caa a22 4500 445861002 CHVBK 20180317145443.0 cr unu---uuuuu 170323e20111101xx s 000 0 eng 10.1007/s00439-011-0974-0 doi (NATIONALLICENCE)springer-10.1007/s00439-011-0974-0 The efficacy of detecting variants with small effects on the Affymetrix 6.0 platform using pooled DNA [Elektronische Daten] [Charleston Chiang, Zofia Gajdos, Joshua Korn, Johannah Butler, Rachel Hackett, Candace Guiducci, Thutrang Nguyen, Rainford Wilks, Terrence Forrester, Katherine Henderson, Loic Le Marchand, Brian Henderson, Christopher Haiman, Richard Cooper, Helen Lyon, Xiaofeng Zhu, Colin McKenzie, Mark Palmert, Joel Hirschhorn] Genome-wide genotyping of a cohort using pools rather than individual samples has long been proposed as a cost-saving alternative for performing genome-wide association (GWA) studies. However, successful disease gene mapping using pooled genotyping has thus far been limited to detecting common variants with large effect sizes, which tend not to exist for many complex common diseases or traits. Therefore, for DNA pooling to be a viable strategy for conducting GWA studies, it is important to determine whether commonly used genome-wide SNP array platforms such as the Affymetrix 6.0 array can reliably detect common variants of small effect sizes using pooled DNA. Taking obesity and age at menarche as examples of human complex traits, we assessed the feasibility of genome-wide genotyping of pooled DNA as a single-stage design for phenotype association. By individually genotyping the top associations identified by pooling, we obtained a 14- to 16-fold enrichment of SNPs nominally associated with the phenotype, but we likely missed the top true associations. In addition, we assessed whether genotyping pooled DNA can serve as an inexpensive screen as the second stage of a multi-stage design with a large number of samples by comparing the most cost-effective 3-stage designs with 80% power to detect common variants with genotypic relative risk of 1.1, with and without pooling. Given the current state of the specific technology we employed and the associated genotyping costs, we showed through simulation that a design involving pooling would be 1.07 times more expensive than a design without pooling. Thus, while a significant amount of information exists within the data from pooled DNA, our analysis does not support genotyping pooled DNA as a means to efficiently identify common variants contributing small effects to phenotypes of interest. While our conclusions were based on the specific technology and study design we employed, the approach presented here will be useful for evaluating the utility of other or future genome-wide genotyping platforms in pooled DNA studies. Springer-Verlag, 2011 Chiang Charleston Department of Genetics, Harvard Medical School, 02115, Boston, MA, USA aut Gajdos Zofia Department of Genetics, Harvard Medical School, 02115, Boston, MA, USA aut Korn Joshua Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA aut Butler Johannah Program in Genomics and Divisions of Genetics and Endocrinology, Children's Hospital, Boston, MA, USA aut Hackett Rachel Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA aut Guiducci Candace Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA aut Nguyen Thutrang Program in Genomics and Divisions of Genetics and Endocrinology, Children's Hospital, Boston, MA, USA aut Wilks Rainford Epidemiology Research Unit, Tropical Medicine Research Institute, University of the West Indies, Kingston, Jamaica aut Forrester Terrence Tropical Metabolism Research Unit, Tropical Medicine Research Institute, University of the West Indies, Kingston, Jamaica aut Henderson Katherine Division of Cancer Etiology, Department of Population Sciences, City of Hope National Medical Center, Duarte, CA, USA aut Le Marchand Loic Epidemiology Program, Cancer Research Center of Hawaii, University of Hawaii, Honolulu, HI, USA aut Henderson Brian Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA aut Haiman Christopher Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA aut Cooper Richard Department of Preventive Medicine and Epidemiology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA aut Lyon Helen Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA aut Zhu Xiaofeng Department of Biostatistics and Epidemiology, Case Western Reserve University, Cleveland, OH, USA aut McKenzie Colin Tropical Metabolism Research Unit, Tropical Medicine Research Institute, University of the West Indies, Kingston, Jamaica aut Palmert Mark Division of Endocrinology, The Hospital for Sick Children, Toronto, ON, Canada aut Hirschhorn Joel Department of Genetics, Harvard Medical School, 02115, Boston, MA, USA aut Human Genetics Springer-Verlag 130/5(2011-11-01), 607-621 0340-6717 130:5<607 2011 130 439 https://doi.org/10.1007/s00439-011-0974-0 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s00439-011-0974-0 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Chiang Charleston Department of Genetics, Harvard Medical School, 02115, Boston, MA, USA aut NATIONALLICENCE 700 1- Gajdos Zofia Department of Genetics, Harvard Medical School, 02115, Boston, MA, USA aut NATIONALLICENCE 700 1- Korn Joshua Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA aut NATIONALLICENCE 700 1- Butler Johannah Program in Genomics and Divisions of Genetics and Endocrinology, Children's Hospital, Boston, MA, USA aut NATIONALLICENCE 700 1- Hackett Rachel Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA aut NATIONALLICENCE 700 1- Guiducci Candace Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA aut NATIONALLICENCE 700 1- Nguyen Thutrang Program in Genomics and Divisions of Genetics and Endocrinology, Children's Hospital, Boston, MA, USA aut NATIONALLICENCE 700 1- Wilks Rainford Epidemiology Research Unit, Tropical Medicine Research Institute, University of the West Indies, Kingston, Jamaica aut NATIONALLICENCE 700 1- Forrester Terrence Tropical Metabolism Research Unit, Tropical Medicine Research Institute, University of the West Indies, Kingston, Jamaica aut NATIONALLICENCE 700 1- Henderson Katherine Division of Cancer Etiology, Department of Population Sciences, City of Hope National Medical Center, Duarte, CA, USA aut NATIONALLICENCE 700 1- Le Marchand Loic Epidemiology Program, Cancer Research Center of Hawaii, University of Hawaii, Honolulu, HI, USA aut NATIONALLICENCE 700 1- Henderson Brian Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA aut NATIONALLICENCE 700 1- Haiman Christopher Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA aut NATIONALLICENCE 700 1- Cooper Richard Department of Preventive Medicine and Epidemiology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA aut NATIONALLICENCE 700 1- Lyon Helen Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA aut NATIONALLICENCE 700 1- Zhu Xiaofeng Department of Biostatistics and Epidemiology, Case Western Reserve University, Cleveland, OH, USA aut NATIONALLICENCE 700 1- McKenzie Colin Tropical Metabolism Research Unit, Tropical Medicine Research Institute, University of the West Indies, Kingston, Jamaica aut NATIONALLICENCE 700 1- Palmert Mark Division of Endocrinology, The Hospital for Sick Children, Toronto, ON, Canada aut NATIONALLICENCE 700 1- Hirschhorn Joel Department of Genetics, Harvard Medical School, 02115, Boston, MA, USA aut NATIONALLICENCE 773 0- Human Genetics Springer-Verlag 130/5(2011-11-01), 607-621 0340-6717 130:5<607 2011 130 439 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer