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Analysis of case-control association studies with known risk variants
Zaitlen, Noah ; Paşaniuc, Bogdan ; Patterson, Nick ; Pollack, Samuela ; Voight, Benjamin ; Groop, Leif ; Altshuler, David ; Henderson, Brian E. ; Kolonel, Laurence N. ; Marchand, Loic Le ; Waters, Kevin ; Haiman, Christopher A. ; Stranger, Barbara E. ; Dermitzakis, Emmanouil T. ; Kraft, Peter ; Price, Alkes L.
In: Bioinformatics, 2012, vol. 28, no. 13, p. 1729-1737
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- Titre
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- Analysis of case-control association studies with known risk variants
- Auteur
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- Zaitlen, Noah. Department of Epidemiology, Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA, Center for Human Genetic Research, Department of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, Departments of Genetics and of Medicine, Harvard Medical School, Boston, MA 02115, Department of Clinical Sciences, Diabetes and Endocrinology Research Unit, Scania University Hospital Lund University, Malm, Sweden SE-205, Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA 90089, Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, HI 96813, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115 and Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland CH-1211
- Paşaniuc, Bogdan. Department of Epidemiology, Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA, Center for Human Genetic Research, Department of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, Departments of Genetics and of Medicine, Harvard Medical School, Boston, MA 02115, Department of Clinical Sciences, Diabetes and Endocrinology Research Unit, Scania University Hospital Lund University, Malm, Sweden SE-205, Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA 90089, Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, HI 96813, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115 and Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland CH-1211
- Patterson, Nick. Department of Epidemiology, Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA, Center for Human Genetic Research, Department of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, Departments of Genetics and of Medicine, Harvard Medical School, Boston, MA 02115, Department of Clinical Sciences, Diabetes and Endocrinology Research Unit, Scania University Hospital Lund University, Malm, Sweden SE-205, Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA 90089, Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, HI 96813, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115 and Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland CH-1211
- Pollack, Samuela. Department of Epidemiology, Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA, Center for Human Genetic Research, Department of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, Departments of Genetics and of Medicine, Harvard Medical School, Boston, MA 02115, Department of Clinical Sciences, Diabetes and Endocrinology Research Unit, Scania University Hospital Lund University, Malm, Sweden SE-205, Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA 90089, Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, HI 96813, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115 and Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland CH-1211
- Voight, Benjamin. Department of Epidemiology, Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA, Center for Human Genetic Research, Department of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, Departments of Genetics and of Medicine, Harvard Medical School, Boston, MA 02115, Department of Clinical Sciences, Diabetes and Endocrinology Research Unit, Scania University Hospital Lund University, Malm, Sweden SE-205, Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA 90089, Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, HI 96813, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115 and Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland CH-1211
- Groop, Leif. Department of Epidemiology, Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA, Center for Human Genetic Research, Department of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, Departments of Genetics and of Medicine, Harvard Medical School, Boston, MA 02115, Department of Clinical Sciences, Diabetes and Endocrinology Research Unit, Scania University Hospital Lund University, Malm, Sweden SE-205, Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA 90089, Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, HI 96813, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115 and Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland CH-1211
- Altshuler, David. Department of Epidemiology, Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA, Center for Human Genetic Research, Department of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, Departments of Genetics and of Medicine, Harvard Medical School, Boston, MA 02115, Department of Clinical Sciences, Diabetes and Endocrinology Research Unit, Scania University Hospital Lund University, Malm, Sweden SE-205, Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA 90089, Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, HI 96813, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115 and Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland CH-1211
- Henderson, Brian E.. Department of Epidemiology, Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA, Center for Human Genetic Research, Department of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, Departments of Genetics and of Medicine, Harvard Medical School, Boston, MA 02115, Department of Clinical Sciences, Diabetes and Endocrinology Research Unit, Scania University Hospital Lund University, Malm, Sweden SE-205, Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA 90089, Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, HI 96813, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115 and Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland CH-1211
- Kolonel, Laurence N.. Department of Epidemiology, Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA, Center for Human Genetic Research, Department of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, Departments of Genetics and of Medicine, Harvard Medical School, Boston, MA 02115, Department of Clinical Sciences, Diabetes and Endocrinology Research Unit, Scania University Hospital Lund University, Malm, Sweden SE-205, Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA 90089, Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, HI 96813, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115 and Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland CH-1211
