genotype (OR: 1.24; 95% CI: 1.16-1.32; p-value: 2.60 x 10-10) than for women with the CT (OR: 1.14; 95% CI: 1.09-1.19; p-value: 1.04 x 10-8) or TT (OR: 1.07; 95% CI: 1.01-1.14; p-value: 0.02) genotypes. CONCLUSION: These results provide novel insights on a potential mechanism through which a SMAD7 variant, previously identified as a susceptibility locus for colorectal cancer, and BMI may influence colorectal cancer risk for women.

6.
PLoS Genet ; 16(3): e1008684, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32226016

RESUMO

Lipid levels are important markers for the development of cardio-metabolic diseases. Although hundreds of associated loci have been identified through genetic association studies, the contribution of genetic factors to variation in lipids is not fully understood, particularly in U.S. minority groups. We performed genome-wide association analyses for four lipid traits in over 45,000 ancestrally diverse participants from the Population Architecture using Genomics and Epidemiology (PAGE) Study, followed by a meta-analysis with several European ancestry studies. We identified nine novel lipid loci, five of which showed evidence of replication in independent studies. Furthermore, we discovered one novel gene in a PrediXcan analysis, minority-specific independent signals at eight previously reported loci, and potential functional variants at two known loci through fine-mapping. Systematic examination of known lipid loci revealed smaller effect estimates in African American and Hispanic ancestry populations than those in Europeans, and better performance of polygenic risk scores based on minority-specific effect estimates. Our findings provide new insight into the genetic architecture of lipid traits and highlight the importance of conducting genetic studies in diverse populations in the era of precision medicine.


Assuntos
Grupos de Populações Continentais/genética , Lipídeos/sangue , Lipídeos/genética , Bases de Dados Genéticas , Feminino , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Lipídeos/análise , Masculino , Metagenômica/métodos , Grupos Minoritários , Herança Multifatorial/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Estados Unidos/epidemiologia
7.
Cancer Med ; 9(10): 3563-3573, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32207560

RESUMO

BACKGROUND: Body mass index (BMI) and diabetes are established risk factors for colorectal cancer (CRC), likely through perturbations in metabolic traits (e.g. insulin resistance and glucose homeostasis). Identification of interactions between variation in genes and these metabolic risk factors may identify novel biologic insights into CRC etiology. METHODS: To improve statistical power and interpretation for gene-environment interaction (G × E) testing, we tested genetic variants that regulate expression of a gene together for interaction with BMI (kg/m2 ) and diabetes on CRC risk among 26 017 cases and 20 692 controls. Each variant was weighted based on PrediXcan analysis of gene expression data from colon tissue generated in the Genotype-Tissue Expression Project for all genes with heritability ≥1%. We used a mixed-effects model to jointly measure the G × E interaction in a gene by partitioning the interactions into the predicted gene expression levels (fixed effects), and residual G × E effects (random effects). G × BMI analyses were stratified by sex as BMI-CRC associations differ by sex. We used false discovery rates to account for multiple comparisons and reported all results with FDR <0.2. RESULTS: Among 4839 genes tested, genetically predicted expressions of FOXA1 (P = 3.15 × 10-5 ), PSMC5 (P = 4.51 × 10-4 ) and CD33 (P = 2.71 × 10-4 ) modified the association of BMI on CRC risk for men; KIAA0753 (P = 2.29 × 10-5 ) and SCN1B (P = 2.76 × 10-4 ) modified the association of BMI on CRC risk for women; and PTPN2 modified the association between diabetes and CRC risk in both sexes (P = 2.31 × 10-5 ). CONCLUSIONS: Aggregating G × E interactions and incorporating functional information, we discovered novel genes that may interact with BMI and diabetes on CRC risk.

