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1. Comprehensive Sex-Stratified Genetic Analysis of 28 Blood Biomarkers and Depression Reveals a Significant Association between Depression and Low Levels of Total Protein in Females.

Author

Kiewa, J, Meltzer-Brody, S, Milgrom, J, Guintivano, J, Hickie, IB, Whiteman, DC, Olsen, CM, Medland, SE, Martin, NG, Wray, NR, Byrne, EM, Kiewa, J, Meltzer-Brody, S, Milgrom, J, Guintivano, J, Hickie, IB, Whiteman, DC, Olsen, CM, Medland, SE, Martin, NG, Wray, NR, and Byrne, EM

Abstract

INTRODUCTION: Major depression (MD) is more common amongst women than men, and MD episodes have been associated with fluctuations in reproductive hormones amongst women. To investigate biological underpinnings of heterogeneity in MD, the associations between depression, stratified by sex and including perinatal depression (PND), and blood biomarkers, using UK Biobank (UKB) data, were evaluated, and extended to include the association of depression with biomarker polygenic scores (PGS), generated as proxy for each biomarker. METHOD: Using female (N = 39,761) and male (N = 38,821) UKB participants, lifetime MD and PND were tested for association with 28 blood biomarkers. A GWAS was conducted for each biomarker and genetic correlations with depression subgroups were estimated. Using independent data from the Australian Genetics of Depression Study, PGS were constructed for each biomarker, and tested for association with depression status (n [female cases/controls] = 9,006/6,442; n [male cases/controls] = 3,106/6,222). Regions of significant local genetic correlation between depression subgroups and biomarkers highlighted by the PGS analysis were identified. RESULTS: Depression in females was significantly associated with levels of twelve biomarkers, including total protein (OR = 0.90, CI = [0.86, 0.94], p = 3.9 × 10-6) and vitamin D (OR = 0.94, CI = [0.90, 0.97], p = 2.6 × 10-4), and PND with five biomarker levels, also including total protein (OR = 0.88, CI = [0.81, 0.96], p = 4.7 × 10-3). Depression in males was significantly associated with levels of eleven biomarkers. In the independent Australian Genetics of Depression Study, PGS analysis found significant associations for female depression and PND with total protein (female depression: OR = 0.93, CI = [0.88, 0.98], p = 3.6 × 10-3; PND: OR = 0.91, CI = [0.86, 0.96], p = 1.1 × 10-3), as well as with vitamin D (female depression: OR = 0.93, CI = [0.89, 0.97], p = 2.0 × 10-3; PND: OR = 0.92, CI = [0.87, 0.97], p = 1.

Published
2024

2. Validation of a risk prediction model for Barrett’s esophagus in an Australian population

Author

Ireland CJ, Gordon AL, Thompson SK, Watson DI, Whiteman DC, Reed RL, and Esterman A

Subjects
Barrett’s esophagus, risk prediction model, screening, validation, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Colin J Ireland,1 Andrea L Gordon,2 Sarah K Thompson,3 David I Watson,4 David C Whiteman,5 Richard L Reed,6 Adrian Esterman1,7 1School of Nursing and Midwifery, Division of Health Sciences, University of South Australia, Adelaide, SA, Australia; 2School of Pharmacy and Medical Science, Division of Health Sciences, University of South Australia, Adelaide, SA, Australia; 3Discipline of Surgery, University of Adelaide, Adelaide, SA, Australia; 4Department of Surgery, Flinders University, Bedford Park, SA, Australia; 5Population Health Department, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia; 6Discipline of General Practice, Flinders University, Bedford Park, SA, Australia; 7Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, QLD, Australia Background: Esophageal adenocarcinoma is a disease that has a high mortality rate, the only known precursor being Barrett’s esophagus (BE). While screening for BE is not cost-effective at the population level, targeted screening might be beneficial. We have developed a risk prediction model to identify people with BE, and here we present the external validation of this model. Materials and methods: A cohort study was undertaken to validate a risk prediction model for BE. Individuals with endoscopy and histopathology proven BE completed a questionnaire containing variables previously identified as risk factors for this condition. Their responses were combined with data from a population sample for analysis. Risk scores were derived for each participant. Overall performance of the risk prediction model in terms of calibration and discrimination was assessed. Results: Scores from 95 individuals with BE and 636 individuals from the general population were analyzed. The Brier score was 0.118, suggesting reasonable overall performance. The area under the receiver operating characteristic was 0.83 (95% CI 0.78–0.87). The Hosmer–Lemeshow statistic was p=0.14. Minimizing false positives and false negatives, the model achieved a sensitivity of 74% and a specificity of 73%. Conclusion: This study has validated a risk prediction model for BE that has a higher sensitivity than previous models. Keywords: Barrett’s esophagus, risk prediction model, screening, validation

Published
2018

3. The genetic basis of endometriosis and comorbidity with other pain and inflammatory conditions

Author

Rahmioglu, N, Mortlock, S, Ghiasi, M, Moller, PL, Stefansdottir, L, Galarneau, G, Turman, C, Danning, R, Law, MH, Sapkota, Y, Christofidou, P, Skarp, S, Giri, A, Banasik, K, Krassowski, M, Lepamets, M, Marciniak, B, Noukas, M, Perro, D, Sliz, E, Sobalska-Kwapis, M, Thorleifsson, G, Topbas-Selcuki, NF, Vitonis, A, Westergaard, D, Arnadottir, R, Burgdorf, KS, Campbell, A, Cheuk, CSK, Clementi, C, Cook, J, De Vivo, I, DiVasta, A, Dorien, O, Donoghue, JF, Edwards, T, Fontanillas, P, Fung, JN, Geirsson, RT, Girling, JE, Harkki, P, Harris, HR, Healey, M, Heikinheimo, O, Holdsworth-Carson, S, Hostettler, IC, Houlden, H, Houshdaran, S, Irwin, JC, Jarvelin, M-R, Kamatani, Y, Kennedy, SH, Kepka, E, Kettunen, J, Kubo, M, Kulig, B, Kurra, V, Laivuori, H, Laufer, MR, Lindgren, CM, MacGregor, S, Mangino, M, Martin, NG, Matalliotaki, C, Matalliotakis, M, Murray, AD, Ndungu, A, Nezhat, C, Olsen, CM, Opoku-Anane, J, Padmanabhan, S, Paranjpe, M, Peters, M, Polak, G, Porteous, DJ, Rabban, J, Rexrode, KM, Romanowicz, H, Saare, M, Saavalainen, L, Schork, AJ, Sen, S, Shafrir, AL, Siewierska-Gorska, A, Slomka, M, Smith, BH, Smolarz, B, Szaflik, T, Szyllo, K, Takahashi, A, Terry, KL, Tomassetti, C, Treloar, SA, Vanhie, A, Vincent, K, Vo, KC, Werring, DJ, Zeggini, E, Zervou, M, Stefansson, K, Nyegaard, M, Uimari, O, Yurttas-Beim, P, Tung, JY, Adachi, S, Buring, JE, Ridker, PM, D'Hooghe, T, Goulielmos, GN, Hapangama, DK, Hayward, C, Horne, AW, Low, S-K, Martikainen, H, Chasman, D, Rogers, PAW, Saunders, PT, Sirota, M, Spector, T, Strapagiel, D, Whiteman, DC, Giudice, LC, Velez-Edwards, DR, Kraft, P, Salumets, A, Nyholt, DR, Magi, R, Becker, CM, Steinthorsdottir, V, Missmer, SA, Montgomery, GW, Morris, AP, Zondervan, KT, Rahmioglu, N, Mortlock, S, Ghiasi, M, Moller, PL, Stefansdottir, L, Galarneau, G, Turman, C, Danning, R, Law, MH, Sapkota, Y, Christofidou, P, Skarp, S, Giri, A, Banasik, K, Krassowski, M, Lepamets, M, Marciniak, B, Noukas, M, Perro, D, Sliz, E, Sobalska-Kwapis, M, Thorleifsson, G, Topbas-Selcuki, NF, Vitonis, A, Westergaard, D, Arnadottir, R, Burgdorf, KS, Campbell, A, Cheuk, CSK, Clementi, C, Cook, J, De Vivo, I, DiVasta, A, Dorien, O, Donoghue, JF, Edwards, T, Fontanillas, P, Fung, JN, Geirsson, RT, Girling, JE, Harkki, P, Harris, HR, Healey, M, Heikinheimo, O, Holdsworth-Carson, S, Hostettler, IC, Houlden, H, Houshdaran, S, Irwin, JC, Jarvelin, M-R, Kamatani, Y, Kennedy, SH, Kepka, E, Kettunen, J, Kubo, M, Kulig, B, Kurra, V, Laivuori, H, Laufer, MR, Lindgren, CM, MacGregor, S, Mangino, M, Martin, NG, Matalliotaki, C, Matalliotakis, M, Murray, AD, Ndungu, A, Nezhat, C, Olsen, CM, Opoku-Anane, J, Padmanabhan, S, Paranjpe, M, Peters, M, Polak, G, Porteous, DJ, Rabban, J, Rexrode, KM, Romanowicz, H, Saare, M, Saavalainen, L, Schork, AJ, Sen, S, Shafrir, AL, Siewierska-Gorska, A, Slomka, M, Smith, BH, Smolarz, B, Szaflik, T, Szyllo, K, Takahashi, A, Terry, KL, Tomassetti, C, Treloar, SA, Vanhie, A, Vincent, K, Vo, KC, Werring, DJ, Zeggini, E, Zervou, M, Stefansson, K, Nyegaard, M, Uimari, O, Yurttas-Beim, P, Tung, JY, Adachi, S, Buring, JE, Ridker, PM, D'Hooghe, T, Goulielmos, GN, Hapangama, DK, Hayward, C, Horne, AW, Low, S-K, Martikainen, H, Chasman, D, Rogers, PAW, Saunders, PT, Sirota, M, Spector, T, Strapagiel, D, Whiteman, DC, Giudice, LC, Velez-Edwards, DR, Kraft, P, Salumets, A, Nyholt, DR, Magi, R, Becker, CM, Steinthorsdottir, V, Missmer, SA, Montgomery, GW, Morris, AP, and Zondervan, KT

Abstract

Endometriosis is a common condition associated with debilitating pelvic pain and infertility. A genome-wide association study meta-analysis, including 60,674 cases and 701,926 controls of European and East Asian descent, identified 42 genome-wide significant loci comprising 49 distinct association signals. Effect sizes were largest for stage 3/4 disease, driven by ovarian endometriosis. Identified signals explained up to 5.01% of disease variance and regulated expression or methylation of genes in endometrium and blood, many of which were associated with pain perception/maintenance (SRP14/BMF, GDAP1, MLLT10, BSN and NGF). We observed significant genetic correlations between endometriosis and 11 pain conditions, including migraine, back and multisite chronic pain (MCP), as well as inflammatory conditions, including asthma and osteoarthritis. Multitrait genetic analyses identified substantial sharing of variants associated with endometriosis and MCP/migraine. Targeted investigations of genetically regulated mechanisms shared between endometriosis and other pain conditions are needed to aid the development of new treatments and facilitate early symptomatic intervention.

Published
2023

4. Multi-trait genetic analysis identifies auto-immune loci associated with cutaneous melanoma

Author

Liyanage, U, MacGregor, S, Bishop, DT, Shi, J, An, J, Ong, JS, Han, X, Scolyer, RA, Martin, NG, Medland, SE, Byrne, EM, Green, AC, Saw, RPM, Thompson, JF, Stretch, J, Spillane, A, Jiang, Y, Tian, C, 23andMe Research Team, Gordon, SG, Duffy, DL, Olsen, CM, Whiteman, DC, Long, GV, Iles, MM, Landi, MT, and Law, MH

Abstract

Genome-wide association studies (GWAS) have identified a number of risk loci for cutaneous melanoma. Cutaneous melanoma shares overlapping genetic risk (genetic correlation) with a number of other traits, including with its risk factors such as sunburn propensity. This genetic correlation can be exploited to identify additional cutaneous melanoma risk loci by multi-trait analysis of GWAS (MTAG). We used bivariate LD-score regression to identify traits that are genetically correlated with clinically-confirmed cutaneous melanoma, and then used publicly available GWAS for these traits in a MTAG. MTAG allows GWAS to be combined while accounting for sample overlap and incomplete genetic correlation. We identified a total of 74 genome-wide independent loci; 19 of them were not previously reported in the input cutaneous melanoma GWAS-meta-analysis. 55 of these loci were replicated (P < 0.05/74), Bonferroni corrected P -value in two independent cutaneous melanoma replication cohorts from Melanoma Institute Australia and 23andMe, Inc. Among the new cutaneous melanoma loci are ones that have also been associated with autoimmune traits including rs715199 near LPP, and rs10858023 near AP4B1. Our analysis indicates genetic correlation between traits can be leveraged to identify new risk genes for cutaneous melanoma.

Published
2022

5. Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Author

Mullins, N, Kang, J, Campos, A, Coleman, JR, Edwards, AC, Galfalvy, H, Levey, DF, Lori, A, Shabalin, A, Starnawska, A, Su, M-H, Watson, HJ, Adams, M, Awasthi, S, Ganda, M, Hafferty, JD, Hishimoto, A, Kim, M, Okazaki, S, Otsuka, I, Ripke, S, Ware, EB, Bergen, AW, Berrettini, WH, Bohus, M, Brandt, H, Chang, X, Chen, WJ, Chen, H-C, Crawford, S, Crow, S, DiBlasi, E, Duriez, P, Fernandez-Aranda, F, Fichter, MM, Gallinger, S, Glatt, SJ, Gorwood, P, Guo, Y, Hakonarson, H, Halmi, KA, Hwu, H-G, Jain, S, Jamain, S, Jimenez-Murcia, S, Johnson, C, Kaplan, AS, Kaye, WH, Keel, PK, Kennedy, JL, Klump, KL, Li, D, Liao, S-C, Lieb, K, Lilenfeld, L, Liu, C-M, Magistretti, PJ, Marshall, CR, Mitchell, JE, Monson, ET, Myers, RM, Pinto, D, Powers, A, Ramoz, N, Roepke, S, Rozanov, V, Scherer, SW, Schmahl, C, Sokolowski, M, Strober, M, Thornton, LM, Treasure, J, Tsuang, MT, Witt, SH, Woodside, DB, Yilmaz, Z, Zillich, L, Adolfsson, R, Agartz, I, Air, TM, Alda, M, Alfredsson, L, Andreassen, OA, Anjorin, A, Appadurai, V, Artigas, MS, Van der Auwera, S, Azevedo, MH, Bass, N, Bau, CHD, Baune, BT, Bellivier, F, Berger, K, Biernacka, JM, Bigdeli, TB, Binder, EB, Boehnke, M, Boks, MP, Bosch, R, Braff, DL, Bryant, R, Budde, M, Byrne, EM, Cahn, W, Casas, M, Castelao, E, Cervilla, JA, Chaumette, B, Cichon, S, Corvin, A, Craddock, N, Craig, D, Degenhardt, F, Djurovic, S, Edenberg, HJ, Fanous, AH, Foo, JC, Forstner, AJ, Frye, M, Fullerton, JM, Gatt, JM, Gejman, P, Giegling, I, Grabe, HJ, Green, MJ, Grevet, EH, Grigoroiu-Serbanescu, M, Gutierrez, B, Guzman-Parra, J, Hamilton, SP, Hamshere, ML, Hartmann, A, Hauser, J, Heilmann-Heimbach, S, Hoffmann, P, Ising, M, Jones, I, Jones, LA, Jonsson, L, Kahn, RS, Kelsoe, JR, Kendler, KS, Kloiber, S, Koenen, KC, Kogevinas, M, Konte, B, Krebs, M-O, Lander, M, Lawrence, J, Leboyer, M, Lee, PH, Levinson, DF, Liao, C, Lissowska, J, Lucae, S, Mayoral, F, McElroy, SL, McGrath, P, McGuffin, P, McQuillin, A, Medland, SE, Mehta, D, Melle, I, Milaneschi, Y, Mitchell, PB, Molina, E, Morken, G, Mortensen, PB, Mueller-Myhsok, B, Nievergelt, C, Nimgaonkar, V, Noethen, MM, O'Donovan, MC, Ophoff, RA, Owen, MJ, Pato, C, Pato, MT, Penninx, BWJH, Pimm, J, Pistis, G, Potash, JB, Power, RA, Preisig, M, Quested, D, Ramos-Quiroga, JA, Reif, A, Ribases, M, Richarte, V, Rietschel, M, Rivera, M, Roberts, A, Roberts, G, Rouleau, GA, Rovaris, DL, Rujescu, D, Sanchez-Mora, C, Sanders, AR, Schofield, PR, Schulze, TG, Scott, LJ, Serretti, A, Shi, J, Shyn, S, Sirignano, L, Sklar, P, Smeland, OB, Smoller, JW, Sonuga-Barke, EJS, Spalletta, G, Strauss, JS, Swiatkowska, B, Trzaskowski, M, Turecki, G, Vilar-Ribo, L, Vincent, JB, Voelzke, H, Walters, JTR, Weickert, CS, Weickert, TW, Weissman, MM, Williams, LM, Wray, NR, Zai, CC, Ashley-Koch, AE, Beckham, JC, Hauser, ER, Hauser, MA, Kimbrel, NA, Lindquist, JH, McMahon, B, Oslin, DW, Qin, X, Agerbo, E, Borglum, AD, Breen, G, Erlangsen, A, Esko, T, Gelernter, J, Hougaard, DM, Kessler, RC, Kranzler, HR, Li, QS, Martin, NG, McIntosh, AM, Mors, O, Nordentoft, M, Olsen, CM, Porteous, D, Ursano, RJ, Wasserman, D, Werge, T, Whiteman, DC, Bulik, CM, Coon, H, Demontis, D, Docherty, AR, Kuo, P-H, Lewis, CM, Mann, JJ, Renteria, ME, Smith, DJ, Stahl, EA, Stein, MB, Streit, F, Willour, V, Ruderfer, DM, Mullins, N, Kang, J, Campos, A, Coleman, JR, Edwards, AC, Galfalvy, H, Levey, DF, Lori, A, Shabalin, A, Starnawska, A, Su, M-H, Watson, HJ, Adams, M, Awasthi, S, Ganda, M, Hafferty, JD, Hishimoto, A, Kim, M, Okazaki, S, Otsuka, I, Ripke, S, Ware, EB, Bergen, AW, Berrettini, WH, Bohus, M, Brandt, H, Chang, X, Chen, WJ, Chen, H-C, Crawford, S, Crow, S, DiBlasi, E, Duriez, P, Fernandez-Aranda, F, Fichter, MM, Gallinger, S, Glatt, SJ, Gorwood, P, Guo, Y, Hakonarson, H, Halmi, KA, Hwu, H-G, Jain, S, Jamain, S, Jimenez-Murcia, S, Johnson, C, Kaplan, AS, Kaye, WH, Keel, PK, Kennedy, JL, Klump, KL, Li, D, Liao, S-C, Lieb, K, Lilenfeld, L, Liu, C-M, Magistretti, PJ, Marshall, CR, Mitchell, JE, Monson, ET, Myers, RM, Pinto, D, Powers, A, Ramoz, N, Roepke, S, Rozanov, V, Scherer, SW, Schmahl, C, Sokolowski, M, Strober, M, Thornton, LM, Treasure, J, Tsuang, MT, Witt, SH, Woodside, DB, Yilmaz, Z, Zillich, L, Adolfsson, R, Agartz, I, Air, TM, Alda, M, Alfredsson, L, Andreassen, OA, Anjorin, A, Appadurai, V, Artigas, MS, Van der Auwera, S, Azevedo, MH, Bass, N, Bau, CHD, Baune, BT, Bellivier, F, Berger, K, Biernacka, JM, Bigdeli, TB, Binder, EB, Boehnke, M, Boks, MP, Bosch, R, Braff, DL, Bryant, R, Budde, M, Byrne, EM, Cahn, W, Casas, M, Castelao, E, Cervilla, JA, Chaumette, B, Cichon, S, Corvin, A, Craddock, N, Craig, D, Degenhardt, F, Djurovic, S, Edenberg, HJ, Fanous, AH, Foo, JC, Forstner, AJ, Frye, M, Fullerton, JM, Gatt, JM, Gejman, P, Giegling, I, Grabe, HJ, Green, MJ, Grevet, EH, Grigoroiu-Serbanescu, M, Gutierrez, B, Guzman-Parra, J, Hamilton, SP, Hamshere, ML, Hartmann, A, Hauser, J, Heilmann-Heimbach, S, Hoffmann, P, Ising, M, Jones, I, Jones, LA, Jonsson, L, Kahn, RS, Kelsoe, JR, Kendler, KS, Kloiber, S, Koenen, KC, Kogevinas, M, Konte, B, Krebs, M-O, Lander, M, Lawrence, J, Leboyer, M, Lee, PH, Levinson, DF, Liao, C, Lissowska, J, Lucae, S, Mayoral, F, McElroy, SL, McGrath, P, McGuffin, P, McQuillin, A, Medland, SE, Mehta, D, Melle, I, Milaneschi, Y, Mitchell, PB, Molina, E, Morken, G, Mortensen, PB, Mueller-Myhsok, B, Nievergelt, C, Nimgaonkar, V, Noethen, MM, O'Donovan, MC, Ophoff, RA, Owen, MJ, Pato, C, Pato, MT, Penninx, BWJH, Pimm, J, Pistis, G, Potash, JB, Power, RA, Preisig, M, Quested, D, Ramos-Quiroga, JA, Reif, A, Ribases, M, Richarte, V, Rietschel, M, Rivera, M, Roberts, A, Roberts, G, Rouleau, GA, Rovaris, DL, Rujescu, D, Sanchez-Mora, C, Sanders, AR, Schofield, PR, Schulze, TG, Scott, LJ, Serretti, A, Shi, J, Shyn, S, Sirignano, L, Sklar, P, Smeland, OB, Smoller, JW, Sonuga-Barke, EJS, Spalletta, G, Strauss, JS, Swiatkowska, B, Trzaskowski, M, Turecki, G, Vilar-Ribo, L, Vincent, JB, Voelzke, H, Walters, JTR, Weickert, CS, Weickert, TW, Weissman, MM, Williams, LM, Wray, NR, Zai, CC, Ashley-Koch, AE, Beckham, JC, Hauser, ER, Hauser, MA, Kimbrel, NA, Lindquist, JH, McMahon, B, Oslin, DW, Qin, X, Agerbo, E, Borglum, AD, Breen, G, Erlangsen, A, Esko, T, Gelernter, J, Hougaard, DM, Kessler, RC, Kranzler, HR, Li, QS, Martin, NG, McIntosh, AM, Mors, O, Nordentoft, M, Olsen, CM, Porteous, D, Ursano, RJ, Wasserman, D, Werge, T, Whiteman, DC, Bulik, CM, Coon, H, Demontis, D, Docherty, AR, Kuo, P-H, Lewis, CM, Mann, JJ, Renteria, ME, Smith, DJ, Stahl, EA, Stein, MB, Streit, F, Willour, V, and Ruderfer, DM

Abstract

BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.

Published
2022

6. Common risk variants for epilepsy are enriched in families previously targeted for rare monogenic variant discovery

Author

Oliver, KL, Ellis, CA, Scheffer, IE, Ganesan, S, Leu, C, Sadleir, LG, Heinzen, EL, Mefford, HC, Bass, AJ, Curtis, SW, Harris, R, Whiteman, DC, Helbig, I, Ottman, R, Epstein, MP, Bahlo, M, Berkovic, SF, Oliver, KL, Ellis, CA, Scheffer, IE, Ganesan, S, Leu, C, Sadleir, LG, Heinzen, EL, Mefford, HC, Bass, AJ, Curtis, SW, Harris, R, Whiteman, DC, Helbig, I, Ottman, R, Epstein, MP, Bahlo, M, and Berkovic, SF

Abstract

BACKGROUND: The epilepsies are highly heritable conditions that commonly follow complex inheritance. While monogenic causes have been identified in rare familial epilepsies, most familial epilepsies remain unsolved. We aimed to determine (1) whether common genetic variation contributes to familial epilepsy risk, and (2) whether that genetic risk is enriched in familial compared with non-familial (sporadic) epilepsies. METHODS: Using common variants derived from the largest epilepsy genome-wide association study, we calculated polygenic risk scores (PRS) for patients with familial epilepsy (n = 1,818 from 1,181 families), their unaffected relatives (n = 771), sporadic patients (n = 1,182), and population controls (n = 15,929). We also calculated separate PRS for genetic generalised epilepsy (GGE) and focal epilepsy. Statistical analyses used mixed-effects regression models to account for familial relatedness, sex, and ancestry. FINDINGS: Patients with familial epilepsies had higher epilepsy PRS compared to population controls (OR 1·20, padj = 5×10-9), sporadic patients (OR 1·11, padj = 0.008), and their own unaffected relatives (OR 1·12, padj = 0.01). The top 1% of the PRS distribution was enriched 3.8-fold for individuals with familial epilepsy when compared to the lowest decile (padj = 5×10-11). Familial PRS enrichment was consistent across epilepsy type; overall, polygenic risk was greatest for the GGE clinical group. There was no significant PRS difference in familial cases with established rare variant genetic etiologies compared to unsolved familial cases. INTERPRETATION: The aggregate effects of common genetic variants, measured as polygenic risk scores, play an important role in explaining why some families develop epilepsy, why specific family members are affected while their relatives are not, and why families manifest specific epilepsy types. Polygenic risk contributes to the complex inheritance of the epilepsies, including in individuals with a known gene

Published
2022

7. The Australian Genetics of Depression Study: New Risk Loci and Dissecting Heterogeneity Between Subtypes

Author

Mitchell, BL, Campos, A, Whiteman, DC, Olsen, CM, Gordon, SD, Walker, AJ, Dean, OM, Berk, M, Hickie, IB, Medland, SE, Wray, NR, Martin, NG, Byrne, EM, Mitchell, BL, Campos, A, Whiteman, DC, Olsen, CM, Gordon, SD, Walker, AJ, Dean, OM, Berk, M, Hickie, IB, Medland, SE, Wray, NR, Martin, NG, and Byrne, EM

Abstract

BACKGROUND: Major depressive disorder (MDD) is a common and highly heterogeneous psychiatric disorder, but little is known about the genetic characterization of this heterogeneity. Understanding the genetic etiology of MDD can be challenging because large sample sizes are needed for gene discovery-often achieved with a trade-off in the depth of phenotyping. METHODS: The Australian Genetics of Depression Study is the largest stand-alone depression cohort with both genetic data and in-depth phenotyping and comprises a total of 15,792 participants of European ancestry, 92% of whom met diagnostic criteria for MDD. We leveraged the unique nature of this cohort to conduct a meta-analysis with the largest publicly available depression genome-wide association study to date and subsequently used polygenic scores to investigate genetic heterogeneity across various clinical subtypes of MDD. RESULTS: We increased the number of known genome-wide significant variants associated with depression from 103 to 126 and found evidence of association of novel genes implicated in neuronal development. We found that a polygenic score for depression explained 5.7% of variance in MDD liability in our sample. Finally, we found strong support for genetic heterogeneity in depression with differential associations of multiple psychiatric and comorbid traits with age of onset, longitudinal course, and various subtypes of MDD. CONCLUSIONS: Until now, this degree of detailed phenotyping in such a large sample of MDD cases has not been possible. Along with the discovery of novel loci, we provide support for differential pathways to illness models that recognize the overlap with other common psychiatric disorders as well as pathophysiological differences.

Published
2022

8. Perinatal depression is associated with a higher polygenic risk for major depressive disorder than non-perinatal depression

Author

Kiewa, J, Meltzer-Brody, S, Milgrom, J, Guintivano, J, Hickie, IB, Whiteman, DC, Olsen, CM, Colodro-Conde, L, Medland, SE, Martin, NG, Wray, NR, Byrne, EM, Kiewa, J, Meltzer-Brody, S, Milgrom, J, Guintivano, J, Hickie, IB, Whiteman, DC, Olsen, CM, Colodro-Conde, L, Medland, SE, Martin, NG, Wray, NR, and Byrne, EM

Abstract

BACKGROUND: Distinctions between major depressive disorder (MDD) and perinatal depression (PND) reflect varying views of PND, from a unique etiological subtype of MDD to an MDD episode that happens to coincide with childbirth. This case-control study investigated genetic differences between PND and MDD outside the perinatal period (non-perinatal depression or NPD). METHODS: We conducted a genome-wide association study using PND cases (Edinburgh Postnatal Depression Scale score ≥ 13) from the Australian Genetics of Depression Study 2018 data (n = 3804) and screened controls (n = 6134). Results of gene-set enrichment analysis were compared with those of women with non-PND. For six psychiatric disorders/traits, genetic correlations with PND were evaluated, and logistic regression analysis reported polygenic score (PGS) association with both PND and NPD. RESULTS: Genes differentially expressed in ovarian tissue were significantly enriched (stdBeta = 0.07, p = 3.3e-04), but were not found to be associated with NPD. The genetic correlation between PND and MDD was 0.93 (SE = 0.07; p = 3.5e-38). Compared with controls, PGS for MDD are higher for PND cases (odds ratio [OR] = 1.8, confidence interval [CI] = [1.7-1.8], p = 9.5e-140) than for NPD cases (OR = 1.6, CI = [1.5-1.7], p = 1.2e-49). Highest risk is for those reporting both antenatal and postnatal depression, irrespective of prior MDD history. CONCLUSIONS: PND has a high genetic overlap with MDD, but points of distinction focus on differential expression in ovarian tissue and higher MDD PGS, particularly for women experiencing both antenatal and postpartum PND.

Published
2022

9. Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology (vol 53, pg 1636, 2021)

Author

van Rheenen, W, van der Spek, RAA, Bakker, MK, van Vugt, JJFA, Hop, PJ, Zwamborn, RAJ, de Klein, N, Westra, HJ, Bakker, OB, Deelen, P, Shireby, G, Hannon, E, Moisse, M, Baird, D, Restuadi, R, Dolzhenko, E, Dekker, AM, Gawor, K, Westeneng, HJ, Tazelaar, GHP, van Eijk, KR, Kooyman, M, Byrne, RP, Doherty, M, Heverin, M, Al Khleifat, A, Iacoangeli, A, Shatunov, A, Ticozzi, N, Cooper-Knock, J, Smith, BN, Gromicho, M, Chandran, S, Pal, S, Morrison, KE, Shaw, PJ, Hardy, J, Orrell, RW, Sendtner, M, Meyer, T, Basak, N, van der Kooi, AJ, Ratti, A, Fogh, I, Gellera, C, Lauria, G, Corti, S, Cereda, C, Sproviero, D, Soraru, G, Siciliano, G, Filosto, M, Padovani, A, Chio, A, Calvo, A, Moglia, C, Brunetti, M, Canosa, A, Grassano, M, Beghi, E, Pupillo, E, Logroscino, G, Nefussy, B, Osmanovic, A, Nordin, A, Lerner, Y, Zabari, M, Gotkine, M, Baloh, RH, Bell, S, Vourc'h, P, Corcia, P, Couratier, P, Millecamps, S, Meininger, V, Salachas, F, Pardina, JMS, Assialioui, A, Rojas-Garcia, R, Dion, PA, Ross, JP, Ludolph, AC, Weishaupt, JH, Brenner, D, Freischmidt, A, Bensimon, G, Brice, A, Durr, A, Payan, CAM, Saker-Delye, S, Wood, NW, Topp, S, Rademakers, R, Tittmann, L, Lieb, W, Franke, A, Ripke, S, Braun, A, Kraft, J, Whiteman, DC, Olsen, CM, Uitterlinden, AG, Hofman, A, Rietschel, M, Cichon, S, Nothen, MM, Amouyel, P, Comi, G, Riva, N, Lunetta, C, Gerardi, F, Cotelli, MS, Rinaldi, F, Chiveri, L, Guaita, MC, Perrone, P, Diamanti, L, Ferrarese, C, Tremolizzo, L, Delodovici, ML, Bono, G, Manera, U, Vasta, R, Bombaci, A, Casale, F, Fuda, G, Salamone, P, Iazzolino, B, Peotta, L, Cugnasco, P, De Marco, G, Torrieri, MC, Palumbo, F, Gallone, S, Barberis, M, Sbaiz, L, Gentile, S, Mauro, A, De Marchi, F, D'Alfonso, S, Bertolotto, A, Gionco, M, Leotta, D, Odddenino, E, Imperiale, D, Cavallo, R, Pignatta, P, De Mattei, M, Geda, C, Papurello, DM, Gusmaroli, G, Comi, C, Labate, C, Ruiz, L, Ferrandi, D, Rota, E, Aguggia, M, Di Vito, N, Meineri, P, Ghiglione, P, Launaro, N, Dotta, M, Di Sapio, A, Giardini, G, Tiloca, C, Peverelli, S, Taroni, F, Pensato, V, Castellotti, B, Comi, GP, Del Bo, R, Ceroni, M, Gagliardi, S, Corrado, L, Mazzini, L, Raggi, F, Simoncini, C, Lo Gerfo, A, Inghilleri, M, Ferlini, A, Simone, IL, Passarella, B, Guerra, V, Zoccolella, S, Nozzoli, C, Mundi, C, Leone, M, Zarrelli, M, Tamma, F, Valluzzi, F, Calabrese, G, Boero, G, Rini, A, Traynor, BJ, Singleton, AB, Neto, MM, Cauchi, RJ, Ophoff, RA, Wiedau-Pazos, M, Lomen-Hoerth, C, van Deerlin, VM, Grosskreutz, J, Roediger, A, Gaur, N, Jork, A, Barthel, T, Theele, E, Ilse, B, Stubendorff, B, Witte, OW, Steinbach, R, Hubner, CA, Graff, C, Brylev, L, Fominykh, V, Demeshonok, V, Ataulina, A, Rogelj, B, Koritnik, B, Zidar, J, Ravnik-Glavac, M, Glavac, D, Stevic, Z, Drory, V, Povedano, M, Blair, IP, Kiernan, MC, Benyamin, B, Henderson, RD, Furlong, S, Mathers, S, McCombe, PA, Needham, M, Ngo, ST, Nicholson, GA, Pamphlett, R, Rowe, DB, Steyn, FJ, Williams, KL, Mather, KA, Sachdev, PS, Henders, AK, Wallace, L, de Carvalho, M, Pinto, S, Petri, S, Weber, M, Rouleau, GA, Silani, V, Curtis, CJ, Breen, G, Glass, JD, Brown, RH, Landers, JE, Shaw, CE, Andersen, PM, Groen, EJN, van Es, MA, Pasterkamp, RJ, Fan, DS, Garton, FC, McRae, AF, Smith, GD, Gaunt, TR, Eberle, MA, Mill, J, McLaughlin, RL, Hardiman, O, Kenna, KP, Wray, NR, Tsai, EL, Runz, H, Franke, L, Al-Chalabi, A, Van Damme, P, van den Berg, LH, Veldink, JH, SLALOM Consortium, PARALS Consortium, SLAGEN Consortium, and SLAP Consortium

Published
2022

11. Predicting deseasonalised serum 25 hydroxy vitamin D concentrations in the D-Health Trial: An analysis using boosted regression trees

Author

Waterhouse, M, Baxter, C, Romero, BD, McLeod, DSA, English, DR, Armstrong, BK, Clarke, MW, Ebeling, PR, Hartel, G, Kimlin, MG, O'Connell, RL, Pham, H, Harris, RMR, van der Pols, JC, Venn, AJ, Webb, PM, Whiteman, DC, Neale, RE, Waterhouse, M, Baxter, C, Romero, BD, McLeod, DSA, English, DR, Armstrong, BK, Clarke, MW, Ebeling, PR, Hartel, G, Kimlin, MG, O'Connell, RL, Pham, H, Harris, RMR, van der Pols, JC, Venn, AJ, Webb, PM, Whiteman, DC, and Neale, RE

Abstract

BACKGROUND: The D-Health Trial aims to determine whether monthly high-dose vitamin D supplementation can reduce the mortality rate and prevent cancer. We did not have adequate statistical power for subgroup analyses, so could not justify the high cost of collecting blood samples at baseline. To enable future exploratory analyses stratified by baseline vitamin D status, we developed models to predict baseline serum 25 hydroxy vitamin D [25(OH)D] concentration. METHODS: We used data and serum 25(OH)D concentrations from participants who gave a blood sample during the trial for compliance monitoring and were randomised to placebo. Data were partitioned into training (80%) and validation (20%) datasets. Deseasonalised serum 25(OH)D concentrations were dichotomised using cut-points of 50, 60 and 75 nmol/L. We fitted boosted regression tree models, based on 13 predictors, and evaluated model performance using the validation data. RESULTS: The training and validation datasets had 1788 (10.5% <50 nmol/L, 23.1% <60 nmol, 48.8 <75 nmol/L) and 447 (11.9% <50 nmol/L, 25.7% <60 nmol/L, and 49.2% <75 nmol/L) samples, respectively. Ambient UV radiation and total intake of vitamin D were the strongest predictors of 'low' serum 25(OH)D concentration. The area under the receiver operating characteristic curves were 0.71, 0.70, and 0.66 for cut-points of <50, <60 and <75 nmol/L respectively. CONCLUSIONS: We exploited compliance monitoring data to develop models to predict serum 25(OH)D concentration for D-Health participants at baseline. This approach may prove useful in other trial settings where there is an obstacle to exhaustive data collection.

