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1. Multitrait genetic association analysis identifies 50 new risk loci for gastro-oesophageal reflux, seven new loci for Barrett’s oesophagus and provides insights into clinical heterogeneity in reflux diagnosis

Author

Priyanka Nandakumar, Rebecca C. Fitzgerald, Jue-Sheng Ong, Jiyuan An, Claire Palles, David A. Hinds, Aaron P. Thrift, Catherine M. Olsen, Puya Gharahkhani, Stuart MacGregor, Xikun Han, Ines Gockel, Matthew F. Buas, Janusz Jankowski, Matthew Law, Anne C. Böhmer, Thomas L. Vaughan, Rachel E. Neale, Bradley J. Kendall, Johannes Schumacher, Ong, Jue-Sheng [0000-0002-6062-710X], Thrift, Aaron P [0000-0002-0084-5308], Kendall, Bradley J [0000-0002-6471-2918], MacGregor, Stuart [0000-0001-6731-8142], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, medicine.medical_specialty, gastro-esophageal reflux disease, Esophageal Neoplasms, Genome-wide association study, Disease, Gastroenterology, Barrett Esophagus, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, genetics, Obesity, Esophagitis, Peptic, Genetic association, business.industry, medicine.disease, humanities, digestive system diseases, Genetic architecture, Barrett's oesophagus, 030104 developmental biology, oesophageal reflux, Multiple comparisons problem, Gastroesophageal Reflux, Etiology, GERD, 030211 gastroenterology & hepatology, business, Body mass index, Genome-Wide Association Study
Abstract

ObjectiveGastro-oesophageal reflux disease (GERD) has heterogeneous aetiology primarily attributable to its symptom-based definitions. GERD genome-wide association studies (GWASs) have shown strong genetic overlaps with established risk factors such as obesity and depression. We hypothesised that the shared genetic architecture between GERD and these risk factors can be leveraged to (1) identify new GERD and Barrett’s oesophagus (BE) risk loci and (2) explore potentially heterogeneous pathways leading to GERD and oesophageal complications.DesignWe applied multitrait GWAS models combining GERD (78 707 cases; 288 734 controls) and genetically correlated traits including education attainment, depression and body mass index. We also used multitrait analysis to identify BE risk loci. Top hits were replicated in 23andMe (462 753 GERD cases, 24 099 BE cases, 1 484 025 controls). We additionally dissected the GERD loci into obesity-driven and depression-driven subgroups. These subgroups were investigated to determine how they relate to tissue-specific gene expression and to risk of serious oesophageal disease (BE and/or oesophageal adenocarcinoma, EA).ResultsWe identified 88 loci associated with GERD, with 59 replicating in 23andMe after multiple testing corrections. Our BE analysis identified seven novel loci. Additionally we showed that only the obesity-driven GERD loci (but not the depression-driven loci) were associated with genes enriched in oesophageal tissues and successfully predicted BE/EA.ConclusionOur multitrait model identified many novel risk loci for GERD and BE. We present strong evidence for a genetic underpinning of disease heterogeneity in GERD and show that GERD loci associated with depressive symptoms are not strong predictors of BE/EA relative to obesity-driven GERD loci.

Published
2021

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

Author

Jue-Sheng Ong, René Thieme, Janusz Jankowski, Jiyuan An, Anne C. Böhmer, Stuart MacGregor, David C. Whiteman, Johannes Schumacher, Claire Palles, Rachel E. Neale, Matthew Law, Puya Gharahkhani, Ines Gockel, John Lai, Catherine M. Olsen, Xikun Han, Beacon, Rebecca C. Fitzgerald, Tom L. Vaughan, Gharahkhani, Puya [0000-0002-4203-5952], Law, Matthew H [0000-0002-4303-8821], Ong, Jue-Sheng [0000-0002-6062-710X], Han, Xikun [0000-0002-3823-7308], Olsen, Catherine M [0000-0003-4483-1888], Böhmer, Anne C [0000-0002-5716-786X], Fitzgerald, Rebecca C [0000-0002-3434-3568], MacGregor, Stuart [0000-0001-6731-8142], and Apollo - University of Cambridge Repository

