Early adult-onset POAG linked to 15q11-13 using ordered subset analysis

Abstract

Purpose: Primary open-angle glaucoma (POAG) is a complex inherited disorder. It has been demonstrated in other complex disorders that phenotypic heterogeneity may be the result of genetic heterogeneity and that stratification analysis can be used to increase the power of detection. Ordered subset analysis (OSA) is a recently described method that utilizes the variability of phenotypic traits to determine underlying genetic heterogeneity.

Methods: Eighty-six multiplex families with POAG were clinically ascertained for genetic analysis. Age at diagnosis (AAD) was used as a surrogate for age of onset in affected family members. Nine genetic markers within the 15q11-13 interval on chromosome 15 were used for OSA analysis.

Results: An 11-cM linkage interval with a peak LOD score of 3.24 centered at the GABRB3 locus (P = 0.013 by permutation test) was identified in a subset of 15 families, which represents 17% of the total dataset (15/86 families). The mean AAD for the affected OSA families was 44.1 +/- 9.1 years (SD). The mean AAD for the complementary group was 61.3 +/- 10.4 years. African-American and white families were well represented in the OSA subset.

Conclusions: Linkage was identified for POAG to an 11-cM region on chromosome 15, designated GLC1I. This result provides further evidence that AAD and other phenotypic traits can be used as stratification variables to identify genes in complex disorders such as POAG and suggests that the 15q11-13 locus is one of the largest genetic contributors to POAG identified to date.

Figure 1

Identification of a genetically homogeneous subpopulation of POAG families within an 81-family dataset. Families are ranked by age at diagnosis, and added sequentially to the linkage analysis. The maximum LOD* score of 3.05 is obtained with a 15-family subset.

Figure 2

The 15q linkage peak in a subset of families with an early-onset form of POAG. Solid line: the linkage peak in all 81 multiplex families analyzed; broken line: the linkage peak in the 15-family OSA subset. The OSA linkage peak was centered at 6.3 cM, with a minimum candidate interval (1 LOD-unit down method) of approximately 11 cM.