8.
BMC Genomics ; 21(1): 228, 2020 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-32171239

RESUMO

BACKGROUND: Quantitative red blood cell (RBC) traits are highly polygenic clinically relevant traits, with approximately 500 reported GWAS loci. The majority of RBC trait GWAS have been performed in European- or East Asian-ancestry populations, despite evidence that rare or ancestry-specific variation contributes substantially to RBC trait heritability. Recently developed combined-phenotype methods which leverage genetic trait correlation to improve statistical power have not yet been applied to these traits. Here we leveraged correlation of seven quantitative RBC traits in performing a combined-phenotype analysis in a multi-ethnic study population. RESULTS: We used the adaptive sum of powered scores (aSPU) test to assess combined-phenotype associations between ~ 21 million SNPs and seven RBC traits in a multi-ethnic population (maximum n = 67,885 participants; 24% African American, 30% Hispanic/Latino, and 43% European American; 76% female). Thirty-nine loci in our multi-ethnic population contained at least one significant association signal (p < 5E-9), with lead SNPs at nine loci significantly associated with three or more RBC traits. A majority of the lead SNPs were common (MAF > 5%) across all ancestral populations. Nineteen additional independent association signals were identified at seven known loci (HFE, KIT, HBS1L/MYB, CITED2/FILNC1, ABO, HBA1/2, and PLIN4/5). For example, the HBA1/2 locus contained 14 conditionally independent association signals, 11 of which were previously unreported and are specific to African and Amerindian ancestries. One variant in this region was common in all ancestries, but exhibited a narrower LD block in African Americans than European Americans or Hispanics/Latinos. GTEx eQTL analysis of all independent lead SNPs yielded 31 significant associations in relevant tissues, over half of which were not at the gene immediately proximal to the lead SNP. CONCLUSION: This work identified seven loci containing multiple independent association signals for RBC traits using a combined-phenotype approach, which may improve discovery in genetically correlated traits. Highly complex genetic architecture at the HBA1/2 locus was only revealed by the inclusion of African Americans and Hispanics/Latinos, underscoring the continued importance of expanding large GWAS to include ancestrally diverse populations.


Assuntos
Afro-Americanos/genética , Eritrócitos/metabolismo , Grupo com Ancestrais do Continente Europeu/genética , Estudo de Associação Genômica Ampla/métodos , Hispano-Americanos/genética , Característica Quantitativa Herdável , Feminino , Genética Populacional , Humanos , Masculino , Herança Multifatorial , Fenótipo , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA , Estados Unidos/etnologia
9.
PLoS One ; 15(1): e0227116, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31951625

RESUMO

In this study we aimed to explore the potential biological effect of ethanol exposure on healthy colon epithelial cells using normal human colon 3D organoid "mini-gut" cultures. In numerous published studies ethanol use has been shown to be an environmental risk factor for colorectal cancer (CRC) development; however, the influence of ethanol exposure on normal colon epithelial cell biology remains poorly understood. We investigated the potential molecular effects of ethanol exposure in normal colon 3D organoids in a small pilot study (n = 3) using RNA-seq and ATAC-seq. We identify 1965 differentially expressed genes and 2217 differentially accessible regions of chromatin in response to ethanol treatment. Further, by cross-referencing our results with previously published analysis in colorectal cancer cell lines, we have not only validated a number of reported differentially expressed genes, but also identified several novel candidates for future investigation. In summary, our data highlights the potential importance for the use of normal colon 3D organoid models as a novel tool for the investigation of the relationship between the effects of environmental risk factors associated with colorectal cancer and the molecular mechanisms through which they confer this risk.


