Linkage and Association Studies: Replication

Abstract

Conclusions regarding identification of disease genes are currently limited by the failure to replicate linkage and association findings across studies. Issues such as heterogeneity, limited power and inadequate marker information should be considered carefully to guide design strategies most likely to provide interpretable results across studies.

Keywords: linkage; association; replication; heterogeneity; power

Figure 1.

Examples of heterogeneity. Locus heterogeneity: mutations (or alleles) in two separate genes each cause disease (see sequences a and b in panel 1, which contain disease‐related mutations on separate chromosomes). Allelic heterogeneity: two different mutations (alleles) in the same gene cause disease (see sequences a versus c on c12 and b, d and e on c20 in panel 1; f versus g in panel 2). Haplotype heterogeneity: identical disease mutations (alleles) have different background haplotypes (and linkage disequilibrium structures) due to different population histories (see sequence d versus g).

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Dahlman I, Eaves IA, Kosoy R, et al. (2002) Parameters for reliable results in genetic association studies in common disease. Nature Genetics 30(2): 149–150.

Ioannidis JPA, Ntzani EE, Trikalinos TA and Contopoulos‐Ioannidis DG (2001) Replication validity of genetic association studies. Nature Genetics 29(3): 306–309.

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Wise LH and Lewis CM (1999) A method for meta‐analysis of genome searches: application to simulated data. Genetic Epidemiology 17(supplement 1): S767–S771.

Xu J, Wiesch DG, Taylor EW and Meyers DA (1999) Evaluation of replication studies, combined data analysis, and analytical methods in complex diseases. Genetic Epidemiology 17(supplement 1): S773–S778.

Web Links

Dopamine receptor D2 (DRD2); Locus ID: 1813.LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=1813

Dopamine receptor D2 (DRD2); MIM number: 126450.OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?126450

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Fallin, M Daniele, and Pulver, Ann E(Jan 2006) Linkage and Association Studies: Replication. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1038/npg.els.0005416]