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1.
Artigo em Inglês | MEDLINE | ID: mdl-33627384

RESUMO

BACKGROUND: Inherited susceptibility is an important contributor to colorectal cancer (CRC) risk and rare variants in key genes or pathways could account in part for the missing proportion of CRC heritability. METHODS: We conducted an exome-wide association study including 2,327 cases and 2,966 controls of European ancestry from three large epidemiologic studies. Single variant associations were tested using logistic regression models adjusting for appropriate study-specific covariates. In addition, we examined the aggregate effects of rare coding variation at the gene and pathway levels using Bayesian model uncertainty techniques. RESULTS: In an exome-wide gene-level analysis, we identified ST6GALNAC2 as the top associated gene based on the Bayesian Risk Index (BRI) method (summary Bayes Factor[BF]BRI= 2604.23). A rare coding variant in this gene, rs139401613, was the top associated variant (P=1.01x10-6) in an exome-wide single variant analysis. Pathway-level association analyses based on the integrative Bayesian Risk Index (iBRI) method found extreme evidence of association with the DNA repair pathway (BFiBRI=17852.4), specifically with the non-homologous end joining (NHEJ, BFiBRI=437.95) and nucleotide excision repair (NER, BFiBRI=36.96) subpathways. The iBRI method also identified RPA2, PRKDC, ERCC5, ERCC8 as the top associated DNA repair genes (summary BFiBRI{greater than or equal to}10), with rs28988897, rs8178232, rs141369732, rs201642761 being the most likely associated variants in these genes, respectively. CONCLUSION: We identified novel variants and genes associated with CRC risk and provided additional evidence for a role of DNA repair in CRC tumorigenesis. IMPACT: This study provides new insights into the genetic predisposition to CRC which has potential for translation into improved risk prediction.

2.
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
3.
Nat Genet ; 51(1): 76-87, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30510241

RESUMO

To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 × 10-8, bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Krüppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.


Assuntos
Neoplasias Colorretais/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Idoso , Estudos de Casos e Controles , Feminino , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , RNA Longo não Codificante/genética , Fatores de Risco , Transdução de Sinais/genética
4.
J Natl Cancer Inst ; 111(2): 146-157, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29917119

RESUMO

BACKGROUND: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk. METHODS: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided. RESULTS: The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0. CONCLUSIONS: This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.


Assuntos
Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Grupos Étnicos/genética , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , Grupos Étnicos/estatística & dados numéricos , Seguimentos , Genótipo , Humanos , Prognóstico , Estados Unidos/epidemiologia
5.
Cancer Epidemiol Biomarkers Prev ; 25(12): 1609-1618, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27587788

RESUMO

BACKGROUND: Genome-wide association studies (GWAS) in European populations have identified genetic risk variants associated with multiple myeloma. METHODS: We performed association testing of common variation in eight regions in 1,318 patients with multiple myeloma and 1,480 controls of European ancestry and 1,305 patients with multiple myeloma and 7,078 controls of African ancestry and conducted a meta-analysis to localize the signals, with epigenetic annotation used to predict functionality. RESULTS: We found that variants in 7p15.3, 17p11.2, 22q13.1 were statistically significantly (P < 0.05) associated with multiple myeloma risk in persons of African ancestry and persons of European ancestry, and the variant in 3p22.1 was associated in European ancestry only. In a combined African ancestry-European ancestry meta-analysis, variation in five regions (2p23.3, 3p22.1, 7p15.3, 17p11.2, 22q13.1) was statistically significantly associated with multiple myeloma risk. In 3p22.1, the correlated variants clustered within the gene body of ULK4 Correlated variants in 7p15.3 clustered around an enhancer at the 3' end of the CDCA7L transcription termination site. A missense variant at 17p11.2 (rs34562254, Pro251Leu, OR, 1.32; P = 2.93 × 10-7) in TNFRSF13B encodes a lymphocyte-specific protein in the TNF receptor family that interacts with the NF-κB pathway. SNPs correlated with the index signal in 22q13.1 cluster around the promoter and enhancer regions of CBX7 CONCLUSIONS: We found that reported multiple myeloma susceptibility regions contain risk variants important across populations, supporting the use of multiple racial/ethnic groups with different underlying genetic architecture to enhance the localization and identification of putatively functional alleles. IMPACT: A subset of reported risk loci for multiple myeloma has consistent effects across populations and is likely to be functional. Cancer Epidemiol Biomarkers Prev; 25(12); 1609-18. ©2016 AACR.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Grupo com Ancestrais do Continente Europeu/genética , Predisposição Genética para Doença , Mieloma Múltiplo/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/metabolismo , Complexo Repressor Polycomb 1/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Repressoras/genética , Proteína Transmembrana Ativadora e Interagente do CAML/genética
6.
Carcinogenesis ; 37(6): 547-556, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27207650