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, Science, General Physics and Astronomy, Genome-wide association study, Disease, Esophageal Diseases, Genome-wide association studies, Polymorphism, Single Nucleotide, Gastroenterology, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Gastro-oesophageal reflux disease, Internal medicine, Humans, Medicine, Genetic Predisposition to Disease, Allele, Esophagus, Risk factor, lcsh:Science, Cancer genetics, Multidisciplinary, business.industry, Esophageal disease, Oesophageal cancer, General Chemistry, medicine.disease, humanities, digestive system diseases, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, Genetic Loci, 030220 oncology & carcinogenesis, Gastroesophageal Reflux, GERD, Adenocarcinoma, lcsh:Q, Female, business, Genome-Wide Association Study
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., Gastroesophageal reflux disease (GERD) is a major risk factor for Barret’s esophagus (BE) and esophageal adenocarcinoma (EA). Here, An et al. report 25 genetic loci for GERD, many of which associate with BE and EA or with other traits such as BMI.

Published
2019

3. Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries

Author

Gharahkhani, Puya, Jorgenson, Eric, Hysi, Pirro, Khawaja, Anthony P, Pendergrass, Sarah, Han, Xikun, Ong, Jue Sheng, Hewitt, Alex W, Segrè, Ayellet V, Rouhana, John M, Hamel, Andrew R, Igo, Robert P, Choquet, Helene, Qassim, Ayub, Josyula, Navya S, Cooke Bailey, Jessica N, Bonnemaijer, Pieter WM, Iglesias, Adriana, Siggs, Owen M, Young, Terri L, Vitart, Veronique, Thiadens, Alberta AHJ, Karjalainen, Juha, Uebe, Steffen, Melles, Ronald B, Nair, K Saidas, Luben, Robert, Simcoe, Mark, Amersinghe, Nishani, Cree, Angela J, Hohn, Rene, Poplawski, Alicia, Chen, Li Jia, Rong, Shi-Song, Aung, Tin, Vithana, Eranga Nishanthie, NEIGHBORHOOD consortium, ANZRAG consortium, Biobank Japan project, FinnGen study, UK Biobank Eye and Vision Consortium, GIGA study group, 23 and Me Research Team, Tamiya, Gen, Shiga, Yukihiro, Yamamoto, Masayuki, Nakazawa, Toru, Currant, Hannah, Birney, Ewan, Wang, Xin, Auton, Adam, Lupton, Michelle K, Martin, Nicholas G, Ashaye, Adeyinka, Olawoye, Olusola, Williams, Susan E, Akafo, Stephen, Ramsay, Michele, Hashimoto, Kazuki, Kamatani, Yoichiro, Akiyama, Masato, Momozawa, Yukihide, Foster, Paul J, Khaw, Peng T, Morgan, James E, Strouthidis, Nicholas G, Kraft, Peter, Kang, Jae H, Pang, Chi Pui, Pasutto, Francesca, Mitchell, Paul, Lotery, Andrew J, Palotie, Aarno, van Duijn, Cornelia, Haines, Jonathan L, Hammond, Chris, Pasquale, Louis R, Klaver, Caroline CW, Hauser, Michael, Khor, Chiea Chuen, Mackey, David A, Kubo, Michiaki, Cheng, Ching-Yu, Craig, Jamie E, MacGregor, Stuart, Wiggs, Janey L, Epidemiology, Ophthalmology, Clinical Genetics, Gharahkhani, Puya [0000-0002-4203-5952], Jorgenson, Eric [0000-0002-5829-8191], Hysi, Pirro [0000-0001-5752-2510], Khawaja, Anthony P [0000-0001-6802-8585], Han, Xikun [0000-0002-3823-7308], Ong, Jue Sheng [0000-0002-6062-710X], Hewitt, Alex W [0000-0002-5123-5999], Rouhana, John M [0000-0002-8599-0271], Igo, Robert P [0000-0002-0024-1993], Choquet, Helene [0000-0001-9839-8667], Josyula, Navya S [0000-0003-2782-8812], Cooke Bailey, Jessica N [0000-0002-4001-8702], Bonnemaijer, Pieter WM [0000-0001-5154-6765], Iglesias, Adriana [0000-0001-5532-764X], Siggs, Owen M [0000-0003-2840-4851], Young, Terri L [0000-0001-6994-9941], Vitart, Veronique [0000-0002-4991-3797], Thiadens, Alberta AHJ [0000-0002-4911-9462], Luben, Robert [0000-0002-5088-6343], Simcoe, Mark [0000-0003-2432-0810], Cree, Angela J [0000-0002-1987-8900], Poplawski, Alicia [0000-0003-2527-0763], Rong, Shi-Song [0000-0001-8352-6363], Vithana, Eranga Nishanthie [0000-0002-8898-0095], Yamamoto, Masayuki [0000-0002-9073-9436], Currant, Hannah [0000-0003-2764-6787], Birney, Ewan [0000-0001-8314-8497], Wang, Xin [0000-0001-7242-357X], Martin, Nicholas G [0000-0003-4069-8020], Olawoye, Olusola [0000-0003-2357-8924], Williams, Susan E [0000-0002-4479-8638], Ramsay, Michele [0000-0002-4156-4801], Kamatani, Yoichiro [0000-0001-8748-5597], Foster, Paul J [0000-0002-4755-177X], Khaw, Peng T [0000-0002-8087-2268], Kraft, Peter [0000-0002-4472-8103], Kang, Jae H [0000-0003-4812-0557], Pasutto, Francesca [0000-0002-0026-5362], Lotery, Andrew J [0000-0001-5541-4305], Haines, Jonathan L [0000-0002-4351-4728], Hammond, Chris [0000-0002-3227-2620], Pasquale, Louis R [0000-0002-5835-3496], Klaver, Caroline CW [0000-0002-2355-5258], Khor, Chiea Chuen [0000-0002-1128-4729], Cheng, Ching-Yu [0000-0003-0655-885X], MacGregor, Stuart [0000-0001-6731-8142], Wiggs, Janey L [0000-0003-1890-3278], Apollo - University of Cambridge Repository, Institute for Molecular Medicine Finland, Helsinki Institute of Life Science HiLIFE, University of Helsinki, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Genomics of Neurological and Neuropsychiatric Disorders, HUSLAB, HUS Helsinki and Uusimaa Hospital District, APH - Mental Health, APH - Methodology, and Amsterdam Neuroscience - Neuroinfection & -inflammation

Subjects
0301 basic medicine, Aging, genetic structures, General Physics and Astronomy, Glaucoma, PROTEIN, Genome-wide association study, Neurodegenerative, Genome, ANNOTATION, Genome-wide association studies, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], 0302 clinical medicine, Polymorphism (computer science), Genotype, 2.1 Biological and endogenous factors, ANZRAG consortium, Aetiology, GENE-EXPRESSION, Genetics, HUMAN-DISEASES, RISK, Multidisciplinary, and Me Research Team, Single Nucleotide, ASSOCIATION, GIGA study group, Biobank Japan project, 3. Good health, PREVALENCE, Open-Angle, Meta-analysis, NEIGHBORHOOD consortium, Optic nerve diseases, Glaucoma, Open-Angle, Asian Continental Ancestry Group, Open angle glaucoma, Science, European Continental Ancestry Group, FinnGen study, Biology, GENOTYPE IMPUTATION, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, UK Biobank Eye and Vision Consortium, Article, White People, 03 medical and health sciences, Asian People, medicine, Humans, Genetic Predisposition to Disease, 3125 Otorhinolaryngology, ophthalmology, Polymorphism, Eye Disease and Disorders of Vision, Genetic association, MUTATIONS, Human Genome, General Chemistry, medicine.disease, eye diseases, 030104 developmental biology, Genetic Loci, DIFFERENTIAL EXPRESSION ANALYSIS, 030221 ophthalmology & optometry, sense organs, Genome-Wide Association Study
Abstract

Primary open-angle glaucoma (POAG), is a heritable common cause of blindness world-wide. To identify risk loci, we conduct a large multi-ethnic meta-analysis of genome-wide association studies on a total of 34,179 cases and 349,321 controls, identifying 44 previously unreported risk loci and confirming 83 loci that were previously known. The majority of loci have broadly consistent effects across European, Asian and African ancestries. Cross-ancestry data improve fine-mapping of causal variants for several loci. Integration of multiple lines of genetic evidence support the functional relevance of the identified POAG risk loci and highlight potential contributions of several genes to POAG pathogenesis, including SVEP1, RERE, VCAM1, ZNF638, CLIC5, SLC2A12, YAP1, MXRA5, and SMAD6. Several drug compounds targeting POAG risk genes may be potential glaucoma therapeutic candidates., Primary open-angle glaucoma (POAG) is highly heritable, yet not well understood from a genetic perspective. Here, the authors perform a meta-analysis of genome-wide association studies in 34,179 POAG cases, identifying 44 previously unreported risk loci and mapping effects across multiple ethnicities.