Published
2021

12. Vitamin D supplementation and risk of falling: outcomes from the randomized, placebo-controlled D-Health Trial

Author

Waterhouse, M, Sanguineti, E, Baxter, C, Romero, BD, McLeod, DSA, English, DR, Armstrong, BK, Ebeling, PR, Hartel, G, Kimlin, MG, O'Connell, RL, Pham, H, van der Pols, JC, Venn, AJ, Webb, PM, Whiteman, DC, Neale, RE, Waterhouse, M, Sanguineti, E, Baxter, C, Romero, BD, McLeod, DSA, English, DR, Armstrong, BK, Ebeling, PR, Hartel, G, Kimlin, MG, O'Connell, RL, Pham, H, van der Pols, JC, Venn, AJ, Webb, PM, Whiteman, DC, and Neale, RE

Abstract

BACKGROUND: Falls cause considerable morbidity and mortality in older people. It is unclear how vitamin D supplementation affects falls risk, particularly when taken at high doses. We sought to determine whether monthly high-dose vitamin D supplementation reduces risk and incidence of falls. METHODS: We used data from the randomized, double-blind, placebo-controlled D-Health Trial conducted in Australia. Between February 2014 and May 2015, 21 315 participants aged 60-84 years were randomized (1:1) to monthly doses of either 60 000 IU of colecalciferol or placebo for a maximum of 5 years. People who reported a history of osteomalacia, sarcoidosis, hyperparathyroidism, hypercalcaemia or kidney stones or who were taking >500 IU/day supplementary vitamin D were ineligible. Each year, we collected blood samples from ~450 randomly sampled participants from each trial arm and measured 25-hydroxyvitamin D [25(OH)D]. Falls, a prespecified tertiary outcome, were ascertained using annual surveys and, for a subset of participants, 3-month falls diaries. The primary outcome for this analysis was any fall in the month before completing an annual survey. As part of our process to maintain blinding, we used random samples of participants (surveys, n = 16 000; diaries, n = 2400), with equal numbers per group. Participants with no outcome data were excluded. Following an intention-to-treat approach, we analysed outcomes using logistic, ordinal and negative binomial regression. Registration: Australian New Zealand Clinical Trials Registry (ACTRN12613000743763); registered 4 July 2013. RESULTS: Mean treatment duration was 4.3 years (standard deviation [SD] = 1.4 years). Mean serum 25(OH)D concentrations during the trial were 114.8 (SD 30.3) nmol/L and 77.5 (SD 25.2) nmol/L in the vitamin D and placebo groups, respectively. Survey and diary analytic sets included 15 416 and 2200 participants, respectively; approximately half were randomized to vitamin D (surveys: 50.1%; diaries: 50.4%).

Published
2021

13. Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies

Author

Munn-Chernoff, MA, Johnson, EC, Chou, YL, Coleman, JRI, Thornton, LM, Walters, RK, Yilmaz, Z, Baker, JH, Hübel, C, Gordon, S, Medland, SE, Watson, HJ, Gaspar, HA, Bryois, J, Hinney, A, Leppä, VM, Mattheisen, M, Ripke, S, Yao, S, Giusti-Rodríguez, P, Hanscombe, KB, Adan, RAH, Alfredsson, L, Ando, T, Andreassen, OA, Berrettini, WH, Boehm, I, Boni, C, Boraska Perica, V, Buehren, K, Burghardt, R, Cassina, M, Cichon, S, Clementi, M, Cone, RD, Courtet, P, Crow, S, Crowley, JJ, Danner, UN, Davis, OS, Zwaan, M, Dedoussis, G, Degortes, D, DeSocio, JE, Dick, DM, Dikeos, D, Dina, C, Dmitrzak-Weglarz, M, Docampo, E, Duncan, LE, Egberts, K, Ehrlich, S, Escaramís, G, Esko, T, Estivill, X, Farmer, A, Favaro, A, Fernández-Aranda, F, Fichter, MM, Fischer, K, Föcker, M, Foretova, L, Forstner, AJ, Forzan, M, Franklin, CS, Gallinger, S, Giegling, I, Giuranna, J, Gonidakis, F, Gorwood, P, Gratacos Mayora, M, Guillaume, S, Guo, Y, Hakonarson, H, Hatzikotoulas, K, Hauser, J, Hebebrand, J, Helder, SG, Herms, S, Herpertz-Dahlmann, B, Herzog, W, Huckins, LM, Hudson, JI, Imgart, H, Inoko, H, Janout, V, Jiménez-Murcia, S, Julià, A, Kalsi, G, Kaminská, D, Karhunen, L, Karwautz, A, Kas, MJH, Kennedy, JL, Keski-Rahkonen, A, Kiezebrink, K, Kim, YR, Klump, KL, Knudsen, GP, La Via, MC, Le Hellard, S, Levitan, RD, Li, D, Lilenfeld, L, Lin, BD, Lissowska, J, Luykx, J, Magistretti, PJ, Maj, M, Mannik, K, Marsal, S, Marshall, CR, Mattingsdal, M, McDevitt, S, McGuffin, P, Metspalu, A, Meulenbelt, I, Micali, N, Mitchell, K, Monteleone, A M, Monteleone, P, Nacmias, B, Navratilova, M, Ntalla, I, O'Toole, JK, Ophoff, Roel, Padyukov, L, Palotie, A, Pantel, J, Papezova, H, Pinto, D, Rabionet, R, Raevuori, A, Ramoz, N, Reichborn-Kjennerud, T, Ricca, V, Ripatti, S, Ritschel, F, Roberts, M, Rotondo, A, Rujescu, D, Rybakowski, F, Santonastaso, P, Scherag, A, Scherer, SW, Schmidt, U, Schork, NJ, Schosser, A, Seitz, J, Slachtova, L, Slagboom, PE, Slof-Op't Landt, MCT, Slopien, A, Sorbi, S, ?wi?tkowska, B, Szatkiewicz, JP, Tachmazidou, I, Tenconi, E, Tortorella, A, Tozzi, F, Treasure, J, Tsitsika, A, Tyszkiewicz-Nwafor, M, Tziouvas, K, van Elburg, AA, van Furth, EF, Wagner, G, Walton, E, Widen, E, Zeggini, E, Zerwas, S, Zipfel, S, Bergen, AW, Boden, JM, Brandt, H, Crawford, S, Halmi, KA, Horwood, LJ, Johnson, C, Kaplan, AS, Kaye, WH, Mitchell, J E, Olsen, CM, Pearson, JF, Pedersen, NL, Strober, M, Werge, T, Whiteman, DC, Woodside, DB, Grove, J, Henders, AK, Larsen, J T, Parker, R, Petersen, LV, Jordan, J, Kennedy, MA, Birgegård, A, Lichtenstein, P, Norring, C, Landén, M, Mortensen, PB, Polimanti, R, McClintick, JN, Adkins, AE, Aliev, F, Bacanu, SA, Batzler, A, Bertelsen, S, Biernacka, JM, Bigdeli, TB, Chen, L S, Clarke, TK, Degenhardt, F, Docherty, AR, Edwards, AC, Foo, JC, Fox, L, Frank, J, Hack, LM, Hartmann, AM, Hartz, SM, Heilmann-Heimbach, S, Hodgkinson, C, Hoffmann, P, Hottenga, JJ, Konte, B, Lahti, J, Lahti-Pulkkinen, M, Lai, D, Ligthart, L, Loukola, A, Maher, BS, Mbarek, H, McIntosh, AM, McQueen, MB, Meyers, JL, Milaneschi, Y, Palviainen, T, Peterson, RE, Ryu, E, Saccone, N L, Salvatore, JE, Sanchez-Roige, S, Schwandt, M, Sherva, R, Streit, F, Strohmaier, J, Thomas, N, Wang, JCY, Webb, BT, Wedow, R, Wetherill, L, Wills, AG, Zhou, H, Boardman, JD, Chen, D, Choi, D S, Copeland, WE, Culverhouse, RC, Dahmen, N, Degenhardt, L, Domingue, BW, Frye, MA, Gäebel, W, Hayward, C, Ising, M, Keyes, M, Kiefer, F, Koller, G, Kramer, J (John), Kuperman, S, Lucae, S, Lynskey, MT, Maier, W, Mann, K, Männistö, S, Müller-Myhsok, B, Murray, AD, Nurnberger, JI, Preuss, U, Räikkönen, K, Reynolds, MD, Ridinger, M, Scherbaum, N, Schuckit, MA, Soyka, M, Treutlein, J, Witt, SH, Wodarz, N, Zill, P, Adkins, DE, Boomsma, DI, Bierut, LJ, Brown, S, Bucholz, KK, Costello, EJ, Wit, HJ, Diazgranados, N, Eriksson, JG, Farrer, LA, Foroud, TM, Gillespie, NA, Goate, AM, Goldman, D, Grucza, RA, Hancock, DB, Harris, KM, Hesselbrock, V, Hewitt, JK, Hopfer, CJ, Iacono, WG, Johnson, E O, Karpyak, VM, Kendler, KS, Kranzler, HR, Krauter, K, Lind, PA, McGue, M, MacKillop, J, Madden, PA, Maes, HH, Magnusson, PKE, Nelson, EC, Nöthen, MM, Palmer, AA, Penninx, BWJH, Porjesz, B, Rice, JP, Rietschel, M, Riley, BP, Rose, RJ, Shen, PH, Silberg, J, Stallings, MC, Tarter, RE, Vanyukov, MM, Vrieze, S, Wall, TL, Whitfield, JB, Zhao, H, Neale, BM, Wade, TD, Heath, AC, Montgomery, GW, Martin, NG, Sullivan, PF, Kaprio, J, Breen, G, Gelernter, J, Edenberg, HJ, Bulik, CM, Agrawal, A, Munn-Chernoff, MA, Johnson, EC, Chou, YL, Coleman, JRI, Thornton, LM, Walters, RK, Yilmaz, Z, Baker, JH, Hübel, C, Gordon, S, Medland, SE, Watson, HJ, Gaspar, HA, Bryois, J, Hinney, A, Leppä, VM, Mattheisen, M, Ripke, S, Yao, S, Giusti-Rodríguez, P, Hanscombe, KB, Adan, RAH, Alfredsson, L, Ando, T, Andreassen, OA, Berrettini, WH, Boehm, I, Boni, C, Boraska Perica, V, Buehren, K, Burghardt, R, Cassina, M, Cichon, S, Clementi, M, Cone, RD, Courtet, P, Crow, S, Crowley, JJ, Danner, UN, Davis, OS, Zwaan, M, Dedoussis, G, Degortes, D, DeSocio, JE, Dick, DM, Dikeos, D, Dina, C, Dmitrzak-Weglarz, M, Docampo, E, Duncan, LE, Egberts, K, Ehrlich, S, Escaramís, G, Esko, T, Estivill, X, Farmer, A, Favaro, A, Fernández-Aranda, F, Fichter, MM, Fischer, K, Föcker, M, Foretova, L, Forstner, AJ, Forzan, M, Franklin, CS, Gallinger, S, Giegling, I, Giuranna, J, Gonidakis, F, Gorwood, P, Gratacos Mayora, M, Guillaume, S, Guo, Y, Hakonarson, H, Hatzikotoulas, K, Hauser, J, Hebebrand, J, Helder, SG, Herms, S, Herpertz-Dahlmann, B, Herzog, W, Huckins, LM, Hudson, JI, Imgart, H, Inoko, H, Janout, V, Jiménez-Murcia, S, Julià, A, Kalsi, G, Kaminská, D, Karhunen, L, Karwautz, A, Kas, MJH, Kennedy, JL, Keski-Rahkonen, A, Kiezebrink, K, Kim, YR, Klump, KL, Knudsen, GP, La Via, MC, Le Hellard, S, Levitan, RD, Li, D, Lilenfeld, L, Lin, BD, Lissowska, J, Luykx, J, Magistretti, PJ, Maj, M, Mannik, K, Marsal, S, Marshall, CR, Mattingsdal, M, McDevitt, S, McGuffin, P, Metspalu, A, Meulenbelt, I, Micali, N, Mitchell, K, Monteleone, A M, Monteleone, P, Nacmias, B, Navratilova, M, Ntalla, I, O'Toole, JK, Ophoff, Roel, Padyukov, L, Palotie, A, Pantel, J, Papezova, H, Pinto, D, Rabionet, R, Raevuori, A, Ramoz, N, Reichborn-Kjennerud, T, Ricca, V, Ripatti, S, Ritschel, F, Roberts, M, Rotondo, A, Rujescu, D, Rybakowski, F, Santonastaso, P, Scherag, A, Scherer, SW, Schmidt, U, Schork, NJ, Schosser, A, Seitz, J, Slachtova, L, Slagboom, PE, Slof-Op't Landt, MCT, Slopien, A, Sorbi, S, ?wi?tkowska, B, Szatkiewicz, JP, Tachmazidou, I, Tenconi, E, Tortorella, A, Tozzi, F, Treasure, J, Tsitsika, A, Tyszkiewicz-Nwafor, M, Tziouvas, K, van Elburg, AA, van Furth, EF, Wagner, G, Walton, E, Widen, E, Zeggini, E, Zerwas, S, Zipfel, S, Bergen, AW, Boden, JM, Brandt, H, Crawford, S, Halmi, KA, Horwood, LJ, Johnson, C, Kaplan, AS, Kaye, WH, Mitchell, J E, Olsen, CM, Pearson, JF, Pedersen, NL, Strober, M, Werge, T, Whiteman, DC, Woodside, DB, Grove, J, Henders, AK, Larsen, J T, Parker, R, Petersen, LV, Jordan, J, Kennedy, MA, Birgegård, A, Lichtenstein, P, Norring, C, Landén, M, Mortensen, PB, Polimanti, R, McClintick, JN, Adkins, AE, Aliev, F, Bacanu, SA, Batzler, A, Bertelsen, S, Biernacka, JM, Bigdeli, TB, Chen, L S, Clarke, TK, Degenhardt, F, Docherty, AR, Edwards, AC, Foo, JC, Fox, L, Frank, J, Hack, LM, Hartmann, AM, Hartz, SM, Heilmann-Heimbach, S, Hodgkinson, C, Hoffmann, P, Hottenga, JJ, Konte, B, Lahti, J, Lahti-Pulkkinen, M, Lai, D, Ligthart, L, Loukola, A, Maher, BS, Mbarek, H, McIntosh, AM, McQueen, MB, Meyers, JL, Milaneschi, Y, Palviainen, T, Peterson, RE, Ryu, E, Saccone, N L, Salvatore, JE, Sanchez-Roige, S, Schwandt, M, Sherva, R, Streit, F, Strohmaier, J, Thomas, N, Wang, JCY, Webb, BT, Wedow, R, Wetherill, L, Wills, AG, Zhou, H, Boardman, JD, Chen, D, Choi, D S, Copeland, WE, Culverhouse, RC, Dahmen, N, Degenhardt, L, Domingue, BW, Frye, MA, Gäebel, W, Hayward, C, Ising, M, Keyes, M, Kiefer, F, Koller, G, Kramer, J (John), Kuperman, S, Lucae, S, Lynskey, MT, Maier, W, Mann, K, Männistö, S, Müller-Myhsok, B, Murray, AD, Nurnberger, JI, Preuss, U, Räikkönen, K, Reynolds, MD, Ridinger, M, Scherbaum, N, Schuckit, MA, Soyka, M, Treutlein, J, Witt, SH, Wodarz, N, Zill, P, Adkins, DE, Boomsma, DI, Bierut, LJ, Brown, S, Bucholz, KK, Costello, EJ, Wit, HJ, Diazgranados, N, Eriksson, JG, Farrer, LA, Foroud, TM, Gillespie, NA, Goate, AM, Goldman, D, Grucza, RA, Hancock, DB, Harris, KM, Hesselbrock, V, Hewitt, JK, Hopfer, CJ, Iacono, WG, Johnson, E O, Karpyak, VM, Kendler, KS, Kranzler, HR, Krauter, K, Lind, PA, McGue, M, MacKillop, J, Madden, PA, Maes, HH, Magnusson, PKE, Nelson, EC, Nöthen, MM, Palmer, AA, Penninx, BWJH, Porjesz, B, Rice, JP, Rietschel, M, Riley, BP, Rose, RJ, Shen, PH, Silberg, J, Stallings, MC, Tarter, RE, Vanyukov, MM, Vrieze, S, Wall, TL, Whitfield, JB, Zhao, H, Neale, BM, Wade, TD, Heath, AC, Montgomery, GW, Martin, NG, Sullivan, PF, Kaprio, J, Breen, G, Gelernter, J, Edenberg, HJ, Bulik, CM, and Agrawal, A

Abstract

Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [rg], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (rg = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (rg = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (rg = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (rgs = −0.19 to −0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotyp

Published
2021

14. Association Between Levels of Hormones and Risk of Esophageal Adenocarcinoma and Barrett's Esophagus

Author

Xie, S-H, Fang, R, Huang, M, Dai, J, Thrift, AP, Anderson, LA, Chow, W-H, Bernstein, L, Gammon, MD, Risch, HA, Shaheen, NJ, Reid, BJ, Wu, AH, Iyer, PG, Liu, G, Corley, DA, Whiteman, DC, Caldas, C, Pharoah, PD, Hardie, LJ, Fitzgerald, RC, Shen, H, Vaughan, TL, and Lagergren, J

Abstract

Background & Aims Esophageal adenocarcinoma (EAC) occurs most frequently in men. We performed a Mendelian randomization analysis to investigate whether genetic factors that regulate levels of sex hormones associated with risk of EAC or Barrett’s esophagus (BE). Methods We conducted a Mendelian randomization analysis using data from patients with EAC (n=2488) or BE (n=3247) and control participants (n=2127), included in international consortia of genome-wide association studies in Australia, Europe, and North America. Genetic risk scores or single nucleotide variants were used as instrumental variables for 9 specific sex hormones. Logistic regression provided odds ratios (ORs) with 95% CIs. Results Higher genetically predicted levels of follicle stimulating hormones were associated with increased risks of EAC and/or BE in men (OR, 1.14 per allele increase; 95% CI, 1.01-1.27) and in women (OR, 1.28; 95% CI, 1.03-1.59). Higher predicted levels of luteinizing hormone were associated with a decreased risk of EAC in men (OR, 0.92 per standard deviation increase; 95% CI, 0.87-0.99) and in women (OR, 0.93; 95% CI, 0.79-1.09), and decreased risks of BE (OR, 0.88; 95% CI, 0.77-0.99) and EAC and/or BE (OR, 0.89; 95% CI, 0.79-1.00) in women. We found no clear associations for other hormones studied, including sex hormone-binding globulin, dehydroepiandrosterone sulphate, testosterone, dihydrotestosterone, estradiol, progesterone, or free androgen index. Conclusions In a Mendelian randomization analysis of data from patients with EAC or BE, we found an association between genetically predicted levels of follicle stimulating and luteinizing hormones and risk of BE and EAC.