RESUMO

Genome-wide association studies (GWAS) have identified 58 susceptibility alleles across 37 regions associated with the risk of colorectal cancer (CRC) with P < 5×10(-8) Most studies have been conducted in non-Hispanic whites and East Asians; however, the generalizability of these findings and the potential for ethnic-specific risk variation in Hispanic and Latino (HL) individuals have been largely understudied. We describe the first GWAS of common genetic variation contributing to CRC risk in HL (1611 CRC cases and 4330 controls). We also examine known susceptibility alleles and implement imputation-based fine-mapping to identify potential ethnicity-specific association signals in known risk regions. We discovered 17 variants across 4 independent regions that merit further investigation due to suggestive CRC associations (P < 1×10(-6)) at 1p34.3 (rs7528276; Odds Ratio (OR) = 1.86 [95% confidence interval (CI): 1.47-2.36); P = 2.5×10(-7)], 2q23.3 (rs1367374; OR = 1.37 (95% CI: 1.21-1.55); P = 4.0×10(-7)), 14q24.2 (rs143046984; OR = 1.65 (95% CI: 1.36-2.01); P = 4.1×10(-7)) and 16q12.2 [rs142319636; OR = 1.69 (95% CI: 1.37-2.08); P=7.8×10(-7)]. Among the 57 previously published CRC susceptibility alleles with minor allele frequency ≥1%, 76.5% of SNPs had a consistent direction of effect and 19 (33.3%) were nominally statistically significant (P < 0.05). Further, rs185423955 and rs60892987 were identified as novel secondary susceptibility variants at 3q26.2 (P = 5.3×10(-5)) and 11q12.2 (P = 6.8×10(-5)), respectively. Our findings demonstrate the importance of fine mapping in HL. These results are informative for variant prioritization in functional studies and future risk prediction modeling in minority populations.


Assuntos
Neoplasias Colorretais/genética , Predisposição Genética para Doença , Hispano-Americanos/genética , Idoso , Alelos , Estudos de Coortes , Feminino , Variação Genética , Genética Populacional , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade
7.
Nicotine Tob Res ; 18(9): 1837-1844, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27113016

RESUMO

INTRODUCTION: Metabolic enzyme variation and other patient and environmental characteristics influence smoking behaviors, treatment success, and risk of related disease. Population-specific variation in metabolic genes contributes to challenges in developing and optimizing pharmacogenetic interventions. We applied a custom genome-wide genotyping array for addiction research (Smokescreen), to three laboratory-based studies of nicotine metabolism with oral or venous administration of labeled nicotine and cotinine, to model nicotine metabolism in multiple populations. The trans-3'-hydroxycotinine/cotinine ratio, the nicotine metabolite ratio (NMR), was the nicotine metabolism measure analyzed. METHODS: Three hundred twelve individuals of self-identified European, African, and Asian American ancestry were genotyped and included in ancestry-specific genome-wide association scans (GWAS) and a meta-GWAS analysis of the NMR. We modeled natural-log transformed NMR with covariates: principal components of genetic ancestry, age, sex, body mass index, and smoking status. RESULTS: African and Asian American NMRs were statistically significantly (P values ≤ 5E-5) lower than European American NMRs. Meta-GWAS analysis identified 36 genome-wide significant variants over a 43 kilobase pair region at CYP2A6 with minimum P = 2.46E-18 at rs12459249, proximal to CYP2A6. Additional minima were located in intron 4 (rs56113850, P = 6.61E-18) and in the CYP2A6-CYP2A7 intergenic region (rs34226463, P = 1.45E-12). Most (34/36) genome-wide significant variants suggested reduced CYP2A6 activity; functional mechanisms were identified and tested in knowledge-bases. Conditional analysis resulted in intergenic variants of possible interest (P values < 5E-5). CONCLUSIONS: This meta-GWAS of the NMR identifies CYP2A6 variants, replicates the top-ranked single nucleotide polymorphism from a recent Finnish meta-GWAS of the NMR, identifies functional mechanisms, and provides pan-continental population biomarkers for nicotine metabolism. IMPLICATIONS: This multiple ancestry meta-GWAS of the laboratory study-based NMR provides novel evidence and replication for genome-wide association of CYP2A6 single nucleotide and insertion-deletion polymorphisms. We identify three regions of genome-wide significance: proximal, intronic, and distal to CYP2A6. We replicate the top-ranking single nucleotide polymorphism from a recent GWAS of the NMR in Finnish smokers, identify a functional mechanism for this intronic variant from in silico analyses of RNA-seq data that is consistent with CYP2A6 expression measured in postmortem lung and liver, and provide additional support for the intergenic region between CYP2A6 and CYP2A7.


Assuntos
Citocromo P-450 CYP2A6/genética , Nicotina/genética , Nicotina/metabolismo , Fumar/genética , Tabagismo/genética , Adulto , Grupo com Ancestrais do Continente Africano/genética , Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Adulto Jovem
8.
BMC Genomics ; 17: 176, 2016 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-26940994

RESUMO

BACKGROUND: For the last decade the conceptual framework of the Genome-Wide Association Study (GWAS) has dominated the investigation of human disease and other complex traits. While GWAS have been successful in identifying a large number of variants associated with various phenotypes, the overall amount of heritability explained by these variants remains small. This raises the question of how best to follow up on a GWAS, localize causal variants accounting for GWAS hits, and as a consequence explain more of the so-called "missing" heritability. Advances in high throughput sequencing technologies now allow for the efficient and cost-effective collection of vast amounts of fine-scale genomic data to complement GWAS. RESULTS: We investigate these issues using a colon cancer dataset. After QC, our data consisted of 1993 cases, 899 controls. Using marginal tests of associations, we identify 10 variants distributed among six targeted regions that are significantly associated with colorectal cancer, with eight of the variants being novel to this study. Additionally, we perform so-called 'SNP-set' tests of association and identify two sets of variants that implicate both common and rare variants in the etiology of colorectal cancer. CONCLUSIONS: Here we present a large-scale targeted re-sequencing resource focusing on genomic regions implicated in colorectal cancer susceptibility previously identified in several GWAS, which aims to 1) provide fine-scale targeted sequencing data for fine-mapping and 2) provide data resources to address methodological questions regarding the design of sequencing-based follow-up studies to GWAS. Additionally, we show that this strategy successfully identifies novel variants associated with colorectal cancer susceptibility and can implicate both common and rare variants.


Assuntos
Estudo de Associação Genômica Ampla , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Análise de Sequência de DNA/métodos , Mapeamento Cromossômico , Neoplasias do Colo/genética , Biologia Computacional , Variação Genética , Humanos
9.
BMC Genomics ; 17: 145, 2016 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-26921259

RESUMO

BACKGROUND: Addictive disorders are a class of chronic, relapsing mental disorders that are responsible for increased risk of mental and medical disorders and represent the largest, potentially modifiable cause of death. Tobacco dependence is associated with increased risk of disease and premature death. While tobacco control efforts and therapeutic interventions have made good progress in reducing smoking prevalence, challenges remain in optimizing their effectiveness based on patient characteristics, including genetic variation. In order to maximize collaborative efforts to advance addiction research, we have developed a genotyping array called Smokescreen. This custom array builds upon previous work in the analyses of human genetic variation, the genetics of addiction, drug metabolism, and response to therapy, with an emphasis on smoking and nicotine addiction. RESULTS: The Smokescreen genotyping array includes 646,247 markers in 23 categories. The array design covers genome-wide common variation (65.67, 82.37, and 90.72% in African (YRI), East Asian (ASN), and European (EUR) respectively); most of the variation with a minor allele frequency ≥ 0.01 in 1014 addiction genes (85.16, 89.51, and 90.49% for YRI, ASN, and EUR respectively); and nearly all variation from the 1000 Genomes Project Phase 1, NHLBI GO Exome Sequencing Project and HapMap databases in the regions related to smoking behavior and nicotine metabolism: CHRNA5-CHRNA3-CHRNB4 and CYP2A6-CYP2B6. Of the 636 pilot DNA samples derived from blood or cell line biospecimens that were genotyped on the array, 622 (97.80%) passed quality control. In passing samples, 90.08% of markers passed quality control. The genotype reproducibility in 25 replicate pairs was 99.94%. For 137 samples that overlapped with HapMap2 release 24, the genotype concordance was 99.76%. In a genome-wide association analysis of the nicotine metabolite ratio in 315 individuals participating in nicotine metabolism laboratory studies, we identified genome-wide significant variants in the CYP2A6 region (min p = 9.10E-15). CONCLUSIONS: We developed a comprehensive genotyping array for addiction research and demonstrated its analytic validity and utility through pilot genotyping of HapMap and study samples. This array allows researchers to perform genome-wide, candidate gene, and pathway-based association analyses of addiction, tobacco-use, treatment response, comorbidities, and associated diseases in a standardized, high-throughput platform.


Assuntos
Genótipo , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Tabagismo/genética , Grupo com Ancestrais do Continente Africano , Grupo com Ancestrais do Continente Asiático , Mapeamento Cromossômico , Grupo com Ancestrais do Continente Europeu , Éxons , Marcadores Genéticos , Estudo de Associação Genômica Ampla , Humanos , Nicotina/metabolismo , Polimorfismo de Nucleotídeo Único , Fumar/genética
11.
Hum Genet ; 134(11-12): 1249-1262, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26404086

RESUMO

Over 50 loci associated with colorectal cancer (CRC) have been uncovered by genome-wide association studies (GWAS). Identifying additional loci has the potential to help elucidate aspects of the underlying biological processes leading to better understanding of the pathogenesis of the disease. We re-evaluated a GWAS by excluding controls that have family history of CRC or personal history of colorectal polyps, as we hypothesized that their inclusion reduces power to detect associations. This is supported empirically and through simulations. Two-phase GWAS analysis was performed in a total of 16,517 cases and 14,487 controls. We identified rs17094983, a SNP associated with risk of CRC [p = 2.5 × 10(-10); odds ratio estimated by re-including all controls (OR) = 0.87, 95% confidence interval (CI) 0.83-0.91; minor allele frequency (MAF) = 13%]. Results were replicated in samples of African descent (1894 cases and 4703 controls; p = 0.01; OR = 0.86, 95% CI 0.77-0.97; MAF = 16 %). Gene expression data in 195 colon adenocarcinomas and 59 normal colon tissues from two different studies revealed that this locus has genotypes that are associated with RTN1 (Reticulon 1) expression (p = 0.001), a protein-coding gene involved in survival and proliferation of cancer cells which is highly expressed in normal colon tissues but has significantly reduced expression in tumor cells (p = 1.3 × 10(-8)).


Assuntos
Adenocarcinoma/genética , Cromossomos Humanos Par 14/genética , Neoplasias Colorretais/genética , Loci Gênicos , Predisposição Genética para Doença , Adenocarcinoma/epidemiologia , Idoso , Estudos de Casos e Controles , Neoplasias Colorretais/epidemiologia , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco
12.
J Natl Cancer Inst ; 107(11)2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26315354

RESUMO

BACKGROUND: Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy, responsible for 13 000 deaths per year in the United States. Risk prediction based on identifying germline mutations in ovarian cancer susceptibility genes could have a clinically significant impact on reducing disease mortality. METHODS: Next generation sequencing was used to identify germline mutations in the coding regions of four candidate susceptibility genes-BRIP1, BARD1, PALB2 and NBN-in 3236 invasive EOC case patients and 3431 control patients of European origin, and in 2000 unaffected high-risk women from a clinical screening trial of ovarian cancer (UKFOCSS). For each gene, we estimated the prevalence and EOC risks and evaluated associations between germline variant status and clinical and epidemiological risk factor information. All statistical tests were two-sided. RESULTS: We found an increased frequency of deleterious mutations in BRIP1 in case patients (0.9%) and in the UKFOCSS participants (0.6%) compared with control patients (0.09%) (P = 1 x 10(-4) and 8 x 10(-4), respectively), but no differences for BARD1 (P = .39), NBN1 ( P = .61), or PALB2 (P = .08). There was also a difference in the frequency of rare missense variants in BRIP1 between case patients and control patients (P = 5.5 x 10(-4)). The relative risks associated with BRIP1 mutations were 11.22 for invasive EOC (95% confidence interval [CI] = 3.22 to 34.10, P = 1 x 10(-4)) and 14.09 for high-grade serous disease (95% CI = 4.04 to 45.02, P = 2 x 10(-5)). Segregation analysis in families estimated the average relative risks in BRIP1 mutation carriers compared with the general population to be 3.41 (95% CI = 2.12 to 5.54, P = 7×10(-7)). CONCLUSIONS: Deleterious germline mutations in BRIP1 are associated with a moderate increase in EOC risk. These data have clinical implications for risk prediction and prevention approaches for ovarian cancer and emphasize the critical need for risk estimates based on very large sample sizes before genes of moderate penetrance have clinical utility in cancer prevention.


Assuntos
Proteínas de Ciclo Celular/genética , Proteínas de Ligação a DNA/genética , Mutação em Linhagem Germinativa , Neoplasias Epiteliais e Glandulares/genética , Proteínas Nucleares/genética , Neoplasias Ovarianas/genética , RNA Helicases/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina-Proteína Ligases/genética , Adulto , Idoso , Carcinoma Epitelial do Ovário , Grupo com Ancestrais do Continente Europeu , Proteína do Grupo de Complementação N da Anemia de Fanconi , Proteínas de Grupos de Complementação da Anemia de Fanconi , Feminino , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Neoplasias Epiteliais e Glandulares/mortalidade , Neoplasias Ovarianas/mortalidade , Valor Preditivo dos Testes , Risco , Estados Unidos/epidemiologia
13.
J Clin Oncol ; 33(26): 2901-7, 2015 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-26261251

RESUMO

PURPOSE: The aim of this study was to estimate the contribution of deleterious mutations in the RAD51B, RAD51C, and RAD51D genes to invasive epithelial ovarian cancer (EOC) in the population and in a screening trial of individuals at high risk of ovarian cancer. PATIENTS AND METHODS: The coding sequence and splice site boundaries of the three RAD51 genes were sequenced and analyzed in germline DNA from a case-control study of 3,429 patients with invasive EOC and 2,772 controls as well as in 2,000 unaffected women who were BRCA1/BRCA2 negative from the United Kingdom Familial Ovarian Cancer Screening Study (UK_FOCSS) after quality-control analysis. RESULTS: In the case-control study, we identified predicted deleterious mutations in 28 EOC cases (0.82%) compared with three controls (0.11%; P < .001). Mutations in EOC cases were more frequent in RAD51C (14 occurrences, 0.41%) and RAD51D (12 occurrences, 0.35%) than in RAD51B (two occurrences, 0.06%). RAD51C mutations were associated with an odds ratio of 5.2 (95% CI, 1.1 to 24; P = .035), and RAD51D mutations conferred an odds ratio of 12 (95% CI, 1.5 to 90; P = .019). We identified 13 RAD51 mutations (0.65%) in unaffected UK_FOCSS participants (RAD51C, n = 7; RAD51D, n = 5; and RAD51B, n = 1), which was a significantly greater rate than in controls (P < .001); furthermore, RAD51 mutation carriers were more likely than noncarriers to have a family history of ovarian cancer (P < .001). CONCLUSION: These results confirm that RAD51C and RAD51D are moderate ovarian cancer susceptibility genes and suggest that they confer levels of risk of EOC that may warrant their use alongside BRCA1 and BRCA2 in routine clinical genetic testing.


Assuntos
Proteínas de Ligação a DNA/genética , Mutação em Linhagem Germinativa , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Ovarianas/genética , Adulto , Idoso , Carcinoma Epitelial do Ovário , Feminino , Genes BRCA1 , Genes BRCA2 , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Neoplasias Epiteliais e Glandulares/etiologia , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/etiologia , Neoplasias Ovarianas/patologia
14.
Nat Commun ; 6: 7138, 2015 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-26151821

RESUMO

Genetic susceptibility to colorectal cancer is caused by rare pathogenic mutations and common genetic variants that contribute to familial risk. Here we report the results of a two-stage association study with 18,299 cases of colorectal cancer and 19,656 controls, with follow-up of the most statistically significant genetic loci in 4,725 cases and 9,969 controls from two Asian consortia. We describe six new susceptibility loci reaching a genome-wide threshold of P<5.0E-08. These findings provide additional insight into the underlying biological mechanisms of colorectal cancer and demonstrate the scientific value of large consortia-based genetic epidemiology studies.


Assuntos
Neoplasias Colorretais/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Estudos de Casos e Controles , Humanos , Razão de Chances , Polimorfismo de Nucleotídeo Único
15.
Invest Ophthalmol Vis Sci ; 56(4): 2737-48, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25813999

RESUMO

PURPOSE: The pathophysiology of ocular hypertension (OH) leading to primary open-angle glaucoma shares many features with a secondary form of OH caused by treatment with glucocorticoids, but also exhibits distinct differences. In this study, a pharmacogenomics approach was taken to discover candidate genes for this disorder. METHODS: A genome-wide association study was performed, followed by an independent candidate gene study, using a cohort enrolled from patients treated with off-label intravitreal triamcinolone, and handling change in IOP as a quantitative trait. RESULTS: An intergenic quantitative trait locus (QTL) was identified at chromosome 6p21.33 near the 5' end of HCG22 that attained the accepted statistical threshold for genome-level significance. The HCG22 transcript, encoding a novel mucin protein, was expressed in trabecular meshwork cells, and expression was stimulated by IL-1, and inhibited by triamcinolone acetate and TGF-ß. Bioinformatic analysis defined the QTL as an approximately 4 kilobase (kb) linkage disequilibrium block containing 10 common single nucleotide polymorphisms (SNPs). Four of these SNPs were identified in the National Center for Biotechnology Information (NCBI) GTEx eQTL browser as modifiers of HCG22 expression. Most are predicted to disrupt or improve motifs for transcription factor binding, the most relevant being disruption of the glucocorticoid receptor binding motif. A second QTL was identified within the predicted signal peptide of the HCG22 encoded protein that could affect its secretion. Translation, O-glycosylation, and secretion of the predicted HCG22 protein was verified in cultured trabecular meshwork cells. CONCLUSIONS: Identification of two independent QTLs that could affect expression of the HCG22 mucin gene product via two different mechanisms (transcription or secretion) is highly suggestive of a role in steroid-induced OH.


Assuntos
Regulação da Expressão Gênica , Pressão Intraocular/efeitos dos fármacos , Mucinas/genética , Hipertensão Ocular/genética , RNA Mensageiro/genética , Triancinolona/efeitos adversos , Adulto , Feminino , Seguimentos , Estudo de Associação Genômica Ampla , Genótipo , Glucocorticoides/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Mucinas/biossíntese , Hipertensão Ocular/induzido quimicamente , Hipertensão Ocular/metabolismo , Malha Trabecular/metabolismo
16.
J Natl Cancer Inst ; 107(5)2015 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-25713168

RESUMO

BACKGROUND: Lung cancer is the leading cause of cancer-related mortality worldwide. Detection of promoter hypermethylation of tumor suppressor genes in exfoliated cells from the lung provides an assessment of field cancerization that in turn predicts lung cancer. The identification of genetic determinants for this validated cancer biomarker should provide novel insights into mechanisms underlying epigenetic reprogramming during lung carcinogenesis. METHODS: A genome-wide association study using generalized estimating equations and logistic regression models was conducted in two geographically independent smoker cohorts to identify loci affecting the propensity for cancer-related gene methylation that was assessed by a 12-gene panel interrogated in sputum. All statistical tests were two-sided. RESULTS: Two single nucleotide polymorphisms (SNPs) at 15q12 (rs73371737 and rs7179575) that drove gene methylation were discovered and replicated with rs73371737 reaching genome-wide significance (P = 3.3×10(-8)). A haplotype carrying risk alleles from the two 15q12 SNPs conferred 57% increased risk for gene methylation (P = 2.5×10(-9)). Rs73371737 reduced GABRB3 expression in lung cells and increased risk for smoking-induced chronic mucous hypersecretion. Furthermore, subjects with variant homozygote of rs73371737 had a two-fold increase in risk for lung cancer (P = .0043). Pathway analysis identified DNA double-strand break repair by homologous recombination (DSBR-HR) as a major pathway affecting susceptibility for gene methylation that was validated by measuring chromatid breaks in lymphocytes challenged by bleomycin. CONCLUSIONS: A functional 15q12 variant was identified as a risk factor for gene methylation and lung cancer. The associations could be mediated by GABAergic signaling that drives the smoking-induced mucous cell metaplasia. Our findings also substantiate DSBR-HR as a critical pathway driving epigenetic gene silencing.


