Abstract

Studies using genome-wide platforms have yielded an unprecedented number of promising signals of association between genomic variants and human traits. This Review addresses the steps required to validate, augment and refine such signals to identify underlying causal variants for well-defined phenotypes. These steps include: large-scale exact replication across both similar and diverse populations; fine mapping and resequencing; determination of the most informative markers and multiple independent informative loci; incorporation of functional information; and improved phenotype mapping of the implicated genetic effects. Even in cases for which replication proves that an effect exists, confident localization of the causal variant often remains elusive.

Author affiliations

1. Clinical and Molecular Epidemiology Unit, Department of Hygiene and Epidemiology, University of Ioannina School of Medicine and Biomedical Research Institute, Foundation for Research and Technology — Hellas, Ioannina 45110, Greece.
2. Center for Genetic Epidemiology and Modelling, Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, and Tufts Clinical and Translational Science Institute, Boston, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
3. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892, USA.
4. Fondation Synergie, INSERM U590, Centre Léon Bérard, 28 Rue Laënnec, 69373 Lyon Cedex 08, France.
5. Center for Human Genetic Research, Massachusetts General Hospital, Richard B. Simches Research Center, Boston, Massachusetts 02114, USA.
6. The Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.

Correspondence to: John P. A. Ioannidis^1,2 Email: jioannid@cc.uoi.gr

MORE ARTICLES LIKE THIS

These links to content published by NPG are automatically generated.