Linkage and Association Studies: Replication


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).



Arinami T, Gao M, Hamaguchi H and Toru M (1997) A functional polymorphism in the promoter region of the dopamine D2 receptor gene is associated with schizophrenia. Human Molecular Genetics 6(4): 577–582.

Arolt V, Lencer R, Purmann S, et al. (1999) Testing for linkage of eye tracking dysfunction and schizophrenia to markers on chromosomes 6, 8, 9, 20, and 22 in families multiply affected with schizophrenia. American Journal of Medical Genetics 88(6): 603–606.

Berrettini WH (2000) Susceptibility loci for bipolar disorder: overlap with inherited vulnerability to schizophrenia. Biological Psychiatry 47(3): 245–251.

Cannon TD, Kaprio J, Lonnqvist J, Huttunen M and Koskenvuo M (1998) The genetic epidemiology of schizophrenia in a Finnish twin cohort. A population‐based modeling study. Archives of General Psychiatry 55(1): 67–74.

Cloninger CR, Kaufmann CA, Faraone SV, et al. (1998) Genome‐wide search for schizophrenia susceptibility loci: the NIMH Genetics Initiative and Millennium Consortium. American Journal of Medical Genetics 81(4): 275–281.

Easterbrook PJ, Berlin JA, Gopalan R and Matthews DR (1991) Publication bias in clinical research. The Lancet 337(8746): 867–872.

Fallin D, Cohen A, Essioux L, et al. (2001) Genetic analysis of case/control data using estimated haplotype frequencies: application to APOE locus variation and Alzheimer disease. Genome Research 11: 143–151.

Gu C, Province MA and Rao DC (2001) Meta‐analysis for model‐free methods. Advances in Genetics 42: 255–272.

Levinson DF, Holmans P, Straub RE, et al. (2000) Multicenter linkage study of schizophrenia candidate regions on chromosomes 5q, 6q, 10p, and 13q: schizophrenia linkage collaborative group III. American Journal of Human Genetics 67(3): 652–663.

NIA Aging and Genetic Epidemiology Working Group (2000) Genetic epidemiologic studies on age‐specified traits. American Journal of Epidemiology 152(11): 1003–1008.

Olson JM (1999) A general conditional‐logistic model for affected‐relative‐pair linkage studies. American Journal of Human Genetics 65(6): 1760–1769.

Potash JB, Willour VL, Chiu YF, et al. (2001) The familial aggregation of psychotic symptoms in bipolar disorder pedigrees. American Journal of Psychiatry 158(8): 1258–1264.

Pritchard JK, Stephens M, Rosenberg NA and Donnelly P (2000) Association mapping in structured populations. American Journal of Human Genetics 67(1): 170–181.

Pulver AE, Mulle J, Nestadt G, et al. (2000) Genetic heterogeneity in schizophrenia: stratification of genome scan data using co‐segregating related phenotypes. Molecular Psychiatry 5(6): 650–653.

Schaid DJ, McDonnell SK and Thibodeau SN (2001) Regression models for linkage heterogeneity applied to familial prostate cancer. American Journal of Human Genetics 68(5): 1189–1196.

Schizophrenia Linkage Collaborative Group for Chromosomes 3, 6 and 8 (1996) Additional support for schizophrenia linkage on chromosomes 6 and 8: a multicenter study. American Journal of Medical Genetics 67(6): 580–594.

Shannon WD, Province MA and Rao DC (2001) Tree‐based recursive partitioning methods for subdividing sibpairs into relatively more homogeneous subgroups. Genetic Epidemiology 20(3): 293–306.

Spurlock G, Williams J, McGuffin P, et al. (1998) European Multicentre Association Study of Schizophrenia: a study of the DRD2 Ser311Cys and DRD3 Ser9Gly polymorphisms. American Journal of Medical Genetics 81(1): 24–28.

Further Reading

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.

Thomson G (2001) Significance levels in genome scans. Advances in Genetics 42: 475–486.

Vieland VJ (2001) The replication requirement. Nature Genetics 29(3): 244–245.

Wang K, Vieland VJ and Huang J (1999) A Bayesian approach to replication of linkage findings. Genetic Epidemiology 17 (supplement 1): S749–S754.

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:

Dopamine receptor D2 (DRD2); MIM number: 126450.OMIM:‐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. [doi: 10.1038/npg.els.0005416]