Published
2020

15. Germline variants are associated with increased primary melanoma tumor thickness at diagnosis

Author

Mangantig, E, MacGregor, S, Iles, MM, Scolyer, RA, Cust, AE, Hayward, NK, Montgomery, GW, Duffy, DL, Thompson, JF, Henders, A, Bowdler, L, Rowe, C, Cadby, G, Mann, GJ, Whiteman, DC, Long, GV, Ward, SV, Khosrotehrani, K, Barrett, JH, and Law, MH

Abstract

Germline genetic variants have been identified, which predispose individuals and families to develop melanoma. Tumor thickness is the strongest predictor of outcome for clinically localized primary melanoma patients. We sought to determine whether there is a heritable genetic contribution to variation in tumor thickness. If confirmed, this will justify the search for specific genetic variants influencing tumor thickness. To address this, we estimated the proportion of variation in tumor thickness attributable to genome-wide genetic variation (variant-based heritability) using unrelated patients with measured primary cutaneous melanoma thickness. As a secondary analysis, we conducted a genome-wide association study (GWAS) of tumor thickness. The analyses utilized 10 604 individuals with primary cutaneous melanoma drawn from nine GWAS datasets from eight cohorts recruited from the general population, primary care and melanoma treatment centers. Following quality control and filtering to unrelated individuals with study phenotypes, 8125 patients were used in the primary analysis to test whether tumor thickness is heritable. An expanded set of 8505 individuals (47.6% female) were analyzed for the secondary GWAS meta-analysis. Analyses were adjusted for participant age, sex, cohort and ancestry. We found that 26.6% (SE 11.9%, P = 0.0128) of variation in tumor thickness is attributable to genome-wide genetic variation. While requiring replication, a chromosome 11 locus was associated (P

Published
2020

16. Does polygenic risk influence associations between sun exposure and melanoma?: a prospective cohort analysis

Author

Olsen, CM, Pandeya, N, Law, MH, MacGregor, S, Iles, MM, Thompson, BS, Green, AC, Neale, RE, Whiteman, DC, and The QSkin Study

Abstract

Melanoma develops as the result of complex interactions between sun exposure and genetic factors. Data on these interactions from prospective studies are scant however. We aimed to quantify the association between ambient and personal ultraviolet (UV) exposure and incident melanoma in a large population‐based prospective study of men and women residing in a high ambient UV setting, and to examine potential gene‐environment interactions. Among participants with genetic data (n=15,373), 420 (2.7%) developed cutaneous melanoma (173 invasive, 247 in situ) during a median follow‐up time of 4.4 years. Country of birth, age at migration, having greater than 50 sunburns in childhood/adolescence and a history of keratinocyte cancer/actinic lesions were significantly associated with melanoma risk. An interaction with polygenic risk was suggested; among people at low polygenic risk, markers of cumulative sun exposure (as measured by actinic damage) were associated with melanoma. In contrast, among people at high polygenic risk, markers of high‐level early life ambient exposure (as measured by place of birth) were associated with melanoma (HR for born in Australia vs. overseas 3.16, 95% CI 1.39‐7.22). These findings suggest interactions between genotype and environment that are consistent with divergent pathways for melanoma development.

Published
2020

17. Body mass index and height and risk of cutaneous melanoma: Mendelian randomization analyses

Author

Dusingize, JC, Olsen, CM, An, J, Pandeya, N, Law, MH, Thompson, BS, Goldstein, AM, Iles, MM, Webb, PM, Neale, RE, Ong, J-S, MacGregor, S, and Whiteman, DC

Abstract

Background Height and body mass index (BMI) have both been positively associated with melanoma risk, although findings for BMI have been less consistent than height. It remains unclear, however, whether these associations reflect causality or are due to residual confounding by environmental and lifestyle risk factors. We re-evaluated these associations using a two-sample Mendelian randomization (MR) approach. Methods We identified single nucleotide polymorphisms (SNPs) for BMI and height from separate genome-wide association study (GWAS) meta-analyses. We obtained melanoma SNPs from the most recent melanoma GWAS meta-analysis comprising 12 874 cases and 23 203 controls. We used the inverse variance-weighted estimator to derive separate causal risk estimates across all SNP instruments for BMI and height. Results Based on the combined estimate derived from 730 SNPs for BMI, we found no evidence of an association between genetically predicted BMI and melanoma [odds ratio (OR) per one standard deviation (1 SD) (4.6 kg/m2) increase in BMI 1.00, 95% confidence interval (CI): 0.91–1.11]. In contrast, we observed a positive association between genetically-predicted height (derived from a pooled estimate of 3290 SNPs) and melanoma risk [OR 1.08, 95% CI: 1.02–1.13, per 1 SD (9.27 cm) increase in height]. Sensitivity analyses using two alternative MR methods yielded similar results. Conclusions These findings provide no evidence for a causal association between higher BMI and melanoma, but support the notion that height is causally associated with melanoma risk. Mechanisms through which height influences melanoma risk remain unclear, and it remains possible that the effect could be mediated through diverse pathways including growth factors and even socioeconomic status.

Published
2020

18. Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility

Author

Landi MT, Bishop DT, MacGregor S, Machiela MJ, Stratigos AJ, Ghiorzo P, Brossard M, Calista D, Choi J, Fargnoli MC, Zhang T, Rodolfo M, Trower AJ, Menin C, Martinez J, Hadjisavvas A, Song L, Stefanaki I, Scolyer R, Yang R, Goldstein AM, Potrony M, Kypreou KP, Pastorino L, Queirolo P, Pellegrini C, Cattaneo L, Zawistowski M, Gimenez-Xavier P, Rodriguez A, Elefanti L, Manoukian S, Rivoltini L, Smith BH, Loizidou MA, Del Regno L, Massi D, Mandala M, Khosrotehrani K, Akslen LA, Amos CI, Andresen PA, Avril MF, Azizi E, Soyer HP, Bataille V, Dalmasso B, Bowdler LM, Burdon KP, Chen WV, Codd V, Craig JE, Debniak T, Falchi M, Fang S, Friedman E, Simi S, Galan P, Garcia-Casado Z, Gillanders EM, Gordon S, Green A, Gruis NA, Hansson J, Harland M, Harris J, Helsing P, Henders A, Hocevar M, Höiom V, Hunter D, Ingvar C, Kumar R, Lang J, Lathrop GM, Lee JE, Li X, Lubinski J, Mackie RM, Malt M, Malvehy J, McAloney K, Mohamdi H, Molven A, Moses EK, Neale RE, Novakovic S, Nyholt DR, Olsson H, Orr N, Fritsche LG, Puig-Butille JA, Qureshi AA, Radford-Smith GL, Randerson-Moor J, Requena C, Rowe C, Samani NJ, Sanna M, Schadendorf D, Schulze HJ, Simms LA, Smithers M, Song F, Swerdlow AJ, van der Stoep N, Kukutsch NA, Visconti A, Wallace L, Ward SV, Wheeler L, Sturm RA, Hutchinson A, Jones K, Malasky M, Vogt A, Zhou W, Pooley KA, Elder DE, Han J, Hicks B, Hayward NK, Kanetsky PA, Brummett C, Montgomery GW, Olsen CM, Hayward C, Dunning AM, Martin NG, Evangelou E, Mann GJ, Long G, Pharoah PDP, Easton DF, Barrett JH, Cust AE, Abecasis G, Duffy DL, Whiteman DC, Gogas H, De Nicolo A, Tucker MA, Newton-Bishop JA, GenoMEL Consortium, Q-MEGA and QTWIN Investigators, ATHENS Melanoma Study Group, 23andMe, SDH Study Group, IBD Investigators, Essen-Heidelberg Investigators, AMFS Investigators, MelaNostrum Consortium, Peris K, Chanock SJ, Demenais F, Brown KM, Puig S, Nagore E, Shi J, Iles MM, and Law MH

Abstract

Meta-analysis of 36,760 cases and 375,188 controls identifies 54 loci associated with susceptibility to cutaneous melanoma. Further analysis combining nevus count and hair color GWAS results provide insights into the genetic architecture of melanoma. Most genetic susceptibility to cutaneous melanoma remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 cases of melanoma (67% newly genotyped) and 375,188 controls identified 54 significant (P < 5 x 10(-8)) loci with 68 independent single nucleotide polymorphisms. Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation. Combining this meta-analysis with GWAS of nevus count and hair color, and transcriptome association approaches, uncovered 31 potential secondary loci for a total of 85 cutaneous melanoma susceptibility loci. These findings provide insights into cutaneous melanoma genetic architecture, reinforcing the importance of nevogenesis, pigmentation and telomere maintenance, together with identifying potential new pathways for cutaneous melanoma pathogenesis.

Published
2020

19. From GWAS to genome sequencing: complementary approaches to identify melanoma predisposition genes

Author

MacGregor S, Brown KM, Stark M, Gartside M, Woods S, Bonazzi V, Aoude L, Dutton-Regester K, Tyagi S, Liu J, Duffy DL, Palmer J, Cust A, Schmid H, Symmons J, Holland E, Agha-Hamilton C, Holohan K, Youngkin D, Gillanders E, Jenkins MA, Kelly J, Whiteman DC, Kefford R, Giles G, Armstrong B, Aitken J, Hopper J, Montgomery G, Schmidt C, Trent JM, Martin NG, Mann GJ, and Hayward NK

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282, Genetics, QH426-470
Published
2012
Full Text
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20. Genome-wide association study identifies eight risk loci and implicates metabo-psychiatric origins for anorexia nervosa

Author

Watson HJ, Yilmaz Z, Thornton LM, Hübel C, Coleman JRI, Gaspar HA, Bryois J, Hinney A, Leppä VM, Mattheisen M, Medland SE, Ripke S, Yao S, Giusti-Rodríguez P, Anorexia Nervosa Genetics Initiative, Hanscombe KB, Purves KL, Eating Disorders Working Group of the Psychiatric Genomics Consortium, Adan RAH, Alfredsson L, Ando T, Andreassen OA, Baker JH, Berrettini WH, Boehm I, Boni C, Perica VB, Buehren K, Burghardt R, Cassina M, Cichon S, Clementi M, Cone RD, Courtet P, Crow S, Crowley JJ, Danner UN, Davis OSP, de Zwaan M, Dedoussis G, Degortes D, DeSocio JE, Dick DM, Dikeos D, Dina C, Dmitrzak-Weglarz M, Docampo E, Duncan LE, Egberts K, Ehrlich S, Escaramís G, Esko T, Estivill X, Farmer A, Favaro A, Fernández-Aranda F, Fichter MM, Fischer K, Föcker M, Foretova L, Forstner AJ, Forzan M, Franklin CS, Gallinger S, Giegling I, Giuranna J, Gonidakis F, Gorwood P, Mayora MG, Guillaume S, Guo Y, Hakonarson H, Hatzikotoulas K, Hauser J, Hebebrand J, Helder SG, Herms S, Herpertz-Dahlmann B, Herzog W, Huckins LM, Hudson JI, Imgart H, Inoko H, Janout V, Jiménez-Murcia S, Julià A, Kalsi G, Kaminská D, Kaprio J, Karhunen L, Karwautz A, Kas MJH, Kennedy JL, Keski-Rahkonen A, Kiezebrink K, Kim YR, Klareskog L, Klump KL, Knudsen GPS, La Via MC, Le Hellard S, Levitan RD, Li D, Lilenfeld L, Lin BD, Lissowska J, Luykx J, Magistretti PJ, Maj M, Mannik K, Marsal S, Marshall CR, Mattingsdal M, McDevitt S, McGuffin P, Metspalu A, Meulenbelt I, Micali N, Mitchell K, Monteleone AM, Monteleone P, Munn-Chernoff MA, Nacmias B, Navratilova M, Ntalla I, O'Toole JK, Ophoff RA, Padyukov L, Palotie A, Pantel J, Papezova H, Pinto D, Raquel Rabionet Janssen, Raevuori A, Ramoz N, Reichborn-Kjennerud T, Ricca V, Ripatti S, Ritschel F, Roberts M, Rotondo A, Rujescu D, Rybakowski F, Santonastaso P, Scherag A, Scherer SW, Schmidt U, Schork NJ, Schosser A, Seitz J, Slachtova L, Slagboom PE, Slof-Op 't Landt MCT, Slopien A, Sorbi S, Swiatkowska B, Szatkiewicz JP, Tachmazidou I, Tenconi E, Tortorella A, Tozzi F, Treasure J, Tsitsika A, Tyszkiewicz-Nwafor M, Tziouvas K, van Elburg AA, van Furth EF, Wagner G, Walton E, Widen E, Zeggini E, Zerwas S, Zipfel S, Bergen AW, Boden JM, Brandt H, Crawford S, Halmi KA, Horwood LJ, Johnson C, Kaplan AS, Kaye WH, Mitchell JE, Olsen CM, Pearson JF, Pedersen NL, Strober M, Werge T, Whiteman DC, Woodside DB, Stuber GD, Gordon S, Grove J, Henders AK, Juréus A, Kirk KM, Larsen JT, Parker R, Petersen L, Jordan J, Kennedy M, Montgomery GW, Wade TD, Birgegård A, Lichtenstein P, Norring C, Landén M, Martin NG, Mortensen PB, Sullivan PF, Breen G, and Bulik CM

Subjects
mental disorders
Abstract

Characterized primarily by a low body-mass index, anorexia nervosa is a complex and serious illness 1 , affecting 0.9-4% of women and 0.3% of men 2-4 , with twin-based heritability estimates of 50-60% 5 . Mortality rates are higher than those in other psychiatric disorders 6 , and outcomes are unacceptably poor 7 . Here we combine data from the Anorexia Nervosa Genetics Initiative (ANGI) 8,9 and the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED) and conduct a genome-wide association study of 16,992 cases of anorexia nervosa and 55,525 controls, identifying eight significant loci. The genetic architecture of anorexia nervosa mirrors its clinical presentation, showing significant genetic correlations with psychiatric disorders, physical activity, and metabolic (including glycemic), lipid and anthropometric traits, independent of the effects of common variants associated with body-mass index. These results further encourage a reconceptualization of anorexia nervosa as a metabo-psychiatric disorder. Elucidating the metabolic component is a critical direction for future research, and paying attention to both psychiatric and metabolic components may be key to improving outcomes.

Published
2019

22. Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways (vol 9, 4774, 2018)

Author

Duffy, DL, Zhu, G, Li, X, Sanna, M, Iles, MM, Jacobs, LC, Evans, DM, Yazar, S, Beesley, J, Law, MH, Kraft, P, Visconti, A, Taylor, JC, Liu, F, Wright, MJ, Henders, AK, Bowdler, L, Glass, D, Ikram, MA, Uitterlinden, AG, Madden, PA, Heath, AC, Nelson, EC, Green, AC, Chanock, S, Barrett, JH, Brown, MA, Hayward, NK, MacGregor, S, Sturm, RA, Hewitt, AW, Kayser, M, Hunter, DJ, Bishop, JAN, Spector, TD, Montgomery, GW, Mackey, DA, Smith, GD, Nijsten, TE, Bishop, DT, Bataille, V, Falchi, M, Han, J, Martin, NG, Lee, JE, Brossard, M, Moses, EK, Song, F, Kumar, R, Easton, DF, Pharoah, PDP, Swerdlow, AJ, Kypreou, KP, Harland, M, Randerson-Moor, J, Akslen, LA, Andresen, PA, Avril, M-F, Azizi, E, Scarra, GB, Brown, KM, Debniak, T, Elder, DE, Fang, S, Friedman, E, Galan, P, Ghiorzo, P, Gillanders, EM, Goldstein, AM, Gruis, NA, Hansson, J, Helsing, P, Hocevar, M, Hoiom, V, Ingvar, C, Kanetsky, PA, Chen, WV, Landi, MT, Lang, J, Lathrop, GM, Lubinski, J, Mackie, RM, Mann, GJ, Molven, A, Novakovic, S, Olsson, H, Puig, S, Puig-Butille, JA, Radford-Smith, GL, van der Stoep, N, van Doorn, R, Whiteman, DC, Craig, JE, Schadendorf, D, Simms, LA, Burdon, KP, Nyholt, DR, Pooley, KA, Orr, N, Stratigos, AJ, Cust, AE, Ward, SV, Schulze, H-J, Dunning, AM, Demenais, F, Amos, CI, Duffy, DL, Zhu, G, Li, X, Sanna, M, Iles, MM, Jacobs, LC, Evans, DM, Yazar, S, Beesley, J, Law, MH, Kraft, P, Visconti, A, Taylor, JC, Liu, F, Wright, MJ, Henders, AK, Bowdler, L, Glass, D, Ikram, MA, Uitterlinden, AG, Madden, PA, Heath, AC, Nelson, EC, Green, AC, Chanock, S, Barrett, JH, Brown, MA, Hayward, NK, MacGregor, S, Sturm, RA, Hewitt, AW, Kayser, M, Hunter, DJ, Bishop, JAN, Spector, TD, Montgomery, GW, Mackey, DA, Smith, GD, Nijsten, TE, Bishop, DT, Bataille, V, Falchi, M, Han, J, Martin, NG, Lee, JE, Brossard, M, Moses, EK, Song, F, Kumar, R, Easton, DF, Pharoah, PDP, Swerdlow, AJ, Kypreou, KP, Harland, M, Randerson-Moor, J, Akslen, LA, Andresen, PA, Avril, M-F, Azizi, E, Scarra, GB, Brown, KM, Debniak, T, Elder, DE, Fang, S, Friedman, E, Galan, P, Ghiorzo, P, Gillanders, EM, Goldstein, AM, Gruis, NA, Hansson, J, Helsing, P, Hocevar, M, Hoiom, V, Ingvar, C, Kanetsky, PA, Chen, WV, Landi, MT, Lang, J, Lathrop, GM, Lubinski, J, Mackie, RM, Mann, GJ, Molven, A, Novakovic, S, Olsson, H, Puig, S, Puig-Butille, JA, Radford-Smith, GL, van der Stoep, N, van Doorn, R, Whiteman, DC, Craig, JE, Schadendorf, D, Simms, LA, Burdon, KP, Nyholt, DR, Pooley, KA, Orr, N, Stratigos, AJ, Cust, AE, Ward, SV, Schulze, H-J, Dunning, AM, Demenais, F, and Amos, CI

Abstract

The original version of this Article contained errors in the spelling of the authors Fan Liu and M. Arfan Ikram, which were incorrectly given as Fan Lui and Arfan M. Ikram. In addition, the original version of this Article also contained errors in the author affiliations which are detailed in the associated Publisher Correction.