Assuntos
Montagem e Desmontagem da Cromatina , Colo/efeitos dos fármacos , Etanol/farmacologia , Organoides/efeitos dos fármacos , Transcriptoma , Adulto , Linhagem Celular Tumoral , Células Cultivadas , Cromatina/efeitos dos fármacos , Cromatina/genética , Cromatina/metabolismo , Colo/citologia , Colo/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Organoides/metabolismo
11.
Int J Epidemiol ; 49(1): 259-269, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31038671

RESUMO

BACKGROUND: Increasing evidence suggests that conventional adenomas (CAs) and serrated polyps (SPs) represent two distinct groups of precursor lesions for colorectal cancer (CRC). The influence of common genetic variants on risk of CAs and SPs remain largely unknown. METHODS: Among 27 426 participants within three prospective cohort studies, we created a weighted genetic risk score (GRS) based on 40 CRC-related single nucleotide polymorphisms (SNPs) identified in previous genome-wide association studies; and we examined the association of GRS (per one standard deviation increment) with risk of CAs, SPs and synchronous CAs and SPs, by multivariable logistic regression. We also analysed individual variants in the secondary analysis. RESULTS: During 18-20 years of follow-up, we documented 2952 CAs, 1585 SPs and 794 synchronous CAs and SPs. Higher GRS was associated with increased risk of CAs [odds ratio (OR) = 1.17, 95% confidence interval (CI): 1.12-1.21] and SPs (OR = 1.09, 95% CI: 1.03-1.14), with a stronger association for CAs than SPs (Pheterogeneity=0.01). An even stronger association was found for patients with synchronous CAs and SPs (OR = 1.32), advanced CAs (OR = 1.22) and multiple CAs (OR = 1.25). Different sets of variants were associated with CAs and SPs, with a Spearman correlation coefficient of 0.02 between the ORs associating the 40 SNPs with the two lesions. After correcting for multiple testing, three variants were associated with CAs (rs3802842, rs6983267 and rs7136702) and two with SPs (rs16892766 and rs4779584). CONCLUSIONS: Common genetic variants play a potential role in the conventional and serrated pathways of CRC. Different sets of variants are identified for the two pathways, further supporting the aetiological heterogeneity of CRC.


Assuntos
Adenoma/genética , Neoplasias do Colo/genética , Neoplasias Colorretais/genética , Pólipos/genética , Idoso , Estudos de Coortes , Neoplasias do Colo/patologia , Neoplasias Colorretais/patologia , Seguimentos , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo de Nucleotídeo Único , Pólipos/patologia , Estudos Prospectivos , Fatores de Risco
12.
Int J Cancer ; 146(2): 363-372, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31209889

RESUMO

Interindividual differences in DNA repair systems may play a role in modulating the individual risk of developing colorectal cancer. To better ascertain the role of DNA repair gene polymorphisms on colon and rectal cancer risk individually, we evaluated 15,419 single nucleotide polymorphisms (SNPs) within 185 DNA repair genes using GWAS data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), which included 8,178 colon cancer, 2,936 rectum cancer cases and 14,659 controls. Rs1800734 (in MLH1 gene) was associated with colon cancer risk (p-value = 3.5 × 10-6 ) and rs2189517 (in RAD51B) with rectal cancer risk (p-value = 5.7 × 10-6 ). The results had statistical significance close to the Bonferroni corrected p-value of 5.8 × 10-6 . Ninety-four SNPs were significantly associated with colorectal cancer risk after Binomial Sequential Goodness of Fit (BSGoF) procedure and confirmed the relevance of DNA mismatch repair (MMR) and homologous recombination pathways for colon and rectum cancer, respectively. Defects in MMR genes are known to be crucial for familial form of colorectal cancer but our findings suggest that specific genetic variations in MLH1 are important also in the individual predisposition to sporadic colon cancer. Other SNPs associated with the risk of colon cancer (e.g., rs16906252 in MGMT) were found to affect mRNA expression levels in colon transverse and therefore working as possible cis-eQTL suggesting possible mechanisms of carcinogenesis.


Assuntos
Neoplasias do Colo/genética , Reparo do DNA/genética , Predisposição Genética para Doença , Neoplasias Retais/genética , Adulto , Idoso , Variação Biológica da População/genética , Carcinogênese/genética , Estudos de Casos e Controles , Colo/patologia , Neoplasias do Colo/patologia , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Proteínas de Ligação a DNA/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL/genética , Polimorfismo de Nucleotídeo Único , Neoplasias Retais/patologia , Reto/patologia , Sistema de Registros/estatística & dados numéricos , Medição de Risco , Proteínas Supressoras de Tumor/genética , Adulto Jovem
13.
Clin Gastroenterol Hepatol ; 18(12): 2717-2723.e3, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31811950

RESUMO

BACKGROUND & AIMS: Many genetic variants have been associated with colorectal cancer risk, although few have been associated with survival times of patients. Identification of genetic variants associated with survival times might improve our understanding of disease progression and aid in outcome prediction. We performed a genome-wide association study to identify variants associated with colon cancer survival time. METHODS: We performed a post hoc analysis of data from NCCTG N0147 (Alliance), a randomized phase 3 trial of patients with resected stage III colon cancer, and from NSABP C-08 (NRG), a phase 3 trial that compared therapy regimens for patients with resected stage II or III colon cancer. Genotype analyses were performed on DNA from blood samples from 4974 patients. We used Cox proportional hazards regression to evaluate the association of each single nucleotide polymorphism with times of overall survival and disease-free survival, adjusting for age at diagnosis, sex, treatment group, and principal components of genetic ancestry. We performed the analysis for studies N0147 and C-08 separately, and results were combined in a fixed-effects meta-analysis. RESULTS: A locus on chromosome 7p15.2 was significantly associated with overall survival time (P ≤ 5x10-08). The most significant variant at this locus, rs76766811 (P = 1.6x10-08), is common among African Americans (minor allele frequency, approximately 18%) but rare in European Americans (minor allele frequency <0.1%). Within strata of self-reported ancestry, this variant was associated with times of overall survival and disease-free survival in only African Americans (hazard ratio for overall survival, 2.82; 95% CI, 1.88-4.23; P = 5.0x10-07 and hazard ratio for disease-free survival, 2.27; 95% CI, 1.62-3.18; P = 1.8x10-06). CONCLUSIONS: In an analysis of data from 2 trials of patients with stage II or III colon cancer, we identified rs76766811 as a potential prognostic variant in African American patients. This finding should be confirmed in additional study populations. ClinicalTrials.gov Identifiers: NCT00096278 (NSABP C-08) and NCT00079274 (NCCTG N0147).

14.
Gastroenterology ; 158(5): 1274-1286.e12, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31866242

RESUMO

BACKGROUND & AIMS: Early-onset colorectal cancer (CRC, in persons younger than 50 years old) is increasing in incidence; yet, in the absence of a family history of CRC, this population lacks harmonized recommendations for prevention. We aimed to determine whether a polygenic risk score (PRS) developed from 95 CRC-associated common genetic risk variants was associated with risk for early-onset CRC. METHODS: We studied risk for CRC associated with a weighted PRS in 12,197 participants younger than 50 years old vs 95,865 participants 50 years or older. PRS was calculated based on single nucleotide polymorphisms associated with CRC in a large-scale genome-wide association study as of January 2019. Participants were pooled from 3 large consortia that provided clinical and genotyping data: the Colon Cancer Family Registry, the Colorectal Transdisciplinary Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium and were all of genetically defined European descent. Findings were replicated in an independent cohort of 72,573 participants. RESULTS: Overall associations with CRC per standard deviation of PRS were significant for early-onset cancer, and were stronger compared with late-onset cancer (P for interaction = .01); when we compared the highest PRS quartile with the lowest, risk increased 3.7-fold for early-onset CRC (95% CI 3.28-4.24) vs 2.9-fold for late-onset CRC (95% CI 2.80-3.04). This association was strongest for participants without a first-degree family history of CRC (P for interaction = 5.61 × 10-5). When we compared the highest with the lowest quartiles in this group, risk increased 4.3-fold for early-onset CRC (95% CI 3.61-5.01) vs 2.9-fold for late-onset CRC (95% CI 2.70-3.00). Sensitivity analyses were consistent with these findings. CONCLUSIONS: In an analysis of associations with CRC per standard deviation of PRS, we found the cumulative burden of CRC-associated common genetic variants to associate with early-onset cancer, and to be more strongly associated with early-onset than late-onset cancer, particularly in the absence of CRC family history. Analyses of PRS, along with environmental and lifestyle risk factors, might identify younger individuals who would benefit from preventive measures.


