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 We examined 32 published and unpublished population and family-based association studies containing up to 14 SNPs spanning the DTNBP1 locus.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.

Keywords:
Genetic association, Heterogeneity, Meta-analysis
This content is only available via PDF.
© 2009 S. Karger AG, Basel
2009
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.