Assuntos
Cromossomos Humanos Par 15/metabolismo , Metilação de DNA , Neoplasias Pulmonares/genética , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Fumar/efeitos adversos , Escarro , Adulto , Idoso , Cromossomos Humanos Par 15/genética , Feminino , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Haplótipos , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Risco
17.
Nat Commun ; 6: 5965, 2015 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-25591454

RESUMO

Common variants at many loci have been robustly associated with asthma but explain little of the overall genetic risk. Here we investigate the role of rare (<1%) and low-frequency (1-5%) variants using the Illumina HumanExome BeadChip array in 4,794 asthma cases, 4,707 non-asthmatic controls and 590 case-parent trios representing European Americans, African Americans/African Caribbeans and Latinos. Our study reveals one low-frequency missense mutation in the GRASP gene that is associated with asthma in the Latino sample (P=4.31 × 10(-6); OR=1.25; MAF=1.21%) and two genes harbouring functional variants that are associated with asthma in a gene-based analysis: GSDMB at the 17q12-21 asthma locus in the Latino and combined samples (P=7.81 × 10(-8) and 4.09 × 10(-8), respectively) and MTHFR in the African ancestry sample (P=1.72 × 10(-6)). Our results suggest that associations with rare and low-frequency variants are ethnic specific and not likely to explain a significant proportion of the 'missing heritability' of asthma.


Assuntos
Asma/genética , Estudo de Associação Genômica Ampla/métodos , Proteínas de Transporte/genética , Feminino , Predisposição Genética para Doença/genética , Humanos , Desequilíbrio de Ligação/genética , Masculino , Proteínas de Membrana/genética , Proteínas de Neoplasias/genética
18.
Am J Psychiatry ; 172(1): 82-93, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25158072

RESUMO

OBJECTIVE: Obsessive-compulsive disorder (OCD) and Tourette's syndrome are highly heritable neurodevelopmental disorders that are thought to share genetic risk factors. However, the identification of definitive susceptibility genes for these etiologically complex disorders remains elusive. The authors report a combined genome-wide association study (GWAS) of Tourette's syndrome and OCD. METHOD: The authors conducted a GWAS in 2,723 cases (1,310 with OCD, 834 with Tourette's syndrome, 579 with OCD plus Tourette's syndrome/chronic tics), 5,667 ancestry-matched controls, and 290 OCD parent-child trios. GWAS summary statistics were examined for enrichment of functional variants associated with gene expression levels in brain regions. Polygenic score analyses were conducted to investigate the genetic architecture within and across the two disorders. RESULTS: Although no individual single-nucleotide polymorphisms (SNPs) achieved genome-wide significance, the GWAS signals were enriched for SNPs strongly associated with variations in brain gene expression levels (expression quantitative loci, or eQTLs), suggesting the presence of true functional variants that contribute to risk of these disorders. Polygenic score analyses identified a significant polygenic component for OCD (p=2×10(-4)), predicting 3.2% of the phenotypic variance in an independent data set. In contrast, Tourette's syndrome had a smaller, nonsignificant polygenic component, predicting only 0.6% of the phenotypic variance (p=0.06). No significant polygenic signal was detected across the two disorders, although the sample is likely underpowered to detect a modest shared signal. Furthermore, the OCD polygenic signal was significantly attenuated when cases with both OCD and co-occurring Tourette's syndrome/chronic tics were included in the analysis (p=0.01). CONCLUSIONS: Previous work has shown that Tourette's syndrome and OCD have some degree of shared genetic variation. However, the data from this study suggest that there are also distinct components to the genetic architectures of these two disorders. Furthermore, OCD with co-occurring Tourette's syndrome/chronic tics may have different underlying genetic susceptibility compared with OCD alone.