Published
2021

4. A comprehensive re-assessment of the association between vitamin D and cancer susceptibility using Mendelian randomization

Author

Ong, Jue-Sheng, Dixon-Suen, Suzanne C., Han, Xikun, An, Jiyuan, Liyanage, Upekha, Dusingize, Jean-Cluade, Schumacher, Johannes, Gockel, Ines, Böhmer, Anne, Jankowski, Janusz, Palles, Claire, O’Mara, Tracy, Spurdle, Amanda, Law, Matthew H., Iles, Mark M., Pharoah, Paul, Berchuck, Andrew, Zheng, Wei, Thrift, Aaron P., Olsen, Catherine, Neale, Rachel E., Gharahkhani, Puya, Webb, Penelope M., MacGregor, Stuart, Fitzgerald, Rebecca, Buas, Matt, Gammon, Marilie D., Corley, Douglas A., Shaheen, Nicholas J., Hardie, Laura J., Bird, Nigel C., Reid, Brian J., Chow, Wong-Ho, Risch, Harvey A., Ye, Weimin, Liu, Geoffrey, Romero, Yvonne, Bernstein, Leslie, Wu, Anna H., Whiteman, David E., Vaughan, Thomas, Agee, M., Alipanahi, B., Auton, A., Bell, R. K., Bryc, K., Elson, S. L., Fontanillas, P., Furlotte, N. A., Hinds, D. A., Huber, K. E., Kleinman, A., Litterman, N. K., McIntyre, M. H., Mountain, J. L., Noblin, E. S., Northover, C. A. M., Pitts, S. J., Sathirapongsasuti, J. Fah, Sazonova, O. V., Shelton, J. F., Shringarpure, S., Tian, C., Tung, J. Y., Vacic, V., Wilson, C. H., Ong, Jue-Sheng [0000-0002-6062-710X], Dixon-Suen, Suzanne C. [0000-0003-3714-8386], Han, Xikun [0000-0002-3823-7308], Gockel, Ines [0000-0001-7423-713X], Böhmer, Anne [0000-0002-5716-786X], O’Mara, Tracy [0000-0002-5436-3232], Spurdle, Amanda [0000-0003-1337-7897], Law, Matthew H. [0000-0002-4303-8821], Iles, Mark M. [0000-0002-2603-6509], Pharoah, Paul [0000-0001-8494-732X], Zheng, Wei [0000-0003-1226-070X], Thrift, Aaron P. [0000-0002-0084-5308], Olsen, Catherine [0000-0003-4483-1888], Gharahkhani, Puya [0000-0002-4203-5952], Webb, Penelope M. [0000-0003-0733-5930], MacGregor, Stuart [0000-0001-6731-8142], and Apollo - University of Cambridge Repository

Subjects
631/67/68, 45/43, article, 692/699/67/2195, 692/4028/67/2324
Abstract

Previous Mendelian randomization (MR) studies on 25-hydroxyvitamin D (25(OH)D) and cancer have typically adopted a handful of variants and found no relationship between 25(OH)D and cancer; however, issues of horizontal pleiotropy cannot be reliably addressed. Using a larger set of variants associated with 25(OH)D (74 SNPs, up from 6 previously), we perform a unified MR analysis to re-evaluate the relationship between 25(OH)D and ten cancers. Our findings are broadly consistent with previous MR studies indicating no relationship, apart from ovarian cancers (OR 0.89; 95% C.I: 0.82 to 0.96 per 1 SD change in 25(OH)D concentration) and basal cell carcinoma (OR 1.16; 95% C.I.: 1.04 to 1.28). However, after adjustment for pigmentation related variables in a multivariable MR framework, the BCC findings were attenuated. Here we report that lower 25(OH)D is unlikely to be a causal risk factor for most cancers, with our study providing more precise confidence intervals than previously possible.

Published
2021
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5. A comprehensive re-assessment of the association between vitamin D and cancer susceptibility using Mendelian randomization