Published
2019

23. A randomized placebo-controlled trial of vitamin D supplementation for reduction of mortality and cancer: Statistical analysis plan for the D-Health Trial

Author

Waterhouse, M, English, DR, Armstrong, BK, Baxter, C, Romero, BD, Ebeling, PR, Hartel, G, Kimlin, MG, McLeod, DSA, O'Connell, RL, van der Pols, JC, Venn, AJ, Webb, PM, Whiteman, DC, Neale, RE, Waterhouse, M, English, DR, Armstrong, BK, Baxter, C, Romero, BD, Ebeling, PR, Hartel, G, Kimlin, MG, McLeod, DSA, O'Connell, RL, van der Pols, JC, Venn, AJ, Webb, PM, Whiteman, DC, and Neale, RE

Abstract

BACKGROUND: Many observational studies have reported an association between vitamin D and non-skeletal health outcomes. The D-Health Trial was launched to determine if supplementing the older population with high monthly doses of Vitamin D can prevent cancer and premature mortality. The intervention is ongoing but here we provide a detailed statistical analysis plan for the primary and secondary outcomes of the D-Health Trial. METHODS/DESIGN: The D-Health Trial is a double-blind, randomized, placebo-controlled trial. Between February 2014 and May 2015, 21,315 people were randomized in a 1:1 ratio to receive monthly doses of either 60,000 IU of cholecalciferol (vitamin D3) or placebo for five years. The primary outcome is all-cause mortality and the secondary outcomes are total cancer incidence and colorectal cancer incidence. These will be ascertained via linkage to death and cancer registries. The primary analysis for each outcome will follow an intention-to-treat approach; we will use flexible parametric survival models to investigate the association between supplementation and time to an event. We describe in detail sophisticated secondary analyses that consider non-compliance and contamination due to off-study supplementation. CONCLUSIONS: Publication of this statistical analysis plan in advance of the intervention's completion, and adherence to it, will avoid data-driven analyses of the primary and secondary outcomes and ensure robust reporting of outcomes. CLINICAL TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry: ACTRN12613000743763. Registered on 4 July 2013.

Published
2019

24. Gastroesophageal reflux GWAS identifies risk loci that also associate with subsequent severe esophageal diseases

Author

An, J, Gharahkhani, P, Law, MH, Ong, J-S, Han, X, Olsen, CM, Neale, RE, Lai, J, Vaughan, TL, Bohmer, AC, Jankowski, J, Fitzgerald, RC, Schumacher, J, Palles, C, Whiteman, DC, MacGregor, S, Gammon, MD, Corley, DA, Shaheen, NJ, Bird, NC, Hardie, LJ, Murray, LJ, Reid, BJ, Chow, W-H, Risch, HA, Ye, W, Liu, G, Romero, Y, Bernstein, L, Wu, AH, Agee, M, Alipanahi, B, Auton, A, Bell, RK, Bryc, K, Elson, SL, Fontanillas, P, Furlotte, NA, Hinds, DA, Huber, KE, Kleinman, A, Litterman, NK, McIntyre, MH, Mountain, JL, Noblin, ES, Northover, CAM, Pitts, SJ, Sathirapongsasuti, JF, Sazonova, OV, Shelton, JF, Shringarpure, S, Tian, C, Tung, JY, Vacic, V, Wilson, CH, An, J, Gharahkhani, P, Law, MH, Ong, J-S, Han, X, Olsen, CM, Neale, RE, Lai, J, Vaughan, TL, Bohmer, AC, Jankowski, J, Fitzgerald, RC, Schumacher, J, Palles, C, Whiteman, DC, MacGregor, S, Gammon, MD, Corley, DA, Shaheen, NJ, Bird, NC, Hardie, LJ, Murray, LJ, Reid, BJ, Chow, W-H, Risch, HA, Ye, W, Liu, G, Romero, Y, Bernstein, L, Wu, AH, Agee, M, Alipanahi, B, Auton, A, Bell, RK, Bryc, K, Elson, SL, Fontanillas, P, Furlotte, NA, Hinds, DA, Huber, KE, Kleinman, A, Litterman, NK, McIntyre, MH, Mountain, JL, Noblin, ES, Northover, CAM, Pitts, SJ, Sathirapongsasuti, JF, Sazonova, OV, Shelton, JF, Shringarpure, S, Tian, C, Tung, JY, Vacic, V, and Wilson, CH

Abstract

Gastroesophageal reflux disease (GERD) is caused by gastric acid entering the esophagus. GERD has high prevalence and is the major risk factor for Barrett's esophagus (BE) and esophageal adenocarcinoma (EA). We conduct a large GERD GWAS meta-analysis (80,265 cases, 305,011 controls), identifying 25 independent genome-wide significant loci for GERD. Several of the implicated genes are existing or putative drug targets. Loci discovery is greatest with a broad GERD definition (including cases defined by self-report or medication data). Further, 91% of the GERD risk-increasing alleles also increase BE and/or EA risk, greatly expanding gene discovery for these traits. Our results map genes for GERD and related traits and uncover potential new drug targets for these conditions.

Published
2019

26. Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways

Author

Duffy, David L, Zhu, Gu, Xin, Li, Sanna, Marianna, Iles, Mark M, Jacobs, Leonie C, Evans, David M, Yazar, Seyhan, Beesley, Jonathan, Law, Matthew H, Kraft, Peter, Visconti, Alessia, Taylor, John C, Lui, Fan, Wright, Margaret J, Henders, Anjali K, Bowdler, Lisa, Glass, Dan, Ikram, Arfan M, Uitterlinden, André G, Madden, Pamela A, Heath, Andrew C, Nelson, Elliot C, Green, Adele C, Chanock, Stephen, Barrett, Jennifer H, Brown, Matthew A, Hayward, Nicholas K, Macgregor, Stuart, Sturm, Richard A, Hewitt, Alex W, Kayser, Manfred, Hunter, David J, Newton Bishop, Julia A, Spector, Timothy D, Montgomery, Grant W, Mackey, David A, Smith, George Davey, Nijsten, Tamar E, Bishop, D Timothy, Bataille, Veronique, Falchi, Mario, Han, Jiali, Martin, Nicholas, G, Lee, Je, Brossard, M, Moses, Ek, Song, F, Kumar, R, Easton, Df, Pharoah, Pdp, Swerdlow, Aj, Kypreou, Kp, Harland, M, Randerson-Moor, J, Akslen, La, Andresen, Pa, Avril, Mf, Azizi, E, Scarrà, Gb, Brown, Km, Dębniak, T, Elder, De, Fang, S, Friedman, E, Galan, P, Ghiorzo, P, Gillanders, Em, Goldstein, Am, Gruis, Na, Hansson, J, Helsing, P, Hočevar, M, Höiom, V, Ingvar, C, Kanetsky, Pa, Chen, Wv, Landi, Mt, Lang, J, Lathrop, Gm, Lubiński, J, Mackie, Rm, Mann, Gj, Molven, A, Novaković, S, Olsson, H, Puig, S, Puig-Butille, Ja, Radford-Smith, Gl, van der Stoep, N, van Doorn, R, Whiteman, Dc, Craig, Je, Schadendorf, D, Simms, La, Burdon, Kp, Nyholt, Dr, Pooley, Ka, Orr, N, Stratigos, Aj, Cust, Ae, Ward, Sv, Schulze, Hj, Dunning, Am, Demenais, F, Amos, Ci., Apollo - University of Cambridge Repository, Dermatology, Genetic Identification, Epidemiology, Internal Medicine, and Consortium, Melanoma Gwas

Subjects
0301 basic medicine, Skin Neoplasms, Medizin, General Physics and Astronomy, Genome-wide association study, Receptors, G-Protein-Coupled, 0302 clinical medicine, Guanine Nucleotide Exchange Factors, lcsh:Science, skin and connective tissue diseases, Melanoma, Telomerase, Genetics, 0303 health sciences, Nevus, Pigmented, Stem Cell Factor, Multidisciplinary, Microfilament Proteins, Nuclear Proteins, RNA-Binding Proteins, Genetic Pleiotropy, Microphthalmia-associated transcription factor, 3. Good health, 030220 oncology & carcinogenesis, Cytochrome P-450 CYP1B1, Interferon Regulatory Factors, Medical genetics, PPARGC1B, Dock8, medicine.medical_specialty, Science, Telomere-Binding Proteins, Single-nucleotide polymorphism, Nerve Tissue Proteins, Biology, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Histone Deacetylases, White People, Group VI Phospholipases A2, 03 medical and health sciences, Genetic predisposition, Pigmented Nevus, medicine, Nevus, Humans, Genetic Predisposition to Disease, neoplasms, 030304 developmental biology, General Chemistry, medicine.disease, Repressor Proteins, MicroRNAs, 030104 developmental biology, Cutaneous melanoma, RNA, lcsh:Q, Carrier Proteins, IRF4, Genome-Wide Association Study
Abstract

The total number of acquired melanocytic nevi on the skin is strongly correlated with melanoma risk. Here we report a meta-analysis of 11 nevus GWAS from Australia, Netherlands, United Kingdom, and United States, comprising a total of 52,506 phenotyped individuals. We confirm known loci including MTAP, PLA2G6, and IRF4, and detect novel SNPs at a genome-wide level of significance in KITLG, DOCK8, and a broad region of 9q32. In a bivariate analysis combining the nevus results with those from a recent melanoma GWAS meta-analysis (12,874 cases, 23,203 controls), SNPs near GPRC5A, CYP1B1, PPARGC1B, HDAC4, FAM208B and SYNE2 reached global significance, and other loci, including MIR146A and OBFC1, reached a suggestive level of significance. Overall, we conclude that most nevus genes affect melanoma risk (KITLG an exception), while many melanoma risk loci do not alter nevus count. For example, variants in TERC and OBFC1 affect both traits, but other telomere length maintenance genes seem to affect melanoma risk only. Our findings implicate multiple pathways in nevogenesis via genes we can show to be expressed under control of the MITF melanocytic cell lineage regulator.

Published
2018

27. Cell-type–specific eQTL of primary melanocytes facilitates identification of melanoma susceptibility genes

Author

Zhang, Tongwu, Choi, Jiyeon, Kovacs, Michael A., Shi, Jianxin, Mai, Xu, Goldstein, Alisa M., Trower, Adam J., Bishop, D. Timothy, Iles, Mark M., Duffy, David L., Macgregor, Stuart, Amundadottir, Laufey T., Law, Matthew H., Loftus, Stacie K., Pavan, William J., Brown, Kevin M., Lee, Je, Brossard, M, Martin, Ng, Moses, Ek, Song, F, Barrett, Jh, Kumar, R, Easton, Df, Pharoah, Pdp, Swerdlow, Aj, Kypreou, Kp, Taylor, Jc, Harland, M, Randerson-Moor, J, Akslen, La, Andresen, Pa, Avril, Mf, Azizi, E, Bianchi Scarrà, G, Dȩbniak, T, Duffy, Dl, Elder, De, Fang, S, Friedman, E, Galan, P, Ghiorzo, P, Gillanders, Em, Goldstein, Am, Gruis, Na, Hansson, J, Helsing, P, Hočevar, M, Höiom, V, Ingvar, C, Kanetsky, Pa, Chen, Wv, Landi, Mt, Lang, J, Lathrop, Gm, Lubiński, J, Mackie, Rm, Mann, Gj, Molven, A, Montgomery, Gw, Novaković, S, Olsson, H, Puig, S, Puig-Butille, Ja, Wu, W, Qureshi, Aa, Radford-Smith, Gl, van der Stoep, N, van Doorn, R, Whiteman, Dc, Craig, Je, Schadendorf, D, Simms, La, Burdon, Kp, Nyholt, Dr, Pooley, Ka, Orr, N, Stratigos, Aj, Cust, Ae, Ward, Sv, Hayward, Nk, Han, J, Schulze, Hj, Dunning, Am, Bishop, Jan, Demenais, F, Amos, Ci, Macgregor, S, Iles, Mm, Barnabas, Bb, Bouffard, Gg, Brooks, Sy, Coleman, H, Dekhtyar, L, Guan, X, Ho, Sl, Legaspi, R, Maduro, Ql, Masiello, Ca, Mcdowell, Jc, Montemayor, C, Mullikin, Jc, Park, M, Riebow, Nl, Schandler, K, Schmidt, B, Sison, C, Smith, R, Stantripop, S, Thomas, Jw, Thomas, Pj, Vemulapalli, M, and Young, Ac.

Subjects
0301 basic medicine, Hemeproteins, Linkage disequilibrium, Quantitative Trait Loci, Single-nucleotide polymorphism, Genome-wide association study, Biology, Quantitative trait locus, Melanocyte, Polymorphism, Single Nucleotide, Linkage Disequilibrium, 03 medical and health sciences, Heme-Binding Proteins, 0302 clinical medicine, Genetics, medicine, Basic Helix-Loop-Helix Transcription Factors, Humans, Genetic Predisposition to Disease, Melanoma, Genetics (clinical), Cells, Cultured, Genetic association, Research, medicine.disease, Repressor Proteins, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Expression quantitative trait loci, Interferon Regulatory Factors, Melanocytes, Carrier Proteins
Abstract

Most expression quantitative trait locus (eQTL) studies to date have been performed in heterogeneous tissues as opposed to specific cell types. To better understand the cell-type–specific regulatory landscape of human melanocytes, which give rise to melanoma but account for cis-eQTL SNPs prior to linkage disequilibrium (LD) pruning and 4997 eGenes (FDR < 0.05). Melanocyte eQTLs differed considerably from those identified in the 44 GTEx tissue types, including skin. Over a third of melanocyte eGenes, including key genes in melanin synthesis pathways, were unique to melanocytes compared to those of GTEx skin tissues or TCGA melanomas. The melanocyte data set also identified trans-eQTLs, including those connecting a pigmentation-associated functional SNP with four genes, likely through cis-regulation of IRF4. Melanocyte eQTLs are enriched in cis-regulatory signatures found in melanocytes as well as in melanoma-associated variants identified through genome-wide association studies. Melanocyte eQTLs also colocalized with melanoma GWAS variants in five known loci. Finally, a transcriptome-wide association study using melanocyte eQTLs uncovered four novel susceptibility loci, where imputed expression levels of five genes (ZFP90, HEBP1, MSC, CBWD1, and RP11-383H13.1) were associated with melanoma at genome-wide significant P-values. Our data highlight the utility of lineage-specific eQTL resources for annotating GWAS findings, and present a robust database for genomic research of melanoma risk and melanocyte biology.

Published
2018

28. Interactions Between Genetic Variants and Environmental Factors Affect Risk of Esophageal Adenocarcinoma and Barrett's Esophagus

Author

Dong, J, Levine, DM, Buas, MF, Zhang, R, Onstad, L, Fitzgerald, RC, Stomach and Oesophageal Cancer Study (SOCS) Consortium, Corley, DA, Shaheen, NJ, Lagergren, J, Hardie, LJ, Reid, BJ, Iyer, PG, Risch, HA, Caldas, C, Caldas, I, Pharoah, PD, Liu, G, Gammon, MD, Chow, W-H, Bernstein, L, Bird, NC, Ye, W, Wu, AH, Anderson, LA, MacGregor, S, Whiteman, DC, Vaughan, TL, Thrift, AP, Fitzgerald, Rebecca [0000-0002-3434-3568], Caldas, Carlos [0000-0003-3547-1489], Pharoah, Paul [0000-0001-8494-732X], and Apollo - University of Cambridge Repository

Subjects
Male, Esophageal Neoplasms, Genetic Variants, Environmental Exposure, Adenocarcinoma, Middle Aged, Polymorphism, Single Nucleotide, Risk Assessment, United Kingdom, Barrett Esophagus, Esophagus, SDG 3 - Good Health and Well-being, Risk Factors, Humans, Female, Genetic Predisposition to Disease, Esophageal Neoplasm, Aged, Genome-Wide Association Study
Abstract

Background & Aims: Genome-wide association studies (GWAS) have identified more than 20 susceptibility loci for esophageal adenocarcinoma (EA) and Barrett’s esophagus (BE). However, variants in these loci account for a small fraction of cases of EA and BE. Genetic factors might interact with environmental factors to affect risk of EA and BE. We aimed to identify single nucleotide polymorphisms (SNPs) that may modify the associations of body mass index (BMI), smoking, and gastroesophageal reflux disease (GERD), with risks of EA and BE. Methods: We collected data on single BMI measurements, smoking status, and symptoms of GERD from 2284 patients with EA, 3104 patients with BE, and 2182 healthy individuals (controls) participating in the Barrett’s and Esophageal Adenocarcinoma Consortium GWAS, the UK Barrett’s Esophagus Gene Study, and the UK Stomach and Oesophageal Cancer Study. We analyzed 993,501 SNPs in DNA samples of all study subjects. We used standard case–control logistic regression to test for gene-environment interactions. Results: For EA, rs13429103 at chromosome 2p25.1, near the RNF144A-LOC339788 gene, showed a borderline significant interaction with smoking status (P=2.18×10-7). Ever smoking was associated with an almost 12-fold increase in risk of EA among individuals with rs13429103-AA genotype (odds ratio=11.82; 95% CI, 4.03–34.67). Three SNPs (rs12465911, rs2341926, rs13396805) at chromosome 2q23.3, near the RND3-RBM43 gene, interacted with GERD symptoms (P=1.70×10-7, P=1.83×10-7, and P=3.58×10-7, respectively) to affect risk of EA. For BE, rs491603 at chromosome 1p34.3, near the EIF2C3 gene, and rs11631094 at chromosome 15q14, at the SLC12A6 gene, interacted with BMI (P=4.44×10-7) and pack-years of smoking history (P=2.82×10-7), respectively. Conclusion: The associations of BMI, smoking, and GERD symptoms with risks of EA and BE appear to vary with SNPs at chromosomes 1, 2, and 15. Validation of these suggestive interactions is warranted.