- Marchand, Loic Le. Department of Epidemiology, Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA, Center for Human Genetic Research, Department of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, Departments of Genetics and of Medicine, Harvard Medical School, Boston, MA 02115, Department of Clinical Sciences, Diabetes and Endocrinology Research Unit, Scania University Hospital Lund University, Malm, Sweden SE-205, Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA 90089, Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, HI 96813, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115 and Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland CH-1211
- Waters, Kevin. Department of Epidemiology, Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA, Center for Human Genetic Research, Department of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, Departments of Genetics and of Medicine, Harvard Medical School, Boston, MA 02115, Department of Clinical Sciences, Diabetes and Endocrinology Research Unit, Scania University Hospital Lund University, Malm, Sweden SE-205, Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA 90089, Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, HI 96813, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115 and Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland CH-1211
- Haiman, Christopher A.. Department of Epidemiology, Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA, Center for Human Genetic Research, Department of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, Departments of Genetics and of Medicine, Harvard Medical School, Boston, MA 02115, Department of Clinical Sciences, Diabetes and Endocrinology Research Unit, Scania University Hospital Lund University, Malm, Sweden SE-205, Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA 90089, Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, HI 96813, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115 and Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland CH-1211
- Stranger, Barbara E.. Department of Epidemiology, Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA, Center for Human Genetic Research, Department of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, Departments of Genetics and of Medicine, Harvard Medical School, Boston, MA 02115, Department of Clinical Sciences, Diabetes and Endocrinology Research Unit, Scania University Hospital Lund University, Malm, Sweden SE-205, Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA 90089, Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, HI 96813, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115 and Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland CH-1211
- Dermitzakis, Emmanouil T.. Department of Epidemiology, Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA, Center for Human Genetic Research, Department of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, Departments of Genetics and of Medicine, Harvard Medical School, Boston, MA 02115, Department of Clinical Sciences, Diabetes and Endocrinology Research Unit, Scania University Hospital Lund University, Malm, Sweden SE-205, Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA 90089, Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, HI 96813, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115 and Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland CH-1211
- Kraft, Peter. Department of Epidemiology, Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA, Center for Human Genetic Research, Department of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, Departments of Genetics and of Medicine, Harvard Medical School, Boston, MA 02115, Department of Clinical Sciences, Diabetes and Endocrinology Research Unit, Scania University Hospital Lund University, Malm, Sweden SE-205, Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA 90089, Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, HI 96813, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115 and Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland CH-1211
- Price, Alkes L.. Department of Epidemiology, Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA, Center for Human Genetic Research, Department of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, Departments of Genetics and of Medicine, Harvard Medical School, Boston, MA 02115, Department of Clinical Sciences, Diabetes and Endocrinology Research Unit, Scania University Hospital Lund University, Malm, Sweden SE-205, Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA 90089, Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, HI 96813, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115 and Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland CH-1211
- Type de document
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- Postprint
- Langue
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- Anglais
- Publié dans
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- Bioinformatics, 2012, vol. 28, no. 13, p. 1729-1737. Oxford University Press
- Autre version électronique
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- Publisher's version : https://doi.org/10.1093/bioinformatics/bts259
- Classification
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- Informatique
- Mots clés
- Identifiant OAI-PMH
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- oai:doc.rero.ch:290013
- Summary
- Motivation: The question of how to best use information from known associated variants when conducting disease association studies has yet to be answered. Some studies compute a marginal P-value for each Several Nucleotide Polymorphisms independently, ignoring previously discovered variants. Other studies include known variants as covariates in logistic regression, but a weakness of this standard conditioning strategy is that it does not account for disease prevalence and non-random ascertainment, which can induce a correlation structure between candidate variants and known associated variants even if the variants lie on different chromosomes. Here, we propose a new conditioning approach, which is based in part on the classical technique of liability threshold modeling. Roughly, this method estimates model parameters for each known variant while accounting for the published disease prevalence from the epidemiological literature. Results: We show via simulation and application to empirical datasets that our approach outperforms both the no conditioning strategy and the standard conditioning strategy, with a properly controlled false-positive rate. Furthermore, in multiple data sets involving diseases of low prevalence, standard conditioning produces a severe drop in test statistics whereas our approach generally performs as well or better than no conditioning. Our approach may substantially improve disease gene discovery for diseases with many known risk variants. Availability: LTSOFT software is available online http://www.hsph.harvard.edu/faculty/alkes-price/software/ Contact: nzaitlen@hsph.harvard.edu; aprice@hsph.harvard.edu Supplementary information: Supplementary data are available at Bioinformatics online