Brion S Maher1, Mark A Reimers, Brien P Riley, Kenneth S Kendler. 1. Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA 23298-0126, USA. bsmaher@vcu.edu
Abstract
BACKGROUND/AIMS: Meta-analysis of genetic association studies is a useful approach when individual investigations do not yield studywise significant results but the evidence across studies is modest and homogeneous. Current meta-analysis methods account for heterogeneity by down-weighting studies as a function of between-study variance. We contend that current approaches may obscure interesting phenomena in genetic association data. However, an appropriate approach to examining heterogeneity across studies is lacking. METHODS: We develop a novel approach, based on the EM algorithm, to detect allelic heterogeneity, identify subpopulations and assign studies to those subpopulations. We then apply these methods to the association between DTNBP1 and schizophrenia (Scz), one of the most studied relationships in complex disease genetics. We examined 32 published and unpublished population and family-based association studies containing up to 14 SNPs spanning the DTNBP1 locus. RESULTS: We explored heterogeneity in several ways including meta-regression and approaches aimed at exploring the mixture of heterogeneous studies at a particular SNP. We found significant evidence for a mixture of association distributions at multiple loci. CONCLUSION: We propose a novel approach that is broadly applicable and may be useful in large scale genetic association meta-analyses to detect significant allelic heterogeneity. Copyright 2009 S. Karger AG, Basel.
BACKGROUND/AIMS: Meta-analysis of genetic association studies is a useful approach when individual investigations do not yield studywise significant results but the evidence across studies is modest and homogeneous. Current meta-analysis methods account for heterogeneity by down-weighting studies as a function of between-study variance. We contend that current approaches may obscure interesting phenomena in genetic association data. However, an appropriate approach to examining heterogeneity across studies is lacking. METHODS: We develop a novel approach, based on the EM algorithm, to detect allelic heterogeneity, identify subpopulations and assign studies to those subpopulations. We then apply these methods to the association between DTNBP1 and schizophrenia (Scz), one of the most studied relationships in complex disease genetics. We examined 32 published and unpublished population and family-based association studies containing up to 14 SNPs spanning the DTNBP1 locus. RESULTS: We explored heterogeneity in several ways including meta-regression and approaches aimed at exploring the mixture of heterogeneous studies at a particular SNP. We found significant evidence for a mixture of association distributions at multiple loci. CONCLUSION: We propose a novel approach that is broadly applicable and may be useful in large scale genetic association meta-analyses to detect significant allelic heterogeneity. Copyright 2009 S. Karger AG, Basel.
Authors: Mousumi Mutsuddi; Derek W Morris; Skye G Waggoner; Mark J Daly; Edward M Scolnick; Pamela Sklar Journal: Am J Hum Genet Date: 2006-10-03 Impact factor: 11.025
Authors: Brion S Maher; Vladimir I Vladimirov; Shawn J Latendresse; Dawn L Thiselton; Rebecca McNamee; Moonsu Kang; Tim B Bigdeli; Xiangning Chen; Brien P Riley; John M Hettema; Howard Chilcoat; Christian Heidbreder; Pierandrea Muglia; E Lenn Murrelle; Danielle M Dick; Fazil Aliev; Arpana Agrawal; Howard J Edenberg; John Kramer; John Nurnberger; Jay A Tischfield; Bernie Devlin; Robert E Ferrell; Galina P Kirillova; Ralph E Tarter; Kenneth S Kendler; Michael M Vanyukov Journal: Biol Psychiatry Date: 2011-04-22 Impact factor: 13.382
Authors: Sarah E Bergen; Ayman H Fanous; Po-Hsiu Kuo; Brandon K Wormley; F Anthony O'Neill; Dermot Walsh; Brien P Riley; Kenneth S Kendler Journal: Am J Med Genet B Neuropsychiatr Genet Date: 2010-03-05 Impact factor: 3.568
Authors: Dilafruz Juraeva; Jens Treutlein; Henrike Scholz; Josef Frank; Franziska Degenhardt; Sven Cichon; Monika Ridinger; Manuel Mattheisen; Stephanie H Witt; Maren Lang; Wolfgang H Sommer; Per Hoffmann; Stefan Herms; Norbert Wodarz; Michael Soyka; Peter Zill; Wolfgang Maier; Elisabeth Jünger; Wolfgang Gaebel; Norbert Dahmen; Norbert Scherbaum; Christine Schmäl; Michael Steffens; Susanne Lucae; Marcus Ising; Michael N Smolka; Ulrich S Zimmermann; Bertram Müller-Myhsok; Markus M Nöthen; Karl Mann; Falk Kiefer; Rainer Spanagel; Benedikt Brors; Marcella Rietschel Journal: Neuropsychopharmacology Date: 2014-07-18 Impact factor: 7.853
Authors: T Bernard Bigdeli; Brion S Maher; Zhongming Zhao; Edwin J C G van den Oord; Dawn L Thiselton; Jingchun Sun; Bradley T Webb; Richard L Amdur; Brandon Wormley; Francis A O'Neill; Dermot Walsh; Brien P Riley; Kenneth S Kendler; Ayman H Fanous Journal: PLoS One Date: 2011-12-29 Impact factor: 3.240