Author

Upekha E Liyanage, Amanda B. Spurdle, K. E. Huber, Anna H. Wu, J. Fah Sathirapongsasuti, Douglas A. Corley, C. Tian, Anne Böhmer, David A. Hinds, A. Auton, Xikun Han, Matt Buas, M. Agee, Rebecca C. Fitzgerald, Puya Gharahkhani, Yvonne Romero, S. L. Elson, Ines Gockel, Johannes Schumacher, Leslie Bernstein, Nigel C. Bird, Thomas L. Vaughan, E. S. Noblin, P. Fontanillas, Laura J. Hardie, Brian J. Reid, V. Vacic, M. H. McIntyre, Jiyuan An, Andrew Berchuck, Claire Palles, Weimin Ye, K. Bryc, S. J. Pitts, Jue-Sheng Ong, Geoffrey Liu, R. K. Bell, Rachel E. Neale, Marilie D. Gammon, J. L. Mountain, C. A. M. Northover, Catherine M. Olsen, C. H. Wilson, Janusz Jankowski, Matthew Law, A. Kleinman, Suzanne C. Dixon-Suen, J. Y. Tung, Aaron P. Thrift, Wong-Ho Chow, Paul Pharoah, Jean-Cluade Dusingize, Suyash Shringarpure, Mark M. Iles, Wei Zheng, N. A. Furlotte, Penelope M. Webb, B. Alipanahi, O. V. Sazonova, Stuart MacGregor, David Whiteman, J. F. Shelton, Harvey A. Risch, N. K. Litterman, Tracy A. O'Mara, Nicholas J. Shaheen, Ong, Jue-Sheng [0000-0002-6062-710X], Dixon-Suen, Suzanne C [0000-0003-3714-8386], Han, Xikun [0000-0002-3823-7308], Gockel, Ines [0000-0001-7423-713X], Böhmer, Anne [0000-0002-5716-786X], O'Mara, Tracy [0000-0002-5436-3232], Spurdle, Amanda [0000-0003-1337-7897], Law, Matthew H [0000-0002-4303-8821], Iles, Mark M [0000-0002-2603-6509], Pharoah, Paul [0000-0001-8494-732X], Zheng, Wei [0000-0003-1226-070X], Thrift, Aaron P [0000-0002-0084-5308], Olsen, Catherine [0000-0003-4483-1888], Gharahkhani, Puya [0000-0002-4203-5952], Webb, Penelope M [0000-0003-0733-5930], MacGregor, Stuart [0000-0001-6731-8142], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, Science, General Physics and Astronomy, Sunburn, Single-nucleotide polymorphism, General Biochemistry, Genetics and Molecular Biology, Article, Cancer prevention, 03 medical and health sciences, 0302 clinical medicine, Cancer epidemiology, Risk Factors, Internal medicine, Neoplasms, Mendelian randomization, Vitamin D and neurology, medicine, Humans, Genetic Predisposition to Disease, 030212 general & internal medicine, Risk factor, Vitamin D, Child, Cancer genetics, Multidisciplinary, business.industry, Pigmentation, Case-control study, Cancer, Mendelian Randomization Analysis, General Chemistry, medicine.disease, Confidence interval, 030104 developmental biology, Case-Control Studies, Multivariate Analysis, business
Abstract

Previous Mendelian randomization (MR) studies on 25-hydroxyvitamin D (25(OH)D) and cancer have typically adopted a handful of variants and found no relationship between 25(OH)D and cancer; however, issues of horizontal pleiotropy cannot be reliably addressed. Using a larger set of variants associated with 25(OH)D (74 SNPs, up from 6 previously), we perform a unified MR analysis to re-evaluate the relationship between 25(OH)D and ten cancers. Our findings are broadly consistent with previous MR studies indicating no relationship, apart from ovarian cancers (OR 0.89; 95% C.I: 0.82 to 0.96 per 1 SD change in 25(OH)D concentration) and basal cell carcinoma (OR 1.16; 95% C.I.: 1.04 to 1.28). However, after adjustment for pigmentation related variables in a multivariable MR framework, the BCC findings were attenuated. Here we report that lower 25(OH)D is unlikely to be a causal risk factor for most cancers, with our study providing more precise confidence intervals than previously possible., Studies of the genetic association between vitamin D and cancer risk have typically been underpowered. Here the authors analyse this using Mendelian Randomisation with more than 70 vitamin D variants obtained from the UK Biobank and large-scale data from various consortia, confirming null associations between vitamin D and most cancers.