Assuntos
Neoplasias Colorretais/genética , Predisposição Genética para Doença , Idade de Início , Estudos de Casos e Controles , Estudos de Coortes , Análise Mutacional de DNA , Conjuntos de Dados como Assunto , Feminino , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Humanos , Estilo de Vida , Masculino , Anamnese , Pessoa de Meia-Idade , Taxa de Mutação , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Sequenciamento Completo do Genoma
15.
PLoS Genet ; 15(12): e1008500, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31869403

RESUMO

Most genome-wide association and fine-mapping studies to date have been conducted in individuals of European descent, and genetic studies of populations of Hispanic/Latino and African ancestry are limited. In addition, these populations have more complex linkage disequilibrium structure. In order to better define the genetic architecture of these understudied populations, we leveraged >100,000 phased sequences available from deep-coverage whole genome sequencing through the multi-ethnic NHLBI Trans-Omics for Precision Medicine (TOPMed) program to impute genotypes into admixed African and Hispanic/Latino samples with genome-wide genotyping array data. We demonstrated that using TOPMed sequencing data as the imputation reference panel improves genotype imputation quality in these populations, which subsequently enhanced gene-mapping power for complex traits. For rare variants with minor allele frequency (MAF) < 0.5%, we observed a 2.3- to 6.1-fold increase in the number of well-imputed variants, with 11-34% improvement in average imputation quality, compared to the state-of-the-art 1000 Genomes Project Phase 3 and Haplotype Reference Consortium reference panels. Impressively, even for extremely rare variants with minor allele count <10 (including singletons) in the imputation target samples, average information content rescued was >86%. Subsequent association analyses of TOPMed reference panel-imputed genotype data with hematological traits (hemoglobin (HGB), hematocrit (HCT), and white blood cell count (WBC)) in ~21,600 African-ancestry and ~21,700 Hispanic/Latino individuals identified associations with two rare variants in the HBB gene (rs33930165 with higher WBC [p = 8.8x10-15] in African populations, rs11549407 with lower HGB [p = 1.5x10-12] and HCT [p = 8.8x10-10] in Hispanics/Latinos). By comparison, neither variant would have been genome-wide significant if either 1000 Genomes Project Phase 3 or Haplotype Reference Consortium reference panels had been used for imputation. Our findings highlight the utility of the TOPMed imputation reference panel for identification of novel rare variant associations not previously detected in similarly sized genome-wide studies of under-represented African and Hispanic/Latino populations.


Assuntos
Afro-Americanos/genética , Hispano-Americanos/genética , Medicina de Precisão/métodos , Sequenciamento Completo do Genoma/métodos , Globinas beta/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biologia Computacional/métodos , Bases de Dados Genéticas , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genética Populacional , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Estados Unidos
17.
Hum Genet ; 138(10): 1091-1104, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31230194

