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Editors Selection IGR 11-2

Genetics: Fine mapping locus on chromosome 2

Comment by Subhabrata Chakrabarti on:

24546 Common variants on chromosome 2 and risk of primary open-angle glaucoma in the Afro-Caribbean population of Barbados, Xiaodong J; Zhenglin Y; Xian Y et al., Proceedings of the National Academy of Sciences of the United States of America, 2009; 106: 17105-17110

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Xiaodong et al. (1405) provide evidence of fine mapping of a previously mapped primary open-angle glaucoma (POAG) locus on chromosome 2 in the Barabados population. This is a well designed study in understanding the underlying molecular genetic mechanisms in POAG. The strength of the study lies in the fact that it was based on whole genome scan and linkage analysis with microsatellite markers in a large number of POAG families (n = 146) from an isolated and homogeneous population. Fine mapping of the linked region was accomplished with microsatellites in these families followed by narrowing of the disease locus with the help of 30 tag-single nucleotide polymorphisms (SNPs) within the mapped region in a case-control cohort drawn from the affected families. Two SNPs exhibited strong association with POAG and were in tight linkage disequilibrium and also formed a risk haplotype within the disease interval. These results were further validated in another unrelated POAG cohort from Barabados. Confounding issues in genetic association studies due to population stratification were convincingly addressed in this population by appropriate statistical algorithms. Thus, this study illustrates the merits of using a relatively less diverse population and also demonstrates a thorough step-wise procedure for gene mapping in a complex disease.

Fine mapping of a primary openangle glaucoma (POAG) locus on chromosome 2

The linked region overlaps a previously mapped locus on chromosome 2 in the Chinese and European populations as well. Thus, it would be intersting to see the replication of this SNP-linked region among the other ethnically different and geographically distant populations, which would further establish the universality of this association. The functional implications of this associated genomic region would be better understood when the precise variation(s) in the specific gene(s) leading to the disease pathogenesis are characterized. Overall, this study identified potential markers for POAG susceptibility in an Afro-Caribbean population that may be useful for predictive testing.

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