title: General Framework for Meta-Analysis of Haplotype Association Tests.
abstract: For complex traits, most associated single nucleotide variants (SNV) discovered to date have a small effect, and detection of association is only possible with large sample sizes. Because of patient confidentiality concerns, it is often not possible to pool genetic data from multiple cohorts, and meta-analysis has emerged as the method of choice to combine results from multiple studies. Many meta-analysis methods are available for single SNV analyses. As new approaches allow the capture of low frequency and rare genetic variation, it is of interest to jointly consider multiple variants to improve power. However, for the analysis of haplotypes formed by multiple SNVs, meta-analysis remains a challenge, because different haplotypes may be observed across studies. We propose a two-stage meta-analysis approach to combine haplotype analysis results. In the first stage, each cohort estimate haplotype effect sizes in a regression framework, accounting for relatedness among observations if appropriate. For the second stage, we use a multivariate generalized least square meta-analysis approach to combine haplotype effect estimates from multiple cohorts. Haplotype-specific association tests and a global test of independence between haplotypes and traits are obtained within our framework. We demonstrate through simulation studies that we control the type-I error rate, and our approach is more powerful than inverse variance weighted meta-analysis of single SNV analysis when haplotype effects are present. We replicate a published haplotype association between fasting glucose-associated locus (G6PC2) and fasting glucose in seven studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium and we provide more precise haplotype effect estimates.
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Shuai
authors.initials: S
authors.lastname: Wang
authors.affiliation: MRC Epidemiology Unit, School of Clinical Medicine, University of Cambridge, Box 285 Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, United Kingdom.
authors.forename: Jing Hua
authors.initials: JH
authors.lastname: Zhao
authors.affiliation: Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Ping
authors.initials: P
authors.lastname: An
authors.affiliation: Department of Pediatrics, The Institute for Translational Genomics and Population Sciences, LABioMed at Harbor-UCLA Medical Center, Torrance, California, United States of America.
authors.forename: Xiuqing
authors.initials: X
authors.lastname: Guo
authors.affiliation: Cardiovascular Health Research Unit, University of Washington, Seattle, Washington, United States of America.|Department of Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Jensen
authors.affiliation: MRC Human Genetics Unit, MRC IGMM, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Marten
authors.affiliation: MRC Human Genetics Unit, MRC IGMM, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Huffman
authors.affiliation: Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.
authors.forename: Karina
authors.initials: K
authors.lastname: Meidtner
authors.affiliation: Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.
authors.forename: Heiner
authors.initials: H
authors.lastname: Boeing
authors.affiliation: Generation Scotland, Centre for Genomic and Experimental Medicine, Institute of Genetic and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh, United Kindom.
authors.forename: Archie
authors.initials: A
authors.lastname: Campbell
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, Washington, United States of America.
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Rice
authors.affiliation: MRC Epidemiology Unit, School of Clinical Medicine, University of Cambridge, Box 285 Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, United Kingdom.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Scott
authors.affiliation: Department of Pediatrics, The Institute for Translational Genomics and Population Sciences, LABioMed at Harbor-UCLA Medical Center, Torrance, California, United States of America.
authors.forename: Jie
authors.initials: J
authors.lastname: Yao
authors.affiliation: Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.|German Center for Diabetes Research (DZD), Germany.
authors.forename: Matthias B
authors.initials: MB
authors.lastname: Schulze
authors.affiliation: MRC Epidemiology Unit, School of Clinical Medicine, University of Cambridge, Box 285 Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, United Kingdom.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Wareham
authors.affiliation: Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Ingrid B
authors.initials: IB
authors.lastname: Borecki
authors.affiliation: Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Province
authors.affiliation: Department of Pediatrics, The Institute for Translational Genomics and Population Sciences, LABioMed at Harbor-UCLA Medical Center, Torrance, California, United States of America.
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington, United States of America.|Generation Scotland, Centre for Genomic and Experimental Medicine, Institute of Genetic and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh, United Kindom.
authors.forename: Caroline
authors.initials: C
authors.lastname: Hayward
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors.forename: Mark O
authors.initials: MO
authors.lastname: Goodarzi
authors.affiliation: General Medicine Division, Massachusetts General Hospital, Boston, Massachusetts, United States of America.|Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: James B
authors.initials: JB
authors.lastname: Meigs
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America.|National Heart, Lung, Blood Institute (NHLBI), Framingham Heart Study, Framingham, Massachusetts, United States of America.
authors.forename: Josée
authors.initials: J
authors.lastname: Dupuis
mesh_terms: D000375:Aging; D056970:Co-Repressor Proteins; D015331:Cohort Studies; D004268:DNA-Binding Proteins; D005215:Fasting / Q000378:metabolism; D005260:Female; D056726:Genetic Association Studies; D014644:Genetic Variation / Q000235:genetics; D005947:Glucose / Q000378:metabolism; D005952:Glucose-6-Phosphatase / Q000235:genetics; D006239:Haplotypes / Q000235:genetics*; D006321:Heart; D006801:Humans; D016018:Least-Squares Analysis; D008297:Male; D015201:Meta-Analysis as Topic; D008957:Models, Genetic; D017720:Molecular Epidemiology; D015999:Multivariate Analysis; D009363:Neoplasm Proteins / Q000235:genetics; D010641:Phenotype; D015203:Reproducibility of Results; D012107:Research Design
chemical_list: D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; C430460:JAZF1 protein, human; D009363:Neoplasm Proteins; D005952:Glucose-6-Phosphatase; C492194:G6PC2 protein, human; D005947:Glucose
keywords: family samples; haplotype association tests; linear mixed effects model; meta-analysis