Published
2018

29. Analysis combining correlated glaucoma traits identifies five new risk loci for open-angle glaucoma

Author

Gharahkhani, P, Burdon, KP, Bailey, JNC, Hewitt, AW, Law, MH, Pasquale, LR, Kang, JH, Haines, JL, Souzeau, E, Zhou, T, Siggs, OM, Landers, J, Awadalla, M, Sharma, S, Mills, RA, Ridge, B, Lynn, D, Casson, R, Graham, SL, Goldberg, I, White, A, Healey, PR, Grigg, J, Lawlor, M, Mitchell, P, Ruddle, J, Coote, M, Walland, M, Best, S, Vincent, A, Gale, J, RadfordSmith, G, Whiteman, DC, Montgomery, GW, Martin, NG, Mackey, DA, Wiggs, JL, MacGregor, S, Craig, JE, Gharahkhani, P, Burdon, KP, Bailey, JNC, Hewitt, AW, Law, MH, Pasquale, LR, Kang, JH, Haines, JL, Souzeau, E, Zhou, T, Siggs, OM, Landers, J, Awadalla, M, Sharma, S, Mills, RA, Ridge, B, Lynn, D, Casson, R, Graham, SL, Goldberg, I, White, A, Healey, PR, Grigg, J, Lawlor, M, Mitchell, P, Ruddle, J, Coote, M, Walland, M, Best, S, Vincent, A, Gale, J, RadfordSmith, G, Whiteman, DC, Montgomery, GW, Martin, NG, Mackey, DA, Wiggs, JL, MacGregor, S, and Craig, JE

Abstract

Open-angle glaucoma (OAG) is a major cause of blindness worldwide. To identify new risk loci for OAG, we performed a genome-wide association study in 3,071 OAG cases and 6,750 unscreened controls, and meta-analysed the results with GWAS data for intraocular pressure (IOP) and optic disc parameters (the overall meta-analysis sample size varying between 32,000 to 48,000 participants), which are glaucoma-related traits. We identified and independently validated four novel genome-wide significant associations within or near MYOF and CYP26A1, LINC02052 and CRYGS, LMX1B, and LMO7 using single variant tests, one additional locus (C9) using gene-based tests, and two genetic pathways - "response to fluid shear stress" and "abnormal retina morphology" - in pathway-based tests. Interestingly, some of the new risk loci contribute to risk of other genetically-correlated eye diseases including myopia and age-related macular degeneration. To our knowledge, this study is the first integrative study to combine genetic data from OAG and its correlated traits to identify new risk variants and genetic pathways, highlighting the future potential of combining genetic data from genetically-correlated eye traits for the purpose of gene discovery and mapping.

Published
2018

30. Large scale meta-analysis identifies new genetic risk loci for esophageal adenocarcinoma (EA) and the first EA risk locus independent of Barrett’s esophagus

Author

Palles, C, Tomlinson, I, Chegwidden, L, Gharahkhani, P, MacGregor, S, Vaughan, TL, Schumacher, J, Jankowski, J, Fitzgerald, R, Gockel, I, Buas, M, Knapp, M, Noethen, MM, Becker, J, Pharaoh, P, and Whiteman, DC

Abstract

Esophageal adenocarcinoma (EA) is an often fatal cancer with rising incidence in the developed world. Barrett’s esophagus (BE) is a pre-cancerous metaplastic precursor of EA. We performed the first genome-wide association study (GWAS) meta-analysis for BE and EA to date, using 6,167 BE cases, 4,112 EA cases, and 17,159 unscreened controls, all of European descent. We identified eight new genome-wide significant associated (P

Published
2016

31. Genome-wide association study identifies novel loci predisposing to cutaneous melanoma†

Author

Amos, Ci, Wang, Le, Lee, Je, Gershenwald, Je, Chen, Wv, Fang, S, Kosoy, R, Zhang, M, Qureshi, Aa, Vattathil, S, Schacherer, Cw, Gardner, Jm, Wang, Y, Bishop, Dt, Barrett, Jh, Macgregor, S, Hayward, Nk, Martin, Ng, Duffy, Dl, Mann, Gj, Cust, A, Hopper, J, Brown, Km, Grimm, Ea, Xu, Y, Han, Y, Jing, K, Mchugh, C, Laurie, Cc, Doheny, Kf, Pugh, Ew, Seldin, Mf, Han, J, Wei, Q, Genomel, Investigators, Mega Investigators, Q., AMFS Investigators Mann GJ, Hopper, Jl, Aitken, Jf, Armstrong, Bk, Giles, Gg, Kefford, Rf, Cust, Ae, Jenkins, Ma, Schmid, H, Aguilera, P, Badenas, C, Carrera, C, Cuellar, F, Gabriel, D, Martinez, E, Gonzalez, M, Iglesias, P, Malvehy, J, Marti Laborda, R, Mila, M, Ogbah, Z, Butille, Ja, Puig, S, Alós, L, Arance, A, Arguís, P, Campo, A, Castel, T, Conill, C, Palou, J, Rull, R, Sánchez, M, Vidal Sicart, S, Vilalta, A, Vilella, R, Montgomery, Gw, Whiteman, Dc, Whiteman, D, Webb, P, Green, A, Parsons, P, Purdie, D, Hayward, N, Landi, Mt, Calista, D, Landi, G, Minghetti, P, Arcangeli, F, Bertazzi, Pa, Bianchi, Giovanna, Ghiorzo, Paola, Pastorino, Lorenza, Bruno, William, Battistuzzi, Linda, Gargiulo, Sara, Nasti, Sabina, Gliori, S, Origone, Paola, Andreotti, V, Queirolo, P, Mackie, R, Lang, J, Bishop, Ja, Affleck, P, Harrison, J, Iles, Mm, Randerson Moor, J, Harland, M, Taylor, Jc, Whittaker, L, Kukalizch, K, Leake, S, Karpavicius, B, Haynes, S, Mack, T, Chan, M, Taylor, Y, Davies, J, King, P, Gruis, Na, van Nieuwpoort FA, Out, C, van der Drift, C, Bergman, W, Kukutsch, N, Bavinck, Jn, Bakker, B, van der Stoep, N, ter Huurne, J, van der Rhee, H, Bekkenk, M, Snels, D, van Praag, M, Brochez, L, Gerritsen, R, Crijns, M, Vasen, H, Olsson, H, Ingvar, C, Jönsson, G, Borg, Å, Måsbäck, A, Lundgren, L, Baeckenhorn, K, Nielsen, K, Casslén, As, Helsing, P, Andresen, Pa, Rootwelt, H, Akslen, La, Molven, A, Avril, Mf, Bressac de Paillerets, B, Chaudru, V, Chateigner, N, Corda, E, Jeannin, P, Lesueur, F, de Lichy, M, Maubec, E, Mohamdi, H, Demenais, F, Andry Benzaquen, P, Bachollet, B, Bérard, F, Berthet, P, Boitier, F, Bonadona, V, Bonafé, Jl, Bonnetblanc, Jm, Cambazard, F, Caron, O, Caux, F, Chevrant Breton, J, Chompret, A, Dalle, S, Demange, L, Dereure, O, Doré, Mx, Doutre, Ms, Dugast, C, Faivre, L, Grange, F, Humbert, P, Joly, P, Kerob, D, Lasset, C, Leccia, Mt, Lenoir, G, Leroux, D, Levang, J, Lipsker, D, Mansard, S, Martin, L, Martin Denavit, T, Mateus, C, Michel, Jl, Morel, P, Olivier Faivre, L, Perrot, Jl, Robert, C, Ronger Savle, S, Sassolas, B, Souteyrand, P, Stoppa Lyonnet, D, Thomas, L, Vabres, P, Wierzbicka, E, Elder, D, Kanetsky, P, Knorr, J, Ming, M, Mitra, N, Ruffin, A, Van Belle, P, Debniak, T, Lubiński, J, Mirecka, A, Ertmański, S, Novakovic, S, Hocevar, M, Peric, B, Cerkovnik, P, Höiom, V, Hansson, J, Holland, Ea, Azizi, E, Galore Haskel, G, Friedman, E, Baron Epel, O, Scope, A, Pavlotsky, F, Yakobson, E, Cohen Manheim, I, Laitman, Y, Milgrom, R, Shimoni, I, and Kozlovaa, E.

Subjects
Genetic Markers, Candidate gene, Skin Neoplasms, Ubiquitin-Protein Ligases, Locus (genetics), Single-nucleotide polymorphism, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Meta-Analysis as Topic, Genetics, Eye color, Guanine Nucleotide Exchange Factors, Humans, SNP, Genetic Predisposition to Disease, Melanoma, Molecular Biology, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Pigmentation, Association Studies Articles, General Medicine, 3. Good health, Chromosomes, Human, Pair 1, Genetic Loci, Genetic marker, Case-Control Studies, 030220 oncology & carcinogenesis, Cutaneous melanoma, Genome-Wide Association Study
Abstract

We performed a multistage genome-wide association study of melanoma. In a discovery cohort of 1804 melanoma cases and 1026 controls, we identified loci at chromosomes 15q13.1 (HERC2/OCA2 region) and 16q24.3 (MC1R) regions that reached genome-wide significance within this study and also found strong evidence for genetic effects on susceptibility to melanoma from markers on chromosome 9p21.3 in the p16/ARF region and on chromosome 1q21.3 (ARNT/LASS2/ANXA9 region). The most significant single-nucleotide polymorphisms (SNPs) in the 15q13.1 locus (rs1129038 and rs12913832) lie within a genomic region that has profound effects on eye and skin color; notably, 50% of variability in eye color is associated with variation in the SNP rs12913832. Because eye and skin colors vary across European populations, we further evaluated the associations of the significant SNPs after carefully adjusting for European substructure. We also evaluated the top 10 most significant SNPs by using data from three other genome-wide scans. Additional in silico data provided replication of the findings from the most significant region on chromosome 1q21.3 rs7412746 (P = 6 × 10(-10)). Together, these data identified several candidate genes for additional studies to identify causal variants predisposing to increased risk for developing melanoma.

Published
2011

32. Genome-wide meta-analysis identifies five new susceptibility loci for cutaneous malignant melanoma

Author

Law, M, Bishop, DT, Lee, JE, Brossard, M, Martin, NG, Moses, EK, Song, F, Barrett, JH, Kumar, R, Easton, DF, Pharoah, PDP, Swerdlow, AJ, Kypreou, KP, Taylor, JC, Harland, M, Randerson-Moor, J, Akslen, LA, Andresen, PA, Avril, MF, Azizi, E, Scarra, GB, Brown, KM, Debniak, T, Duffy, DL, Elder, DE, Fang, S, Friedman, E, Galan, P, Ghiorzo, P, Gillanders, EM, Goldstein, AM, Gruis, NE, Hansson, J, Helsing, P, Hocevar, M, Hoiom, V, Ingvar, C, Kanetsky, PA, Chen, WV, GenoMEL Consortium, Essen-Heidelberg Investigators, The SDH Study Group, Q-MEGA and QTWIN Investigators, AMFS Investigators, ATHENS Melanoma Study Group, Landi, MT, Lang, J, Lathrop, M, Lubinski, J, Mackie, RM, Mann, GJ, Molvern, A, Montgomery, GW, Novakovic, S, Olsson, H, Puig, S, Puig-Butille, JA, Qureshi, AA, Radford-Smith, GL, van der Stoep, N, van Doorn, R, Whiteman, DC, Craig, JE, Schadendorf, D, Simms, LA, Burdon, KP, Nyholt, DR, Pooley, KA, Orr, N, Stratigos, AJ, Cust, AE, Ward, SV, Hayward, NK, Han, J, Schulze, HJ, Dunning, AM, Newton-Bishop, JA, Demenais, F, Amos, CI, MacGregor, S, Iles, MM, Easton, Douglas [0000-0003-2444-3247], Pharoah, Paul [0000-0001-8494-732X], Pooley, Karen [0000-0002-1274-9460], Dunning, Alison [0000-0001-6651-7166], and Apollo - University of Cambridge Repository

Subjects
Candidate gene, Skin Neoplasms, Medizin, Single-nucleotide polymorphism, Genome-wide association study, Biology, Genome, Polymorphism, Single Nucleotide, Article, Polymorphism (computer science), ATHENS Melanoma Study Group, Genetics, Chromosomes, Human, Humans, Genetic Predisposition to Disease, AMFS Investigators, Melanoma, Genetic association, 11 Medical And Health Sciences, 06 Biological Sciences, GenoMEL Consortium, Human genetics, 3. Good health, Genetic Loci, Case-Control Studies, SDH Study Group, Expression quantitative trait loci, Q-MEGA and QTWIN Investigators, Essen-Heidelberg Investigators, Developmental Biology, Genome-Wide Association Study
Abstract

© 2015 Nature America, Inc. All rights reserved.Thirteen common susceptibility loci have been reproducibly associated with cutaneous malignant melanoma (CMM). We report the results of an international 2-stage meta-analysis of CMM genome-wide association studies (GWAS). This meta-analysis combines 11 GWAS (5 previously unpublished) and a further three stage 2 data sets, totaling 15,990 CMM cases and 26,409 controls. Five loci not previously associated with CMM risk reached genome-wide significance (P < 5 × 10-8), as did 2 previously reported but unreplicated loci and all 13 established loci. Newly associated SNPs fall within putative melanocyte regulatory elements, and bioinformatic and expression quantitative trait locus (eQTL) data highlight candidate genes in the associated regions, including one involved in telomere biology.

Published
2015

33. Polymorphisms Near TBX5 and GDF7 Are Associated With Increased Risk for Barrett's Esophagus

Author

Palles, C, Chegwidden, L, Li, X, Findlay, JM, Farnham, G, Giner, FC, Peppelenbosch, MP, Kovac, M, Adams, CL, Prenen, H, Briggs, S, Harrison, R, Sanders, S, MacDonald, D, Haigh, C, Tucker, A, Love, S, Nanji, M, Decaestecker, J, Ferry, D, Rathbone, B, Hapeshi, J, Barr, H, Moayyedi, P, Watson, P, Zietek, B, Maroo, N, Gay, L, Underwood, T, Boulter, L, McMurtry, H, Monk, D, Patel, P, Ragunath, K, Al Dulaimi, D, Murray, I, Koss, K, Veitch, A, Trudgill, N, Nwokolo, C, Rembacken, B, Atherfold, P, Green, E, Ang, Y, Kuipers, EJ, Chow, W, Paterson, S, Kadri, S, Beales, I, Grimley, C, Mullins, P, Beckett, C, Farrant, M, Dixon, A, Kelly, S, Johnson, M, Wajed, S, Dhar, A, Sawyer, E, Roylance, R, Onstad, L, Gammon, MD, Corley, DA, Shaheen, NJ, Bird, NC, Hardie, LJ, Reid, BJ, Ye, W, Liu, G, Romero, Y, Bernstein, L, Wu, AH, Casson, AG, Fitzgerald, R, Whiteman, DC, Risch, HA, Levine, DM, Vaughan, TL, Verhaar, AP, van den Brande, J, Toxopeus, EL, Spaander, MC, Wijnhoven, BPL, van der Laan, LJW, Krishnadath, K, Wijmenga, C, Trynka, G, McManus, R, Reynolds, JV, O'Sullivan, J, MacMathuna, P, McGarrigle, SA, Kelleher, D, Vermeire, S, Cleynen, I, Bisschops, R, Tomlinson, I, Jankowski, J, Gastroenterology & Hepatology, Surgery, Fitzgerald, Rebecca [0000-0002-3434-3568], Apollo - University of Cambridge Repository, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, CCA -Cancer Center Amsterdam, and Gastroenterology and Hepatology

Subjects
Risk, SUSCEPTIBILITY LOCI, Esophageal Neoplasms, GASTROESOPHAGEAL-REFLUX DISEASE, ADENOCARCINOMA, PROGRESSION, RS6983267, VARIANTS, Polymorphism, Single Nucleotide, COLORECTAL-CANCER, Growth Differentiation Factors, Barrett Esophagus, Intestinal Metaplasia, Susceptibility, Bone Morphogenetic Proteins, Humans, Genetic Predisposition to Disease, EAC, GENOME-WIDE ASSOCIATION, FOXF1, T-Box Domain Proteins, COMMON, Genome-Wide Association Study, Cancer
Abstract

Background & Aims\ud \ud Barrett's esophagus (BE) increases the risk of esophageal adenocarcinoma (EAC). We found the risk to be BE has been associated with single nucleotide polymorphisms (SNPs) on chromosome 6p21 (within the HLA region) and on 16q23, where the closest protein-coding gene is FOXF1. Subsequently, the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) identified risk loci for BE and esophageal adenocarcinoma near CRTC1 and BARX1, and within 100 kb of FOXP1. We aimed to identify further SNPs that increased BE risk and to validate previously reported associations.\ud \ud Methods\ud \ud We performed a genome-wide association study (GWAS) to identify variants associated with BE and further analyzed promising variants identified by BEACON by genotyping 10,158 patients with BE and 21,062 controls.\ud \ud Results\ud \ud We identified 2 SNPs not previously associated with BE: rs3072 (2p24.1; odds ratio [OR] = 1.14; 95% CI: 1.09–1.18; P = 1.8 × 10−11) and rs2701108 (12q24.21; OR = 0.90; 95% CI: 0.86–0.93; P = 7.5 × 10−9). The closest protein-coding genes were respectively GDF7 (rs3072), which encodes a ligand in the bone morphogenetic protein pathway, and TBX5 (rs2701108), which encodes a transcription factor that regulates esophageal and cardiac development. Our data also supported in BE cases 3 risk SNPs identified by BEACON (rs2687201, rs11789015, and rs10423674). Meta-analysis of all data identified another SNP associated with BE and esophageal adenocarcinoma: rs3784262, within ALDH1A2 (OR = 0.90; 95% CI: 0.87–0.93; P = 3.72 × 10−9).\ud \ud Conclusions\ud \ud We identified 2 loci associated with risk of BE and provided data to support a further locus. The genes we found to be associated with risk for BE encode transcription factors involved in thoracic, diaphragmatic, and esophageal development or proteins involved in the inflammatory response.

Published
2015

34. Self-Reported Changes in Sun-Protection Behaviors at Different Latitudes in Australia

Author

Djaja, N, Janda, M, Lucas, RM, Harrison, SL, van der Mei, I, Ebeling, PR, Neale, RE, Whiteman, DC, Nowak, M, Kimlin, MG, Djaja, N, Janda, M, Lucas, RM, Harrison, SL, van der Mei, I, Ebeling, PR, Neale, RE, Whiteman, DC, Nowak, M, and Kimlin, MG

Abstract

Sun exposure is the most important source of vitamin D, but is also a risk factor for skin cancer. This study investigated attitudes toward vitamin D, and changes in sun-exposure behavior due to concern about adequate vitamin D. Participants (n = 1002) were recruited from four regions of Australia and completed self- and interviewer-administered surveys. Chi-square tests were used to assess associations between participants' latitude of residence, vitamin D-related attitudes and changes in sun-exposure behaviors during the last summer. Multivariate logistic regression analyses were used to model the association between attitudes and behaviors. Overall, people who worried about their vitamin D status were more likely to have altered sun protection and spent more time in the sun people not concerned about vitamin D. Concern about vitamin D was also more common with increasing latitude. Use of novel item response theory analysis highlighted the potential impact of self-reported behavior change on skin cancer predisposition due concern to vitamin. This cross-sectional study shows that the strongest determinants of self-reported sun-protection behavior changes due to concerns about vitamin D were attitudes and location, with people at higher latitudes worrying more.

