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Sampson, Joshua N.,Wheeler, William A.,Yeager, Meredith,Panagiotou, Orestis,Wang, Zhaoming,Berndt, Sonja I.,Lan, Qing,Abnet, Christian C.,Amundadottir, Laufey T.,Figueroa, Jonine D.,Landi, Maria Teres U.S. Dept. of Health, Education, and Welfare, Publ 2015 Journal of the National Cancer Institute Vol.107 No.12
<P>Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. Results: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, h(l)(2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (rho = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (rho = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (rho = 0.51, SE = 0.18), and bladder and lung (rho = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. Conclusion: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.</P>
Won, Jong Ho,Humphrey, Elizabeth L,Yeager, Kelly R,Martinez, Alexis A,Robinson, Camryn H,Mills, Kristen E,Johnstone, Patti M,Moon, Il Joon,Woo, Jihwan American Institute of Physics for the Acoustical S 2014 JOURNAL OF THE ACOUSTICAL SOCIETY OF AMERICA - Vol.136 No.5
<P>The hypothesis of this study was that broader patterns of physiological channel interactions in the local region of the cochlea are associated with poorer spectral resolution in the same region. Electrically evoked compound action potentials (ECAPs) were measured for three to six probe electrodes per subject to examine the channel interactions in different regions across the electrode array. To evaluate spectral resolution at a confined location within the cochlea, spectral-ripple discrimination (SRD) was measured using narrowband ripple stimuli with the bandwidth spanning five electrodes: Two electrodes apical and basal to the ECAP probe electrode. The relationship between the physiological channel interactions, spectral resolution in the local cochlear region, and vowel identification was evaluated. Results showed that (1) there was within- and across-subject variability in the widths of ECAP channel interaction functions and in narrowband SRD performance, (2) significant correlations were found between the widths of the ECAP functions and narrowband SRD thresholds, and between mean bandwidths of ECAP functions averaged across multiple probe electrodes and broadband SRD performance across subjects, and (3) the global spectral resolution reflecting the entire electrode array, not the local region, predicts vowel identification.</P>
Park, S. K.,Andreotti, G.,Sakoda, L. C.,Gao, Y.-T.,Rashid, A.,Chen, J.,Chen, B. E.,Rosenberg, P. S.,Shen, M.-C.,Wang, B.-S.,Han, T.-Q.,Zhang, B.-H.,Yeager, M.,Chanock, S.,Hsing, A. W. Oxford University Press 2009 Carcinogenesis Vol.30 No.4
<P>Biliary tract cancers, encompassing gallbladder, extrahepatic bile duct and ampulla of Vater cancers, are uncommon but often fatal malignancies. Hormone-related factors, including parity, oral contraceptive use, obesity, and gallstones, have been implicated in the etiology of these cancers. To further clarify the role of hormones in biliary tract cancers and biliary stones, we genotyped 18 single-nucleotide polymorphisms (SNPs) in nine genes involved in steroid hormone biosynthesis, metabolism and transport in a population-based case-control study in Shanghai, China. This study included subjects who completed an interview and provided blood, which totaled 411 biliary tract cancer and 893 biliary stone patients and 786 healthy Shanghai residents. The CYP1A1 IVS1 + 606 (rs2606345) T allele was associated with gallbladder [odds ratio (OR) = 2.0, 95% confidence interval (CI), 1.3-3.0] and bile duct cancers (OR = 1.8, 95% CI = 1.1-3.1), whereas the CYP1A1 Ex7 + 131 (rs1048943) G allele was associated with ampulla of Vater cancer (OR = 2.9, 95% CI = 1.5-5.4). After taking into account multiple comparisons for SNPs within each gene, CYP1A1 was significantly associated with gallbladder (P = 0.004) and ampulla of Vater cancers (P = 0.01), but borderline with bile duct cancer (P = 0.06). The effect of CYP1A1 IVS1 + 606 on gallbladder cancer was more pronounced among non-obese (body mass index < 23) (OR = 3.3, 95% CI = 1.8-6.1; P interaction = 0.001). Among women taking oral contraceptives, the effect of SHBG Ex8 + 6 (rs6259) on gallbladder cancer (OR = 6.7, 95% CI = 2.2-20.5; P interaction = 0.001) and stones (OR = 2.3, 95% CI = 1.1-4.9; P-interaction = 0.05) was statistically significant. Our findings suggest that common variants in hormone-related genes contribute to the risk of biliary tract cancers and stones, possibly by modulating hormone metabolism.</P>