RESUMO

Although genome-wide association studies (GWAS) have identified hundreds of risk loci for breast and prostate cancer, only a few studies have characterized the GWAS association signals across functional genomic annotations with a particular focus on single nucleotide polymorphisms (SNPs) located in DNA regulatory elements. In this study, we investigated the enrichment pattern of GWAS signals for breast and prostate cancer in genomic functional regions located in normal tissue and cancer cell lines. We quantified the overall enrichment of SNPs with breast and prostate cancer association p values < 1 × 10-8 across regulatory categories. We then obtained annotations for DNaseI hypersensitive sites (DHS), typical enhancers, and super enhancers across multiple tissue types, to assess if significant GWAS signals were selectively enriched in annotations found in disease-related tissue. Finally, we quantified the enrichment of breast and prostate cancer SNP heritability in regulatory regions, and compared the enrichment pattern of SNP heritability with GWAS signals. DHS, typical enhancers, and super enhancers identified in the breast cancer cell line MCF-7 were observed with the highest enrichment of genome-wide significant variants for breast cancer. For prostate cancer, GWAS signals were mostly enriched in DHS and typical enhancers identified in the prostate cancer cell line LNCaP. With progressively stringent GWAS p value thresholds, an increasing trend of enrichment was observed for both diseases in DHS, typical enhancers, and super enhancers located in disease-related tissue. Results from heritability enrichment analysis supported the selective enrichment pattern of functional genomic regions in disease-related cell lines for both breast and prostate cancer. Our results suggest the importance of studying functional annotations identified in disease-related tissues when characterizing GWAS results, and further demonstrate the role of germline DNA regulatory elements from disease-related tissue in breast and prostate carcinogenesis.


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença , Variação Genética , Neoplasias da Próstata/genética , Sequências Reguladoras de Ácido Nucleico , Biomarcadores Tumorais , Linhagem Celular Tumoral , Biologia Computacional/métodos , Feminino , Estudos de Associação Genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Anotação de Sequência Molecular , Especificidade de Órgãos
19.
Nature ; 570(7762): 514-518, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31217584

RESUMO

Genome-wide association studies (GWAS) have laid the foundation for investigations into the biology of complex traits, drug development and clinical guidelines. However, the majority of discovery efforts are based on data from populations of European ancestry1-3. In light of the differential genetic architecture that is known to exist between populations, bias in representation can exacerbate existing disease and healthcare disparities. Critical variants may be missed if they have a low frequency or are completely absent in European populations, especially as the field shifts its attention towards rare variants, which are more likely to be population-specific4-10. Additionally, effect sizes and their derived risk prediction scores derived in one population may not accurately extrapolate to other populations11,12. Here we demonstrate the value of diverse, multi-ethnic participants in large-scale genomic studies. The Population Architecture using Genomics and Epidemiology (PAGE) study conducted a GWAS of 26 clinical and behavioural phenotypes in 49,839 non-European individuals. Using strategies tailored for analysis of multi-ethnic and admixed populations, we describe a framework for analysing diverse populations, identify 27 novel loci and 38 secondary signals at known loci, as well as replicate 1,444 GWAS catalogue associations across these traits. Our data show evidence of effect-size heterogeneity across ancestries for published GWAS associations, substantial benefits for fine-mapping using diverse cohorts and insights into clinical implications. In the United States-where minority populations have a disproportionately higher burden of chronic conditions13-the lack of representation of diverse populations in genetic research will result in inequitable access to precision medicine for those with the highest burden of disease. We strongly advocate for continued, large genome-wide efforts in diverse populations to maximize genetic discovery and reduce health disparities.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Grupo com Ancestrais do Continente Asiático/genética , Estudo de Associação Genômica Ampla/métodos , Hispano-Americanos/genética , Grupos Minoritários , Herança Multifatorial/genética , Saúde da Mulher , Estatura/genética , Estudos de Coortes , Feminino , Genética Médica/métodos , Equidade em Saúde/tendências , Disparidades nos Níveis de Saúde , Humanos , Masculino , Estados Unidos
20.
Br J Cancer ; 120(12): 1087-1089, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31110328

RESUMO

Pleiotropy, a phenomenon in which a single gene affects multiple phenotypes, is becoming very common among different cancer types and cancer-related phenotypes, such as those in hormonal, cardiometabolic and inflammatory/immune conditions. The discovery of pleiotropic associations can improve our understanding of cancer and help to target investigation of genes with greater clinical relevance.


Assuntos
Neoplasias/genética , Pleiotropia Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Penetrância , Fenótipo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA