title: MGAS: a powerful tool for multivariate gene-based genome-wide association analysis.
abstract: BACKGROUND
  Standard genome-wide association studies, testing the association between one phenotype and a large number of single nucleotide polymorphisms (SNPs), are limited in two ways: (i) traits are often multivariate, and analysis of composite scores entails loss in statistical power and (ii) gene-based analyses may be preferred, e.g. to decrease the multiple testing problem.
  
  
  RESULTS
  Here we present a new method, multivariate gene-based association test by extended Simes procedure (MGAS), that allows gene-based testing of multivariate phenotypes in unrelated individuals. Through extensive simulation, we show that under most trait-generating genotype-phenotype models MGAS has superior statistical power to detect associated genes compared with gene-based analyses of univariate phenotypic composite scores (i.e. GATES, multiple regression), and multivariate analysis of variance (MANOVA). Re-analysis of metabolic data revealed 32 False Discovery Rate controlled genome-wide significant genes, and 12 regions harboring multiple genes; of these 44 regions, 30 were not reported in the original analysis.
  
  
  CONCLUSIONS
  MGAS allows researchers to conduct their multivariate gene-based analyses efficiently, and without the loss of power that is often associated with an incorrectly specified genotype-phenotype models.
  
  
  METHODS
  MGAS is freely available in KGG v3.0 (http://statgenpro.psychiatry.hku.hk/limx/kgg/download.php). Access to the metabolic dataset can be requested at dbGaP (https://dbgap.ncbi.nlm.nih.gov/). The R-simulation code is available from http://ctglab.nl/people/sophie_van_der_sluis.
  
  
  BACKGROUND
  Supplementary data are available at Bioinformatics online.
authors.affiliation: Department of Complex Trait Genetics, Section Clinical Genetics, Center for Neurogenomics and Cognitive Research (CNCR), VU Medical Center, Amsterdam, The Netherlands, Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands,Department of Biochemistry, State Key Laboratory for Cognitive and Brain Sciences, The Centre for Reproduction, Development and Growth, The Centre for Genomic Sciences and Department of Psychiatry, The University of Hong Kong, Pokfulam, Hong Kong and Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research (CNCR), VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: Sophie
authors.initials: S
authors.lastname: Van der Sluis
authors.affiliation: Department of Complex Trait Genetics, Section Clinical Genetics, Center for Neurogenomics and Cognitive Research (CNCR), VU Medical Center, Amsterdam, The Netherlands, Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands,Department of Biochemistry, State Key Laboratory for Cognitive and Brain Sciences, The Centre for Reproduction, Development and Growth, The Centre for Genomic Sciences and Department of Psychiatry, The University of Hong Kong, Pokfulam, Hong Kong and Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research (CNCR), VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: Conor V
authors.initials: CV
authors.lastname: Dolan
authors.affiliation: Department of Complex Trait Genetics, Section Clinical Genetics, Center for Neurogenomics and Cognitive Research (CNCR), VU Medical Center, Amsterdam, The Netherlands, Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands,Department of Biochemistry, State Key Laboratory for Cognitive and Brain Sciences, The Centre for Reproduction, Development and Growth, The Centre for Genomic Sciences and Department of Psychiatry, The University of Hong Kong, Pokfulam, Hong Kong and Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research (CNCR), VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: Jiang
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Complex Trait Genetics, Section Clinical Genetics, Center for Neurogenomics and Cognitive Research (CNCR), VU Medical Center, Amsterdam, The Netherlands, Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands,Department of Biochemistry, State Key Laboratory for Cognitive and Brain Sciences, The Centre for Reproduction, Development and Growth, The Centre for Genomic Sciences and Department of Psychiatry, The University of Hong Kong, Pokfulam, Hong Kong and Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research (CNCR), VU University Amsterdam, Amsterdam, The Netherlands Department of Complex Trait Genetics, Section Clinical Genetics, Center for Neurogenomics and Cognitive Research (CNCR), VU Medical Center, Amsterdam, The Netherlands, Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands,Department of Biochemistry, State Key Laboratory for Cognitive and Brain Sciences, The Centre for Reproduction, Development and Growth, The Centre for Genomic Sciences and Department of Psychiatry, The University of Hong Kong, Pokfulam, Hong Kong and Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research (CNCR), VU University Amsterdam, Amsterdam, The Netherlands Department of Complex Trait Genetics, Section Clinical Genetics, Center for Neurogenomics and Cognitive Research (CNCR), VU Medical Center, Amsterdam, The Netherlands, Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands,Department of Biochemistry, State Key Laboratory for Cognitive and Brain Sciences, The Centre for Reproduction, Development and Growth, The Centre for Genomic Sciences and Department of Psychiatry, The University of Hong Kong, Pokfulam, Hong Kong and Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research (CNCR), VU University Amsterdam, Amsterdam, The Netherlands Department of Complex Trait Genetics, 
authors.forename: Youqiang
authors.initials: Y
authors.lastname: Song
authors.affiliation: Department of Complex Trait Genetics, Section Clinical Genetics, Center for Neurogenomics and Cognitive Research (CNCR), VU Medical Center, Amsterdam, The Netherlands, Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands,Department of Biochemistry, State Key Laboratory for Cognitive and Brain Sciences, The Centre for Reproduction, Development and Growth, The Centre for Genomic Sciences and Department of Psychiatry, The University of Hong Kong, Pokfulam, Hong Kong and Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research (CNCR), VU University Amsterdam, Amsterdam, The Netherlands Department of Complex Trait Genetics, Section Clinical Genetics, Center for Neurogenomics and Cognitive Research (CNCR), VU Medical Center, Amsterdam, The Netherlands, Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands,Department of Biochemistry, State Key Laboratory for Cognitive and Brain Sciences, The Centre for Reproduction, Development and Growth, The Centre for Genomic Sciences and Department of Psychiatry, The University of Hong Kong, Pokfulam, Hong Kong and Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research (CNCR), VU University Amsterdam, Amsterdam, The Netherlands Department of Complex Trait Genetics, Section Clinical Genetics, Center for Neurogenomics and Cognitive Research (CNCR), VU Medical Center, Amsterdam, The Netherlands, Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands,Department of Biochemistry, State Key Laboratory for Cognitive and Brain Sciences, The Centre for Reproduction, Development and Growth, The Centre for Genomic Sciences and Department of Psychiatry, The University of Hong Kong, Pokfulam, Hong Kong and Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research (CNCR), VU University Amsterdam, Amsterdam, The Netherlands Department of Complex Trait Genetics, 
authors.forename: Pak
authors.initials: P
authors.lastname: Sham
authors.affiliation: Department of Complex Trait Genetics, Section Clinical Genetics, Center for Neurogenomics and Cognitive Research (CNCR), VU Medical Center, Amsterdam, The Netherlands, Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands,Department of Biochemistry, State Key Laboratory for Cognitive and Brain Sciences, The Centre for Reproduction, Development and Growth, The Centre for Genomic Sciences and Department of Psychiatry, The University of Hong Kong, Pokfulam, Hong Kong and Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research (CNCR), VU University Amsterdam, Amsterdam, The Netherlands Department of Complex Trait Genetics, Section Clinical Genetics, Center for Neurogenomics and Cognitive Research (CNCR), VU Medical Center, Amsterdam, The Netherlands, Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands,Department of Biochemistry, State Key Laboratory for Cognitive and Brain Sciences, The Centre for Reproduction, Development and Growth, The Centre for Genomic Sciences and Department of Psychiatry, The University of Hong Kong, Pokfulam, Hong Kong and Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research (CNCR), VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: Danielle
authors.initials: D
authors.lastname: Posthuma
authors.affiliation: Department of Complex Trait Genetics, Section Clinical Genetics, Center for Neurogenomics and Cognitive Research (CNCR), VU Medical Center, Amsterdam, The Netherlands, Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands,Department of Biochemistry, State Key Laboratory for Cognitive and Brain Sciences, The Centre for Reproduction, Development and Growth, The Centre for Genomic Sciences and Department of Psychiatry, The University of Hong Kong, Pokfulam, Hong Kong and Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research (CNCR), VU University Amsterdam, Amsterdam, The Netherlands Department of Complex Trait Genetics, Section Clinical Genetics, Center for Neurogenomics and Cognitive Research (CNCR), VU Medical Center, Amsterdam, The Netherlands, Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands,Department of Biochemistry, State Key Laboratory for Cognitive and Brain Sciences, The Centre for Reproduction, Development and Growth, The Centre for Genomic Sciences and Department of Psychiatry, The University of Hong Kong, Pokfulam, Hong Kong and Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research (CNCR), VU University Amsterdam, Amsterdam, The Netherlands Department of Complex Trait Genetics, Section Clinical Genetics, Center for Neurogenomics and Cognitive Research (CNCR), VU Medical Center, Amsterdam, The Netherlands, Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands,Department of Biochemistry, State Key Laboratory for Cognitive and Brain Sciences, The Centre for Reproduction, Development and Growth, The Centre for Genomic Sciences and Department of Psychiatry, The University of Hong Kong, Pokfulam, Hong Kong and Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research (CNCR), VU University Amsterdam, Amsterdam, The Netherlands Department of Complex Trait Genetics, 
authors.forename: Miao-Xin
authors.initials: MX
authors.lastname: Li
mesh_terms: D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D024821:Metabolic Syndrome / Q000235:genetics*; D015999:Multivariate Analysis; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012984:Software