Dataset Information

Identification of a novel susceptibility locus at 13q34 and refinement of the 20p12.2 region as a multi-signal locus associated with bladder cancer risk in individuals of European ancestry.

ABSTRACT: Candidate gene and genome-wide association studies (GWAS) have identified 15 independent genomic regions associated with bladder cancer risk. In search for additional susceptibility variants, we followed up on four promising single-nucleotide polymorphisms (SNPs) that had not achieved genome-wide significance in 6911 cases and 11 814 controls (rs6104690, rs4510656, rs5003154 and rs4907479, P < 1 × 10(-6)), using additional data from existing GWAS datasets and targeted genotyping for studies that did not have GWAS data. In a combined analysis, which included data on up to 15 058 cases and 286 270 controls, two SNPs achieved genome-wide statistical significance: rs6104690 in a gene desert at 20p12.2 (P = 2.19 × 10(-11)) and rs4907479 within the MCF2L gene at 13q34 (P = 3.3 × 10(-10)). Imputation and fine-mapping analyses were performed in these two regions for a subset of 5551 bladder cancer cases and 10 242 controls. Analyses at the 13q34 region suggest a single signal marked by rs4907479. In contrast, we detected two signals in the 20p12.2 region-the first signal is marked by rs6104690, and the second signal is marked by two moderately correlated SNPs (r(2) = 0.53), rs6108803 and the previously reported rs62185668. The second 20p12.2 signal is more strongly associated with the risk of muscle-invasive (T2-T4 stage) compared with non-muscle-invasive (Ta, T1 stage) bladder cancer (case-case P ? 0.02 for both rs62185668 and rs6108803). Functional analyses are needed to explore the biological mechanisms underlying these novel genetic associations with risk for bladder cancer.

SUBMITTER: Figueroa JD

PROVIDER: S-EPMC4817084 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Identification of a novel susceptibility locus at 13q34 and refinement of the 20p12.2 region as a multi-signal locus associated with bladder cancer risk in individuals of European ancestry.

Figueroa Jonine D JD Middlebrooks Candace D CD Banday A Rouf AR Ye Yuanqing Y Garcia-Closas Montserrat M Chatterjee Nilanjan N Koutros Stella S Kiemeney Lambertus A LA Rafnar Thorunn T Bishop Timothy T Furberg Helena H Matullo Giuseppe G Golka Klaus K Gago-Dominguez Manuela M Taylor Jack A JA Fletcher Tony T Siddiq Afshan A Cortessis Victoria K VK Kooperberg Charles C Cussenot Olivier O Benhamou Simone S Prescott Jennifer J Porru Stefano S Dinney Colin P CP Malats Núria N Baris Dalsu D Purdue Mark P MP Jacobs Eric J EJ Albanes Demetrius D Wang Zhaoming Z Chung Charles C CC Vermeulen Sita H SH Aben Katja K KK Galesloot Tessel E TE Thorleifsson Gudmar G Sulem Patrick P Stefansson Kari K Kiltie Anne E AE Harland Mark M Teo Mark M Offit Kenneth K Vijai Joseph J Bajorin Dean D Kopp Ryan R Fiorito Giovanni G Guarrera Simonetta S Sacerdote Carlotta C Selinski Silvia S Hengstler Jan G JG Gerullis Holger H Ovsiannikov Daniel D Blaszkewicz Meinolf M Castelao Jose Esteban JE Calaza Manuel M Martinez Maria Elena ME Cordeiro Patricia P Xu Zongli Z Panduri Vijayalakshmi V Kumar Rajiv R Gurzau Eugene E Koppova Kvetoslava K Bueno-De-Mesquita H Bas HB Ljungberg Börje B Clavel-Chapelon Françoise F Weiderpass Elisabete E Krogh Vittorio V Dorronsoro Miren M Travis Ruth C RC Tjønneland Anne A Brennan Paul P Chang-Claude Jenny J Riboli Elio E Conti David D Stern Marianna C MC Pike Malcolm C MC Van Den Berg David D Yuan Jian-Min JM Hohensee Chancellor C Jeppson Rebecca P RP Cancel-Tassin Geraldine G Roupret Morgan M Comperat Eva E Turman Constance C De Vivo Immaculata I Giovannucci Edward E Hunter David J DJ Kraft Peter P Lindstrom Sara S Carta Angela A Pavanello Sofia S Arici Cecilia C Mastrangelo Giuseppe G Kamat Ashish M AM Zhang Liren L Gong Yilei Y Pu Xia X Hutchinson Amy A Burdett Laurie L Wheeler William A WA Karagas Margaret R MR Johnson Alison A Schned Alan A Monawar Hosain G M GM Schwenn Molly M Kogevinas Manolis M Tardón Adonina A Serra Consol C Carrato Alfredo A García-Closas Reina R Lloreta Josep J Andriole Gerald G Grubb Robert R Black Amanda A Diver W Ryan WR Gapstur Susan M SM Weinstein Stephanie S Virtamo Jarmo J Haiman Christopher A CA Landi Maria Teresa MT Caporaso Neil E NE Fraumeni Joseph F JF Vineis Paolo P Wu Xifeng X Chanock Stephen J SJ Silverman Debra T DT Prokunina-Olsson Ludmila L Rothman Nathaniel N