Assuntos
Transtorno Obsessivo-Compulsivo/genética , Síndrome de Tourette/genética , Adulto , Comorbidade , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Transtorno Obsessivo-Compulsivo/diagnóstico , Transtorno Obsessivo-Compulsivo/epidemiologia , Polimorfismo de Nucleotídeo Único , Escalas de Graduação Psiquiátrica , Índice de Gravidade de Doença , Síndrome de Tourette/diagnóstico , Síndrome de Tourette/epidemiologia
19.
PLoS One ; 9(11): e111914, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25375357

RESUMO

Genome-wide association studies (GWAS) of colorectal cancer (CRC) have led to the identification of a number of common variants associated with modest risk. Several risk variants map within the vicinity of TGFß/BMP signaling pathway genes, including rs4939827 within an intron of SMAD7 at 18q21.1. A previous study implicated a novel SNP (novel 1 or rs58920878) as a functional variant within an enhancer element in SMAD7 intron 4. In this study, we show that four SNPs including novel 1 (rs6507874, rs6507875, rs8085824, and rs58920878) in linkage disequilibrium (LD) with the index SNP rs4939827 demonstrate allele-specific enhancer effects in a large, multi-component enhancer of SMAD7. All four SNPs demonstrate allele-specific protein binding to nuclear extracts of CRC cell lines. Furthermore, some of the risk-associated alleles correlate with increased expression of SMAD7 in normal colon tissues. Finally, we show that the enhancer is responsive to BMP4 stimulation. Taken together, we propose that the associated CRC risk at 18q21.1 is due to four functional variants that regulate SMAD7 expression and potentially perturb a BMP negative feedback loop in TGFß/BMP signaling pathways.


Assuntos
Proteínas Morfogenéticas Ósseas/metabolismo , Neoplasias Colorretais/genética , Polimorfismo de Nucleotídeo Único , Proteína Smad7/genética , Linhagem Celular Tumoral , Cromossomos Humanos Par 18/genética , Elementos Facilitadores Genéticos , Variação Genética , Células HCT116 , Células HEK293 , Humanos , Desequilíbrio de Ligação , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo
20.
Am J Med Genet A ; 164A(10): 2572-80, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25099202

RESUMO

Genome-wide association studies (GWAS) for orofacial clefts have identified several susceptibility regions, but have largely focused on non-Hispanic White populations in developed countries. We performed a targeted genome-wide study of single nucleotide polymorphisms (SNPs) in exons using the Illumina HumanExome+ array with custom fine mapping of 16 cleft susceptibility regions in three underserved populations: Congolese (87 case-mother, 210 control-mother pairs), Vietnamese (131 case-parent trios), and Filipinos (42 case-mother, 99 control-mother pairs). All cases were children with cleft lip with or without cleft palate. Families were recruited from local hospitals and parental exposures were collected using interviewer-administered questionnaires. We used logistic regression models for case-control analyses, family-based association tests for trios, and fixed-effect meta-analyses to determine individual SNP effects corrected for multiple testing. Of the 16 known susceptibility regions tested, SNPs in four regions reached statistical significance in one or more of these populations: 1q32.2 (IRF6), 10q25.3 (VAX1), and 17q22 (NOG). Due to different linkage disequilibrium patterns, significant SNPs in these regions differed between the Vietnamese and Filipino populations from the index SNP selected from previous GWAS studies. Among Africans, there were no significant associations identified for any of the susceptibility regions. rs10787738 near VAX1 (P = 4.98E-3) and rs7987165 (P = 6.1E-6) were significant in the meta-analysis of all three populations combined. These results confirm several known susceptibility regions and identify novel risk alleles in understudied populations.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Grupo com Ancestrais do Continente Asiático/genética , Fenda Labial/genética , Fissura Palatina/genética , Predisposição Genética para Doença/genética , Adulto , Alelos , Estudos de Casos e Controles , Feminino , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Desequilíbrio de Ligação/genética , Modelos Logísticos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Adulto Jovem
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