Published
2020

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

Author

An, Jiyuan, Gharahkhani, Puya, Law, Matthew H., Ong, Jue-Sheng, Han, Xikun, Olsen, Catherine M., Neale, Rachel E., Lai, John, Vaughan, Tom L., Gockel, Ines, Thieme, René, Böhmer, Anne C., Jankowski, Janusz, Fitzgerald, Rebecca C., Schumacher, Johannes, Palles, Claire, Whiteman, David C., MacGregor, Stuart, Gammon, Marilie D., Corley, Douglas A., Shaheen, Nicholas J., Bird, Nigel C., Hardie, Laura J., Murray, Liam J., Reid, Brian J., Chow, Wong-Ho, Risch, Harvey A., Ye, Weimin, Liu, Geoffrey, Romero, Yvonne, Bernstein, Leslie, Wu, Anna H., Agee, M., Alipanahi, B., Auton, A., Bell, R. K., Bryc, K., Elson, S. L., Fontanillas, P., Furlotte, N. A., Hinds, D. A., Huber, K. E., Kleinman, A., Litterman, N. K., McIntyre, M. H., Mountain, J. L., Noblin, E. S., Northover, C. A. M., Pitts, S. J., Sathirapongsasuti, J. Fah, Sazonova, O. V., Shelton, J. F., Shringarpure, S., Tian, C., Tung, J. Y., Vacic, V., Wilson, C. H., Gharahkhani, Puya [0000-0002-4203-5952], Law, Matthew H. [0000-0002-4303-8821], Ong, Jue-Sheng [0000-0002-6062-710X], Han, Xikun [0000-0002-3823-7308], Olsen, Catherine M. [0000-0003-4483-1888], Böhmer, Anne C. [0000-0002-5716-786X], Fitzgerald, Rebecca C. [0000-0002-3434-3568], MacGregor, Stuart [0000-0001-6731-8142], and Apollo - University of Cambridge Repository

Subjects
631/67/1504/1477, 631/208/205/2138, 45/43, article, 38/39, 631/208/68, 692/699/1503/1476/196, health care economics and organizations, humanities, digestive system diseases
Abstract

Funder: The Swedish Esophageal Cancer Study was funded by grants (R01 CA57947-03) from the National Cancer Institute he California Tobacco Related Research Program (3RT-0122; and; 10RT-0251) Marit Peterson Fund for Melanoma Research. CIDR is supported by contract HHSN268200782096C, 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

7. Evaluating the role of alcohol consumption in breast and ovarian cancer susceptibility using population‐based cohort studies and two‐sample Mendelian randomization analyses

Author

Per Hall, Stig E. Bojesen, Liang-Dar Hwang, Jue-Sheng Ong, Georgia Chenevix-Trench, Keitaro Matsuo, Paul D.P. Pharoah, Eske M. Derks, Douglas F. Easton, Stuart MacGregor, Penelope M. Webb, Mikael Eriksson, Linda E. Kelemen, Andrew Berchuck, Jiyuan An, Ong, Jue-Sheng [0000-0002-6062-710X], Matsuo, Keitaro [0000-0003-1761-6314], Bojesen, Stig E [0000-0002-4061-4133], and Apollo - University of Cambridge Repository

Subjects
Oncology, Cancer Research, medicine.medical_specialty, Alcohol Drinking, Breast Neoplasms, Carcinoma, Ovarian Epithelial, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, breast cancer, Internal medicine, Mendelian randomization, medicine, Odds Ratio, Humans, causal inference, Ovarian Neoplasms, Proportional hazards model, business.industry, Hazard ratio, Confounding, Cancer, Mendelian Randomization Analysis, medicine.disease, 3. Good health, Causality, ovarian cancer, 030220 oncology & carcinogenesis, Observational study, Female, business, Cohort study, alcohol intake
Abstract

Alcohol consumption is correlated positively with risk for breast cancer in observational studies, but observational studies are subject to reverse causation and confounding. The association with epithelial ovarian cancer (EOC) is unclear. We performed both observational Cox regression and two-sample Mendelian randomization (MR) analyses using data from various European cohort studies (observational) and publicly available cancer consortia (MR). These estimates were compared to World Cancer Research Fund (WCRF) findings. In our observational analyses, the multivariable-adjusted hazard ratios (HR) for a one standard drink/day increase was 1.06 (95% confidence interval [CI]; 1.04, 1.08) for breast cancer and 1.00 (0.92, 1.08) for EOC, both of which were consistent with previous WCRF findings. MR ORs per genetically predicted one standard drink/day increase estimated via 34 SNPs using MR-PRESSO were 1.00 (0.93, 1.08) for breast cancer and 0.95 (0.85, 1.06) for EOC. Stratification by EOC subtype or estrogen receptor status in breast cancers made no meaningful difference to the results. For breast cancer, the CIs for the genetically derived estimates include the point-estimate from observational studies so are not inconsistent with a small increase in risk. Our data provide additional evidence that alcohol intake is unlikely to have anything other than a very small effect on risk of EOC.

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