Early Adult-Onset POAG Linked to 15q11-13 Using Ordered Subset Analysis

Primary open-angle glaucoma (POAG) is a complex inherited disorder. At least eight loci have been defined for POAG using family-based linkage studies and a small number of pedigrees (GLC1A-GLC1H) (Wirtz MK, et al. IOVS 1998;39: ARVO Abstract 512).1–3 Mutations in genes located in the GLC1A, GLC1E, and GLC1G loci have been identified in families with POAG. Mutations in MYOC (GLC1A) are associated with approximately 3% to 5% of adult-onset POAG and 10% to 20% of cases of the autosomal dominant juvenile-onset form of POAG.4 Mutations in OPTN (GLC1E) have been found in kindreds in which most family members have an autosomal dominant form of normal-tension glaucoma, a variant of POAG in which statistically elevated intraocular pressure (IOP) is not present.5 In a recent study, mutations in WDR36, a gene located on the long arm of chromosome 5 (GLC1G), have been reported to cause adult-onset POAG.6 Sequence variations of WDR36 were identified in approximately 5% of familial and sporadic cases of POAG. Additional regions of interest have emerged from genome-wide scans using nonparametric methods, completed for mainly white patients with POAG7 and African-Caribbean patients in Barbados.8 These studies have identified nine genomic regions that may harbor POAG-susceptibility genes. Two of these chromosomal regions, 14q11 and 15q11–13 have continued to show evidence of POAG-susceptibility loci after follow-up studies, using additional sibling pairs and additional makers in the regions of interest (Wiggs JL et al., manuscript in preparation). One method used to address genetic heterogeneity and strengthen linkage findings is to incorporate phenotypic subsetting of the data. Most phenotypic stratification approaches require that subsets be identified before linkage studies. An alternative to traditional stratification approaches for incorporating a trait-related covariate is ordered subset analysis (OSA).9 This method provides maximum evidence of linkage, by using the covariate without a priori specification of families to a subset. With this approach, families are ordered by a phenotypic variable (e.g., age of onset, cup-to-disc ratio, or IOP). Linkage analysis with a specific genetic marker set is performed on the first family in the list and then repeated, adding one family each time. In this way, the subset of families with the greatest evidence of linkage can be determined. The goal of OSA is to identify regions of increased linkage in a subset of families. By increasing genetic homogeneity, OSA can also reduce the linkage interval. Subsets with evidence of increased linkage can be used for candidate gene analysis. This approach has been successfully used to confirm and narrow the area of proposed linkage, as well as to define novel regions of linkage in several complex traits, including diabetes,10 Alzheimer disease,11 autism,12 and macular degeneration.13 The age of onset of POAG is difficult to determine because of the absence of symptoms in the early stages of the disease; however, it is well known that the prevalence of POAG is low in persons younger than 50 years and increases dramatically after age 70.14–16 There is some evidence that the age at diagnosis (AAD) has a genetic contribution in POAG. For example, POAG associated with myocilin mutations is frequently diagnosed between 20 and 40 years of age,17 whereas that associated with optineurin mutations is diagnosed at an average of 44 years of age.5 In this report we discuss the use of OSA using age at diagnosis as a covariate in a large POAG multiplex family dataset to identify linkage to a locus on the long arm of chromosome 15, region 11–13, originally identified in a genome-wide scan.7