title: Meta-analysis of gene-level tests for rare variant association.
abstract: The majority of reported complex disease associations for common genetic variants have been identified through meta-analysis, a powerful approach that enables the use of large sample sizes while protecting against common artifacts due to population structure and repeated small-sample analyses sharing individual-level data. As the focus of genetic association studies shifts to rare variants, genes and other functional units are becoming the focus of analysis. Here we propose and evaluate new approaches for performing meta-analysis of rare variant association tests, including burden tests, weighted burden tests, variable-threshold tests and tests that allow variants with opposite effects to be grouped together. We show that our approach retains useful features from single-variant meta-analysis approaches and demonstrate its use in a study of blood lipid levels in ∼18,500 individuals genotyped with exome arrays.
authors: 1] Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan, USA. [2].
authors: Dajiang J
authors: DJ
authors: Liu
authors: 1] Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [2] Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA. [3] Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA. [4].
authors: Gina M
authors: GM
authors: Peloso
authors: 1] Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan, USA. [2].
authors: Xiaowei
authors: X
authors: Zhan
authors: 1] HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, Norway. [2] St. Olav Hospital, Trondheim University Hospital, Trondheim, Norway. [3].
authors: Oddgeir L
authors: OL
authors: Holmen
authors: Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan, USA.
authors: Matthew
authors: M
authors: Zawistowski
authors: Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan, USA.
authors: Shuang
authors: S
authors: Feng
authors: University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
authors: Majid
authors: M
authors: Nikpay
authors: 1] Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. [2] School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin, USA.
authors: Paul L
authors: PL
authors: Auer
authors: 1] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. [2] Department of Cardiovascular Medicine, University of Oxford, Oxford, UK.
authors: Anuj
authors: A
authors: Goel
authors: 1] Division of Cardiology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA. [2] Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors: He
authors: H
authors: Zhang
authors: 1] Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. [2] Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington, USA.
authors: Ulrike
authors: U
authors: Peters
authors: 1] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. [2] Department of Cardiovascular Medicine, University of Oxford, Oxford, UK.
authors: Martin
authors: M
authors: Farrall
authors: 1] Department of Cardiovascular Medicine, University of Oxford, Oxford, UK. [2] Department of Clinical Sciences, Lund University, Malmö, Sweden.
authors: Marju
authors: M
authors: Orho-Melander
authors: 1] Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. [2] Department of Biostatistics, University of Washington School of Public Health, Seattle, Washington, USA.
authors: Charles
authors: C
authors: Kooperberg
authors: University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
authors: Ruth
authors: R
authors: McPherson
authors: 1] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. [2] Department of Cardiovascular Medicine, University of Oxford, Oxford, UK.
authors: Hugh
authors: H
authors: Watkins
authors: 1] Division of Cardiology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA. [2] Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors: Cristen J
authors: CJ
authors: Willer
authors: 1] HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, Norway. [2] Department of Medicine, Levanger Hospital, Nord-Trøndelag Health Trust, Levanger, Norway.
authors: Kristian
authors: K
authors: Hveem
authors: 1] Department of Cardiovascular Medicine, University of Oxford, Oxford, UK. [2] Department of Clinical Sciences, Lund University, Malmö, Sweden.
authors: Olle
authors: O
authors: Melander
authors: 1] Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [2] Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA. [3] Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA. [4] Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. [5].
authors: Sekar
authors: S
authors: Kathiresan
authors: 1] Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan, USA. [2].
authors: Gonçalo R
authors: GR
authors: Abecasis
mesh_terms: D003627:Data Interpretation, Statistical; D059472:Exome / Q000235:genetics; D056726:Genetic Association Studies / Q000379:methods*; D014644:Genetic Variation; D005828:Genetics, Population; D005838:Genotype; D006801:Humans; D008055:Lipids / Q000097:blood / Q000235:genetics*; D015201:Meta-Analysis as Topic; D008957:Models, Genetic; D009010:Monte Carlo Method; D012107:Research Design
chemical_list: D008055:Lipids