Published
2016

35. Identification of the CIMP-like subtype and aberrant methylation of members of the chromosomal segregation and spindle assembly pathways in esophageal adenocarcinoma

Author

Krause, L, Nones, K, Loffler, KA, Nancarrow, D, Oey, H, Tang, YH, Wayte, NJ, Patch, AM, Patel, K, Brosda, S, Manning, S, Lampe, G, Clouston, A, Thomas, J, Stoye, J, Hussey, DJ, Watson, DI, Lord, RV, Phillips, WA, Gotley, D, Smithers, BM, Whiteman, DC, Hayward, NK, Grimmond, SM, Waddell, N, Barbour, AP, Krause, L, Nones, K, Loffler, KA, Nancarrow, D, Oey, H, Tang, YH, Wayte, NJ, Patch, AM, Patel, K, Brosda, S, Manning, S, Lampe, G, Clouston, A, Thomas, J, Stoye, J, Hussey, DJ, Watson, DI, Lord, RV, Phillips, WA, Gotley, D, Smithers, BM, Whiteman, DC, Hayward, NK, Grimmond, SM, Waddell, N, and Barbour, AP

Abstract

The incidence of esophageal adenocarcinoma (EAC) has risen significantly over recent decades. Although survival has improved, cure rates remain poor, with <20% of patients surviving 5 years. This is the first study to explore methylome, transcriptome and ENCODE data to characterize the role of methylation in EAC. We investigate the genome-wide methylation profile of 250 samples including 125 EAC, 19 Barrett's esophagus (BE), 85 squamous esophagus and 21 normal stomach. Transcriptome data of 70 samples (48 EAC, 4 BE and 18 squamous esophagus) were used to identify changes in methylation associated with gene expression. BE and EAC showed similar methylation profiles, which differed from squamous tissue. Hypermethylated sites in EAC and BE were mainly located in CpG-rich promoters. A total of 18575 CpG sites associated with 5538 genes were differentially methylated, 63% of these genes showed significant correlation between methylation and mRNA expression levels. Pathways involved in tumorigenesis including cell adhesion, TGF and WNT signaling showed enrichment for genes aberrantly methylated. Genes involved in chromosomal segregation and spindle formation were aberrantly methylated. Given the recent evidence that chromothripsis may be a driver mechanism in EAC, the role of epigenetic perturbation of these pathways should be further investigated. The methylation profiles revealed two EAC subtypes, one associated with widespread CpG island hypermethylation overlapping H3K27me3 marks and binding sites of the Polycomb proteins. These subtypes were supported by an independent set of 89 esophageal cancer samples. The most hypermethylated tumors showed worse patient survival.

Published
2016

36. MIC-1/GDF15 in Barrett's oesophagus and oesophageal adenocarcinoma

Author

Fisher, OM, Levert-Mignon, AJ, Lord, SJ, Lee-Ng, KKM, Botelho, NK, Falkenback, D, Thomas, ML, Bobryshev, YV, Whiteman, DC, Brown, DA, Breit, SN, Lord, RV, Fisher, OM, Levert-Mignon, AJ, Lord, SJ, Lee-Ng, KKM, Botelho, NK, Falkenback, D, Thomas, ML, Bobryshev, YV, Whiteman, DC, Brown, DA, Breit, SN, and Lord, RV

Abstract

Background:Biomarkers are needed to improve current diagnosis and surveillance strategies for patients with Barrett's oesophagus (BO) and oesophageal adenocarcinoma (OAC). Macrophage inhibitory cytokine 1/growth differentiation factor 15 (MIC-1/GDF15) tissue and plasma levels have been shown to predict disease progression in other cancer types and was therefore evaluated in BO/OAC.Methods:One hundred thirty-eight patients were studied: 45 normal oesophagus (NE), 37 BO, 16 BO with low-grade dysplasia (LGD) and 40 OAC.Results:Median tissue expression of MIC-1/GDF15 mRNA was ≥25-fold higher in BO and LGD compared to NE (P<0.001); two-fold higher in OAC vs BO (P=0.039); and 47-fold higher in OAC vs NE (P<0.001). Relative MIC-1/GDF15 tissue expression >720 discriminated between the presence of either OAC or LGD vs NE with 94% sensitivity and 71% specificity (ROC AUC 0.86, 95% CI 0.73-0.96; P<0.001). Macrophage inhibitory cytokine 1/growth differentiation factor 15 plasma values were also elevated in patients with OAC vs NE (P<0.001) or BO (P=0.015).High MIC-1/GDF15 plasma levels (≥1140 pg ml-1) were an independent predictor of poor survival for patients with OAC (HR 3.87, 95% CI 1.01-14.75; P=0.047).Conclusions:Plasma and tissue levels of MIC-1/GDF15 are significantly elevated in patients with BO, LGD and OAC. Plasma MIC-1/GDF15 may have value in diagnosis and monitoring of Barrett's disease.

Published
2015

37. Genome-wide meta-analysis identifies five new susceptibility loci for cutaneous malignant melanoma

Author

Law, MH, Bishop, DT, Lee, JE, Brossard, M, Martin, NG, Moses, EK, Song, F, Barrett, JH, Kumar, R, Easton, DF, Pharoah, PDP, Swerdlow, AJ, Kypreou, KP, Taylor, JC, Harland, M, Randerson-Moor, J, Akslen, LA, Andresen, PA, Avril, M-F, Azizi, E, Scarra, GB, Brown, KM, Debniak, T, Duffy, DL, Elder, DE, Fang, S, Friedman, E, Galan, P, Ghiorzo, P, Gillanders, EM, Goldstein, AM, Gruis, NA, Hansson, J, Helsing, P, Hocevar, M, Hoeiom, V, Ingvar, C, Kanetsky, PA, Chen, WV, Landi, MT, Lang, J, Lathrop, GM, Lubinski, J, Mackie, RM, Mann, GJ, Molven, A, Montgomery, GW, Novakovic, S, Olsson, H, Puig, S, Puig-Butille, JA, Qureshi, AA, Radford-Smith, GL, van der Stoep, N, van Doorn, R, Whiteman, DC, Craig, JE, Schadendorf, D, Simms, LA, Burdon, KP, Nyholt, DR, Pooley, KA, Orr, N, Stratigos, AJ, Cust, AE, Ward, SV, Hayward, NK, Han, J, Schulze, H-J, Dunning, AM, Bishop, JAN, Demenais, F, Amos, CI, MacGregor, S, Iles, MM, Law, MH, Bishop, DT, Lee, JE, Brossard, M, Martin, NG, Moses, EK, Song, F, Barrett, JH, Kumar, R, Easton, DF, Pharoah, PDP, Swerdlow, AJ, Kypreou, KP, Taylor, JC, Harland, M, Randerson-Moor, J, Akslen, LA, Andresen, PA, Avril, M-F, Azizi, E, Scarra, GB, Brown, KM, Debniak, T, Duffy, DL, Elder, DE, Fang, S, Friedman, E, Galan, P, Ghiorzo, P, Gillanders, EM, Goldstein, AM, Gruis, NA, Hansson, J, Helsing, P, Hocevar, M, Hoeiom, V, Ingvar, C, Kanetsky, PA, Chen, WV, Landi, MT, Lang, J, Lathrop, GM, Lubinski, J, Mackie, RM, Mann, GJ, Molven, A, Montgomery, GW, Novakovic, S, Olsson, H, Puig, S, Puig-Butille, JA, Qureshi, AA, Radford-Smith, GL, van der Stoep, N, van Doorn, R, Whiteman, DC, Craig, JE, Schadendorf, D, Simms, LA, Burdon, KP, Nyholt, DR, Pooley, KA, Orr, N, Stratigos, AJ, Cust, AE, Ward, SV, Hayward, NK, Han, J, Schulze, H-J, Dunning, AM, Bishop, JAN, Demenais, F, Amos, CI, MacGregor, S, and Iles, MM

Abstract

Thirteen common susceptibility loci have been reproducibly associated with cutaneous malignant melanoma (CMM). We report the results of an international 2-stage meta-analysis of CMM genome-wide association studies (GWAS). This meta-analysis combines 11 GWAS (5 previously unpublished) and a further three stage 2 data sets, totaling 15,990 CMM cases and 26,409 controls. Five loci not previously associated with CMM risk reached genome-wide significance (P < 5 × 10(-8)), as did 2 previously reported but unreplicated loci and all 13 established loci. Newly associated SNPs fall within putative melanocyte regulatory elements, and bioinformatic and expression quantitative trait locus (eQTL) data highlight candidate genes in the associated regions, including one involved in telomere biology.

Published
2015

38. InterSCOPE Study: Associations Between Esophageal Squamous Cell Carcinoma and Human Papillomavirus Serological Markers

Author

Sitas F, Malekzadeh R, Pawlita M, Dawsey SM, Waterboer T, Webb PM, Green AC, Hayward NK, Zaridze D, Holcatova I, Mates D, Egger S, Szeszenia-Dabrowska N, Ferro G, Janout V, Curado MP, Menezes AM, Koifman S, Islami F, Nasrollahzadeh D, Hu N, Goldstein AM, Urban MI, Gao Y, Ding T, Kamangar F, Taylor PR, Abnet CC, Boffetta P, O'Connell DL, Whiteman DC, Brennan P, Sitas, F., Egger, S., Urban, M.I., Taylor, P.R., Abnet, C.C., Boffetta, P., O'Connell, D.L., Whiteman, D.C., Brennan, P., Malekzadeh, R., Pawlita, M., Dawsey, S.M., Waterboer, T., Webb, P.M., Green, A.C., Hayward, N.K., Zaridze, D., Holcatova, I., Mates, D., Szeszenia-Dabrowska, N., Ferro, G., Janout, V., Curado, M.P., Menezes, A.M., Koifman, S., Islami, F., Nasrollahzadeh, D., Hu, N., Goldstein, A.M., Gao, Y., Ding, T., and Kamangar, F.

Subjects
Male, Cancer Research, Pathology, Esophageal Neoplasms, Etiology - Endogenous Factors in the Origin and Cause of Cancer, Alphapapillomavirus, Antibodies, Viral, Serology, 0302 clinical medicine, Risk Factors, Odds Ratio, 030212 general & internal medicine, Antigens, Viral, Cancer Type - Oesophageal Cancer, Human papillomavirus 16, Human papillomavirus 18, biology, Smoking, virus diseases, Mucous membrane, Confounding Factors, Epidemiologic, Articles, Middle Aged, Esophageal cancer, Koilocyte, 3. Good health, esophageal squamous cell carcinoma, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Carcinoma, Squamous Cell, Female, epidemiology, Antibody, Adult, Risk, medicine.medical_specialty, HPV, food.ingredient, Risk Assessment, Sensitivity and Specificity, methods, 03 medical and health sciences, food, medicine, Confidence Intervals, Humans, cancer, Aged, business.industry, case-control studies, Research, Papillomavirus Infections, Case-control study, Australia, Cancer, Proteins, medicine.disease, human papillomavirus (HPV), Tumor Virus Infections, Logistic Models, Case-Control Studies, biology.protein, Other, business
Abstract

Background The role of human papillomavirus (HPV) in the causation of esophageal squamous cell carcinoma is unclear. We examined the associations between esophageal squamous cell carcinoma and 28 centrally measured HPV serological markers in serum from six existing case-control studies conducted in regions with differing Background risks of esophageal cancer. Methods We used centralized multiplex serology to test serum samples from 1561 case subjects and 2502 control subjects from six case-control studies for antibodies to the major HPV capsid protein (L1) and/or the early proteins E6 and/or E7 of eight high-risk, two low-risk, and four cutaneous HPV types. Study-specific odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using conditional logistic regression with adjustment for smoking, alcohol consumption, and other potential confounders. Pooled odds ratios and 95% confidence intervals were calculated using either a linear mixed-effects approach or a joint fixed-effects approach. All statistical tests were two-sided. ResultsWe found statistically significant associations between esophageal squamous cell carcinoma and antibodies to E6 for HPV16 (OR = 1.89, 95% CI = 1.09 to 3.29, P =. 023) and HPV6 (OR = 2.53, 95% CI = 1.51 to 4.25, P

Published
2012

39. The effect on melanoma risk of genes previously associated with telomere length.

Author

Iles, MM, Bishop, DT, Taylor, JC, Hayward, NK, Brossard, M, Cust, AE, Dunning, AM, Lee, JE, Moses, EK, Akslen, LA, AMFS Investigators, Andresen, PA, Avril, M-F, Azizi, E, Scarrà, GB, Brown, KM, Dębniak, T, Elder, DE, Friedman, E, Ghiorzo, P, Gillanders, EM, Goldstein, AM, Gruis, NA, Hansson, J, Harland, M, Helsing, P, Hočevar, M, Höiom, V, IBD investigators, Ingvar, C, Kanetsky, PA, Landi, MT, Lang, J, Lathrop, GM, Lubiński, J, Mackie, RM, Martin, NG, Molven, A, Montgomery, GW, Novaković, S, Olsson, H, Puig, S, Puig-Butille, JA, QMEGA and QTWIN Investigators, Radford-Smith, GL, Randerson-Moor, J, SDH Study Group, van der Stoep, N, van Doorn, R, Whiteman, DC, MacGregor, S, Pooley, KA, Ward, SV, Mann, GJ, Amos, CI, Pharoah, PDP, Demenais, F, Law, MH, Newton Bishop, JA, Barrett, JH, GenoMEL Consortium, Iles, MM, Bishop, DT, Taylor, JC, Hayward, NK, Brossard, M, Cust, AE, Dunning, AM, Lee, JE, Moses, EK, Akslen, LA, AMFS Investigators, Andresen, PA, Avril, M-F, Azizi, E, Scarrà, GB, Brown, KM, Dębniak, T, Elder, DE, Friedman, E, Ghiorzo, P, Gillanders, EM, Goldstein, AM, Gruis, NA, Hansson, J, Harland, M, Helsing, P, Hočevar, M, Höiom, V, IBD investigators, Ingvar, C, Kanetsky, PA, Landi, MT, Lang, J, Lathrop, GM, Lubiński, J, Mackie, RM, Martin, NG, Molven, A, Montgomery, GW, Novaković, S, Olsson, H, Puig, S, Puig-Butille, JA, QMEGA and QTWIN Investigators, Radford-Smith, GL, Randerson-Moor, J, SDH Study Group, van der Stoep, N, van Doorn, R, Whiteman, DC, MacGregor, S, Pooley, KA, Ward, SV, Mann, GJ, Amos, CI, Pharoah, PDP, Demenais, F, Law, MH, Newton Bishop, JA, Barrett, JH, and GenoMEL Consortium

Abstract

Telomere length has been associated with risk of many cancers, but results are inconsistent. Seven single nucleotide polymorphisms (SNPs) previously associated with mean leukocyte telomere length were either genotyped or well-imputed in 11108 case patients and 13933 control patients from Europe, Israel, the United States and Australia, four of the seven SNPs reached a P value under .05 (two-sided). A genetic score that predicts telomere length, derived from these seven SNPs, is strongly associated (P = 8.92x10(-9), two-sided) with melanoma risk. This demonstrates that the previously observed association between longer telomere length and increased melanoma risk is not attributable to confounding via shared environmental effects (such as ultraviolet exposure) or reverse causality. We provide the first proof that multiple germline genetic determinants of telomere length influence cancer risk.

Published
2014

40. Common variants near ABCA1, AFAP1 and GMDS confer risk of primary open-angle glaucoma

Author

Gharahkhani, P, Burdon, KP, Fogarty, R, Sharma, S, Hewitt, AW, Martin, S, Law, MH, Cremin, K, Bailey, JNC, Loomis, SJ, Pasquale, LR, Haines, JL, Hauser, MA, Viswanathan, AC, McGuffin, P, Topouzis, F, Foster, PJ, Graham, SL, Casson, RJ, Chehade, M, White, AJ, Zhou, T, Souzeau, E, Landers, J, Fitzgerald, JT, Klebe, S, Ruddle, JB, Goldberg, I, Healey, PR, Mills, RA, Wang, JJ, Montgomery, GW, Martin, NG, Radford-Smith, G, Whiteman, DC, Brown, MA, Wiggs, JL, Mackey, DA, Mitchell, P, MacGregor, S, Craig, JE, Gharahkhani, P, Burdon, KP, Fogarty, R, Sharma, S, Hewitt, AW, Martin, S, Law, MH, Cremin, K, Bailey, JNC, Loomis, SJ, Pasquale, LR, Haines, JL, Hauser, MA, Viswanathan, AC, McGuffin, P, Topouzis, F, Foster, PJ, Graham, SL, Casson, RJ, Chehade, M, White, AJ, Zhou, T, Souzeau, E, Landers, J, Fitzgerald, JT, Klebe, S, Ruddle, JB, Goldberg, I, Healey, PR, Mills, RA, Wang, JJ, Montgomery, GW, Martin, NG, Radford-Smith, G, Whiteman, DC, Brown, MA, Wiggs, JL, Mackey, DA, Mitchell, P, MacGregor, S, and Craig, JE

Abstract

Primary open-angle glaucoma (POAG) is a major cause of irreversible blindness worldwide. We performed a genome-wide association study in an Australian discovery cohort comprising 1,155 cases with advanced POAG and 1,992 controls. We investigated the association of the top SNPs from the discovery stage in two Australian replication cohorts (932 cases and 6,862 controls total) and two US replication cohorts (2,616 cases and 2,634 controls total). Meta-analysis of all cohorts identified three loci newly associated with development of POAG. These loci are located upstream of ABCA1 (rs2472493[G], odds ratio (OR) = 1.31, P = 2.1 × 10(-19)), within AFAP1 (rs4619890[G], OR = 1.20, P = 7.0 × 10(-10)) and within GMDS (rs11969985[G], OR = 1.31, P = 7.7 × 10(-10)). Using RT-PCR and immunolabeling, we show that these genes are expressed within human retina, optic nerve and trabecular meshwork and that ABCA1 and AFAP1 are also expressed in retinal ganglion cells.