Human molecular genetics 20160104 6

Candidate gene and genome-wide association studies (GWAS) have identified 15 independent genomic regions associated with bladder cancer risk. In search for additional susceptibility variants, we followed up on four promising single-nucleotide polymorphisms (SNPs) that had not achieved genome-wide significance in 6911 cases and 11 814 controls (rs6104690, rs4510656, rs5003154 and rs4907479, P < 1 × 10(-6)), using additional data from existing GWAS datasets and targeted genotyping for studies that ...[more]

PMID: 26732427

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Project description:IntroductionHeritability estimates of nicotine dependence (ND) range from 40% to 70%, but discovery GWAS of ND are underpowered and have limited predictive utility. In this work, we leverage genetically correlated traits and diseases to increase the accuracy of polygenic risk prediction.MethodsWe employed a multi-trait model using summary statistic-based best linear unbiased predictors (SBLUP) of genetic correlates of DSM-IV diagnosis of ND in 6394 individuals of European Ancestry (prevalence = 45.3%, %female = 46.8%, µ age = 40.08 [s.d. = 10.43]) and 3061 individuals from a nationally-representative sample with Fagerström Test for Nicotine Dependence symptom count (FTND; 51.32% female, mean age = 28.9 [s.d. = 1.70]). Polygenic predictors were derived from GWASs known to be phenotypically and genetically correlated with ND (i.e., Cigarettes per Day [CPD], the Alcohol Use Disorders Identification Test [AUDIT-Consumption and AUDIT-Problems], Neuroticism, Depression, Schizophrenia, Educational Attainment, Body Mass Index [BMI], and Self-Perceived Risk-Taking); including Height as a negative control. Analyses controlled for age, gender, study site, and the first 10 ancestral principal components.ResultsThe multi-trait model accounted for 3.6% of the total trait variance in DSM-IV ND. Educational Attainment (β = -0.125; 95% CI: [-0.149,-0.101]), CPD (0.071 [0.047,0.095]), and Self-Perceived Risk-Taking (0.051 [0.026,0.075]) were the most robust predictors. PGS effects on FTND were limited.ConclusionsRisk for ND is not only polygenic, but also pleiotropic. Polygenic effects on ND that are accessible by these traits are limited in size and act additively to explain risk.ImplicationsThese findings enhance our understanding of inherited genetic factors for nicotine dependence. The data show that genome-wide association study (GWAS) findings across pre- and comorbid conditions of smoking are differentially associated with nicotine dependence and that when combined explain significantly more trait variance. These findings underscore the utility of multivariate approaches to understand the validity of polygenic scores for nicotine dependence, especially as the power of GWAS of broadly-defined smoking behaviors increases. Realizing the potential of GWAS to inform complex smoking behaviors will require similar theory-driven models that reflect the myriad of mechanisms that drive individual differences.

Dataset Information

Identification of a novel susceptibility locus at 13q34 and refinement of the 20p12.2 region as a multi-signal locus associated with bladder cancer risk in individuals of European ancestry.

Publications

Identification of a novel susceptibility locus at 13q34 and refinement of the 20p12.2 region as a multi-signal locus associated with bladder cancer risk in individuals of European ancestry.

Similar Datasets

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