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R.R. Allingham, E.R. Hauser, J.L. Wiggs, M.A. Hauser, F.L. Graham, K.R. Abramson, E.A. del Bono, J.R. Shi, J.L. Haines, M.A. Pericak-Vance; Ordered Subset Analysis in Primary Open-Angle Glaucoma (POAG): Evidence for Linkage to Chromosomes 14 and 15 . Invest. Ophthalmol. Vis. Sci. 2003;44(13):3170.
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Purpose: We have previously identified regions on chromosomes 14 and 15 that are associated with early-onset POAG (Allingham et al, 2001). Ordered Subset Analysis (OSA) can be used to further reduce the impact of phenotypic heterogeneity in complex diseases (Hauser et al. 1998; Ghosh et al. 2000). In this study we used OSA to identify homogeneous family subgroups on the basis of age of diagnosis (AOD). Methods: POAG was defined as: age of onset (AOO) (based on age of first diagnosis (AOD)) > 35yrs for the proband and 2 of the following criteria: untreated IOP > 21 mmHg OU; glaucomatous optic neuropathy OU; and visual field loss in at least one eye. Secondary causes of glaucoma were excluded. OSA analysis was performed on regions in chromosomes 14 and 15 discussed above. Multipoint lod scores were calculated using information from all available affected relative pairs via GENEHUNTER-PLUS software package incorporating Kong and Cox's model (Kruglyak et al. 1996; Kong et. al. 1997). These multipoint lod scores were used to calculate the OSA statistic. Results: Eighty-six multiplex families with completed genotype and covariate information were included in this analysis. The AOD covariate information yielded a significant increase in the LOD scores seen in chromosomes 14 and 15 with empirical p-values £ 0.05. When this data set was analyzed using mean AOD, the peak OSA LOD score for chromosome 14 was 3.68 (DLOD=1.90) at D14S72 (subset=fourteen families). Similarly, the peak for chromosome 15 was 3.19 (DLOD=1.78) at GABRB3 (subset= sixteen families). We had similar increases in the peak LOD score when we analyzed minimum AOD. There is significant overlap between the families linking to both chromosomes. Conclusions: We have identified homogeneous phenotypic subsets of families that contribute to linkage on both chromosomes 14 and 15. These data provide additional evidence that AOD is a useful stratification variable in identifying genes in POAG.
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