Published
2014

41. Genomic catastrophes frequently arise in esophageal adenocarcinoma and drive tumorigenesis

Author

Nones, K, Waddell, N, Wayte, N, Patch, A-M, Bailey, P, Newell, F, Holmes, O, Fink, JL, Quinn, MCJ, Tang, YH, Lampe, G, Quek, K, Loffler, KA, Manning, S, Idrisoglu, S, Miller, D, Xu, Q, Wilson, PJ, Bruxner, TJC, Christ, AN, Harliwong, I, Nourse, C, Nourbakhsh, E, Anderson, M, Kazakoff, S, Leonard, C, Wood, S, Simpson, PT, Reid, LE, Krause, L, Hussey, DJ, Watson, DI, Lord, RV, Nancarrow, D, Phillips, WA, Gotley, D, Smithers, BM, Whiteman, DC, Hayward, NK, Campbell, PJ, Pearson, JV, Grimmond, SM, Barbour, AP, Nones, K, Waddell, N, Wayte, N, Patch, A-M, Bailey, P, Newell, F, Holmes, O, Fink, JL, Quinn, MCJ, Tang, YH, Lampe, G, Quek, K, Loffler, KA, Manning, S, Idrisoglu, S, Miller, D, Xu, Q, Wilson, PJ, Bruxner, TJC, Christ, AN, Harliwong, I, Nourse, C, Nourbakhsh, E, Anderson, M, Kazakoff, S, Leonard, C, Wood, S, Simpson, PT, Reid, LE, Krause, L, Hussey, DJ, Watson, DI, Lord, RV, Nancarrow, D, Phillips, WA, Gotley, D, Smithers, BM, Whiteman, DC, Hayward, NK, Campbell, PJ, Pearson, JV, Grimmond, SM, and Barbour, AP

Abstract

Oesophageal adenocarcinoma (EAC) incidence is rapidly increasing in Western countries. A better understanding of EAC underpins efforts to improve early detection and treatment outcomes. While large EAC exome sequencing efforts to date have found recurrent loss-of-function mutations, oncogenic driving events have been underrepresented. Here we use a combination of whole-genome sequencing (WGS) and single-nucleotide polymorphism-array profiling to show that genomic catastrophes are frequent in EAC, with almost a third (32%, n=40/123) undergoing chromothriptic events. WGS of 22 EAC cases show that catastrophes may lead to oncogene amplification through chromothripsis-derived double-minute chromosome formation (MYC and MDM2) or breakage-fusion-bridge (KRAS, MDM2 and RFC3). Telomere shortening is more prominent in EACs bearing localized complex rearrangements. Mutational signature analysis also confirms that extreme genomic instability in EAC can be driven by somatic BRCA2 mutations. These findings suggest that genomic catastrophes have a significant role in the malignant transformation of EAC.

Published
2014

42. Genome-wide association study identifies three new melanoma susceptibility loci

Author

Barrett, JH, Iles, MM, Harland, M, Taylor, JC, Aitken, JF, Andresen, PA, Akslen, LA, Armstrong, BK, Avril, M-F, Azizi, E, Bakker, B, Bergman, W, Bianchi-Scarra, G, Bressac-de Paillerets, B, Calista, D, Cannon-Albright, LA, Corda, E, Cust, AE, Debniak, T, Duffy, D, Dunning, AM, Easton, DF, Friedman, E, Galan, P, Ghiorzo, P, Giles, GG, Hansson, J, Hocevar, M, Hoeiom, V, Hopper, JL, Ingvar, C, Janssen, B, Jenkins, MA, Joensson, G, Kefford, RF, Landi, G, Landi, MT, Lang, J, Lubinski, J, Mackie, R, Malvehy, J, Martin, NG, Molven, A, Montgomery, GW, van Nieuwpoort, FA, Novakovic, S, Olsson, H, Pastorino, L, Puig, S, Puig-Butille, JA, Randerson-Moor, J, Snowden, H, Tuominen, R, VanBelle, P, van der Stoep, N, Whiteman, DC, Zelenika, D, Han, J, Fang, S, Lee, JE, Wei, Q, Lathrop, GM, Gillanders, EM, Brown, KM, Goldstein, AM, Kanetsky, PA, Mann, GJ, MacGregor, S, Elder, DE, Amos, CI, Hayward, NK, Gruis, NA, Demenais, F, Bishop, JAN, Bishop, DT, Barrett, JH, Iles, MM, Harland, M, Taylor, JC, Aitken, JF, Andresen, PA, Akslen, LA, Armstrong, BK, Avril, M-F, Azizi, E, Bakker, B, Bergman, W, Bianchi-Scarra, G, Bressac-de Paillerets, B, Calista, D, Cannon-Albright, LA, Corda, E, Cust, AE, Debniak, T, Duffy, D, Dunning, AM, Easton, DF, Friedman, E, Galan, P, Ghiorzo, P, Giles, GG, Hansson, J, Hocevar, M, Hoeiom, V, Hopper, JL, Ingvar, C, Janssen, B, Jenkins, MA, Joensson, G, Kefford, RF, Landi, G, Landi, MT, Lang, J, Lubinski, J, Mackie, R, Malvehy, J, Martin, NG, Molven, A, Montgomery, GW, van Nieuwpoort, FA, Novakovic, S, Olsson, H, Pastorino, L, Puig, S, Puig-Butille, JA, Randerson-Moor, J, Snowden, H, Tuominen, R, VanBelle, P, van der Stoep, N, Whiteman, DC, Zelenika, D, Han, J, Fang, S, Lee, JE, Wei, Q, Lathrop, GM, Gillanders, EM, Brown, KM, Goldstein, AM, Kanetsky, PA, Mann, GJ, MacGregor, S, Elder, DE, Amos, CI, Hayward, NK, Gruis, NA, Demenais, F, Bishop, JAN, and Bishop, DT

Abstract

We report a genome-wide association study for melanoma that was conducted by the GenoMEL Consortium. Our discovery phase included 2,981 individuals with melanoma and 1,982 study-specific control individuals of European ancestry, as well as an additional 6,426 control subjects from French or British populations, all of whom were genotyped for 317,000 or 610,000 single-nucleotide polymorphisms (SNPs). Our analysis replicated previously known melanoma susceptibility loci. Seven new regions with at least one SNP with P < 10(-5) and further local imputed or genotyped support were selected for replication using two other genome-wide studies (from Australia and Texas, USA). Additional replication came from case-control series from the UK and The Netherlands. Variants at three of the seven loci replicated at P < 10(-3): an SNP in ATM (rs1801516, overall P = 3.4 × 10(-9)), an SNP in MX2 (rs45430, P = 2.9 × 10(-9)) and an SNP adjacent to CASP8 (rs13016963, P = 8.6 × 10(-10)). A fourth locus near CCND1 remains of potential interest, showing suggestive but inconclusive evidence of replication (rs1485993, overall P = 4.6 × 10(-7) under a fixed-effects model and P = 1.2 × 10(-3) under a random-effects model). These newly associated variants showed no association with nevus or pigmentation phenotypes in a large British case-control series.

Published
2011

43. Genome-wide association study identifies a new melanoma susceptibility locus at 1q21.3

Author

MacGregor, S, Montgomery, GW, Liu, JZ, Zhao, ZZ, Henders, AK, Stark, M, Schmid, H, Holland, EA, Duffy, DL, Zhang, M, Painter, JN, Nyholt, DR, Maskiell, JA, Jetann, J, Ferguson, M, Cust, AE, Jenkins, MA, Whiteman, DC, Olsson, H, Puig, S, Bianchi-Scarra, G, Hansson, J, Demenais, F, Landi, MT, Debniak, T, Mackie, R, Azizi, E, Bressac-de Paillerets, B, Goldstein, AM, Kanetsky, PA, Gruis, NA, Elder, DE, Newton-Bishop, JA, Bishop, DT, Iles, MM, Helsing, P, Amos, CI, Wei, Q, Wang, L-E, Lee, JE, Qureshi, AA, Kefford, RF, Giles, GG, Armstrong, BK, Aitken, JF, Han, J, Hopper, JL, Trent, JM, Brown, KM, Martin, NG, Mann, GJ, Hayward, NK, MacGregor, S, Montgomery, GW, Liu, JZ, Zhao, ZZ, Henders, AK, Stark, M, Schmid, H, Holland, EA, Duffy, DL, Zhang, M, Painter, JN, Nyholt, DR, Maskiell, JA, Jetann, J, Ferguson, M, Cust, AE, Jenkins, MA, Whiteman, DC, Olsson, H, Puig, S, Bianchi-Scarra, G, Hansson, J, Demenais, F, Landi, MT, Debniak, T, Mackie, R, Azizi, E, Bressac-de Paillerets, B, Goldstein, AM, Kanetsky, PA, Gruis, NA, Elder, DE, Newton-Bishop, JA, Bishop, DT, Iles, MM, Helsing, P, Amos, CI, Wei, Q, Wang, L-E, Lee, JE, Qureshi, AA, Kefford, RF, Giles, GG, Armstrong, BK, Aitken, JF, Han, J, Hopper, JL, Trent, JM, Brown, KM, Martin, NG, Mann, GJ, and Hayward, NK

Abstract

We performed a genome-wide association study of melanoma in a discovery cohort of 2,168 Australian individuals with melanoma and 4,387 control individuals. In this discovery phase, we confirm several previously characterized melanoma-associated loci at MC1R, ASIP and MTAP-CDKN2A. We selected variants at nine loci for replication in three independent case-control studies (Europe: 2,804 subjects with melanoma, 7,618 control subjects; United States 1: 1,804 subjects with melanoma, 1,026 control subjects; United States 2: 585 subjects with melanoma, 6,500 control subjects). The combined meta-analysis of all case-control studies identified a new susceptibility locus at 1q21.3 (rs7412746, P = 9.0 × 10(-11), OR in combined replication cohorts of 0.89 (95% CI 0.85-0.95)). We also show evidence suggesting that melanoma associates with 1q42.12 (rs3219090, P = 9.3 × 10(-8)). The associated variants at the 1q21.3 locus span a region with ten genes, and plausible candidate genes for melanoma susceptibility include ARNT and SETDB1. Variants at the 1q21.3 locus do not seem to be associated with human pigmentation or measures of nevus density.

Published
2011

44. A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma

Author

Yokoyama, S, Woods, SL, Boyle, GM, Aoude, LG, MacGregor, S, Zismann, V, Gartside, M, Cust, AE, Haq, R, Harland, M, Taylor, JC, Duffy, DL, Holohan, K, Dutton-Regester, K, Palmer, JM, Bonazzi, V, Stark, MS, Symmons, J, Law, MH, Schmidt, C, Lanagan, C, O'Connor, L, Holland, EA, Schmid, H, Maskiell, JA, Jetann, J, Ferguson, M, Jenkins, MA, Kefford, RF, Giles, G, Armstrong, BK, Aitken, JF, Hopper, JL, Whiteman, DC, Pharoah, PD, Easton, DF, Dunning, AM, Newton-Bishop, JA, Montgomery, GW, Martin, NG, Mann, GJ, Bishop, DT, Tsao, H, Trent, JM, Fisher, DE, Hayward, NK, Brown, KM, Yokoyama, S, Woods, SL, Boyle, GM, Aoude, LG, MacGregor, S, Zismann, V, Gartside, M, Cust, AE, Haq, R, Harland, M, Taylor, JC, Duffy, DL, Holohan, K, Dutton-Regester, K, Palmer, JM, Bonazzi, V, Stark, MS, Symmons, J, Law, MH, Schmidt, C, Lanagan, C, O'Connor, L, Holland, EA, Schmid, H, Maskiell, JA, Jetann, J, Ferguson, M, Jenkins, MA, Kefford, RF, Giles, G, Armstrong, BK, Aitken, JF, Hopper, JL, Whiteman, DC, Pharoah, PD, Easton, DF, Dunning, AM, Newton-Bishop, JA, Montgomery, GW, Martin, NG, Mann, GJ, Bishop, DT, Tsao, H, Trent, JM, Fisher, DE, Hayward, NK, and Brown, KM

Abstract

So far, two genes associated with familial melanoma have been identified, accounting for a minority of genetic risk in families. Mutations in CDKN2A account for approximately 40% of familial cases, and predisposing mutations in CDK4 have been reported in a very small number of melanoma kindreds. Here we report the whole-genome sequencing of probands from several melanoma families, which we performed in order to identify other genes associated with familial melanoma. We identify one individual carrying a novel germline variant (coding DNA sequence c.G1075A; protein sequence p.E318K; rs149617956) in the melanoma-lineage-specific oncogene microphthalmia-associated transcription factor (MITF). Although the variant co-segregated with melanoma in some but not all cases in the family, linkage analysis of 31 families subsequently identified to carry the variant generated a log of odds (lod) score of 2.7 under a dominant model, indicating E318K as a possible intermediate risk variant. Consistent with this, the E318K variant was significantly associated with melanoma in a large Australian case-control sample. Likewise, it was similarly associated in an independent case-control sample from the United Kingdom. In the Australian sample, the variant allele was significantly over-represented in cases with a family history of melanoma, multiple primary melanomas, or both. The variant allele was also associated with increased naevus count and non-blue eye colour. Functional analysis of E318K showed that MITF encoded by the variant allele had impaired sumoylation and differentially regulated several MITF targets. These data indicate that MITF is a melanoma-predisposition gene and highlight the utility of whole-genome sequencing to identify novel rare variants associated with disease susceptibility.

Published
2011

45. Body mass index, long-term weight change, and esophageal squamous cell carcinoma: is the inverse association modified by smoking status?

Author

Lahmann PH, Pandeya N, Webb PM, Green AC, Whiteman DC, Australian Cancer Study, Lahmann, Petra H, Pandeya, Nirmala, Webb, Penelope M, Green, Adèle C, and Whiteman, David C

Abstract

Background: Observational studies suggest that body mass index (BMI) is inversely associated with esophageal squamous cell carcinoma (ESCC). However, questions remain regarding reverse causation and confounding, especially by smoking, as alternative explanations.Methods: The authors examined the association between BMI and measures of weight history and risk of ESCC in a population-based Australian case-control study (from 2002 to 2005) comprising 287 patients with ESCC (cases) and a control group of 1544 individuals who were sampled from a population registry. Stratified analyses were performed specifically to explore whether this association was influenced by smoking. Multivariable logistic regression models were used to derive odds ratios (ORs).Results: After adjusting for smoking, significant inverse associations with ESCC for BMI and weight 1 year before diagnosis, maximum adult BMI, and weight gain since age 20 years were observed (all P(trend) < .001). The risk of ESCC was reduced by 35% (range, 23%-44%) per 5-unit increase in recent BMI. Participants who gained weight after age 20 years had a lower risk than those who maintained their weight during adult life (OR for gain of >20 kg, 0.51; 95% confidence interval [CI], 0.33-0.77). In stratified analyses, higher BMI was associated with a decreasing risk of ESCC both in never-smokers (OR, 0.32; 95% CI 0.13-0.76) and smokers (OR 0.22, 95%CI 0.07-0.67) comparing the highest versus the lowest BMI quintile.Conclusions: In this study, the inverse associations between BMI, long-term weight gain, and other body measures and ESCC appeared to be robust and could not be explained by smoking status or potential confounding factors. [ABSTRACT FROM AUTHOR]

Published
2012
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46. Associations of duration, intensity, and quantity of smoking with adenocarcinoma and squamous cell carcinoma of the esophagus.

Author

Pandeya N, Williams GM, Sadhegi S, Green AC, Webb PM, and Whiteman DC

Abstract

Smoking has been identified as a risk factor for esophageal cancer; however, there is evidence that magnitudes and patterns of association differ by histologic type. The authors aimed to measure and compare the independent effects of various dimensions of smoking (duration, intensity, total dose, and time since quitting) on risks of esophageal adenocarcinoma (EAC), gastroesophageal junction adenocarcinoma (GEJAC), and esophageal squamous cell carcinoma (ESCC). They used data from a population-based Australian case-control study (2002-2005) comprising 367 EAC cases, 426 GEJAC cases, and 309 ESCC cases and 1,580 controls. Multivariate logistic and generalized additive logistic regression (for nonlinear dose effects) were used. Ever smokers had significantly higher risks of EAC (odds ratio (OR) = 1.7, 95% confidence interval (CI): 1.3, 2.3), GEJAC (OR = 2.4, 95% CI: 1.8, 3.2), and ESCC (OR = 2.8, 95% CI: 2.0, 4.0) than did never smokers; however, there were significant differences in magnitude and patterns of association between subtypes. When multiple dimensions of smoking were assessed concurrently, duration was significantly associated with all three subtypes but intensity was associated only with GEJAC and ESCC, and the associations were nonlinear. For all types of esophageal cancer, time since quitting was independently associated with approximately 15-19% risk reductions per decade. [ABSTRACT FROM AUTHOR]

Published
2008
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48. Reproducibility of a short semi-quantitative food group questionnaire and its performance in estimating nutrient intake compared with a 7-day diet diary in the Million Women Study.

Author

Roddam AW, Spencer E, Banks E, Beral V, Reeves G, Appleby P, Barnes I, Whiteman DC, Key TJ, Roddam, Andrew W, Spencer, Elizabeth, Banks, Emily, Beral, Valerie, Reeves, Gillian, Appleby, Paul, Barnes, Isobel, Whiteman, David C, and Key, Timothy J

Abstract

Objectives: To assess the short- and long-term reproducibility of a short food group questionnaire, and to compare its performance for estimating nutrient intakes in comparison with a 7-day diet diary.Design: Participants for the reproducibility study completed the food group questionnaire at two time points, up to 2 years apart. Participants for the performance study completed both the food group questionnaire and a 7-day diet diary a few months apart. Reproducibility was assessed by kappa statistics and percentage change between the two questionnaires; performance was assessed by kappa statistics, rank correlations and percentages of participants classified into the same and opposite thirds of intake.Setting: A random sample of participants in the Million Women Study, a population-based prospective study in the UK.Subjects: In total, 12 221 women aged 50-64 years.Results: In the reproducibility study, 75% of the food group items showed at least moderate agreement for all four time-point comparisons. Items showing fair agreement or worse tended to be those where few respondents reported eating them more than once a week, those consumed in small amounts and those relating to types of fat consumed. Compared with the diet diary, the food group questionnaire showed consistently reasonable performance for the nutrients carbohydrate, saturated fat, cholesterol, total sugars, alcohol, fibre, calcium, riboflavin, folate and vitamin C.Conclusions: The short food group questionnaire used in this study has been shown to be reproducible over time and to perform reasonably well for the assessment of a number of dietary nutrients. [ABSTRACT FROM AUTHOR]

Published
2005
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