Browsing by Author "Challa, P."

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GALC deletions increase the risk of primary Open-Angle Glaucoma: The role of mendelian variants in complex disease
(Public Library of Science, 2013) Liu, Y.; Gibson, J.; Wheeler, J.; Kwee, L.C.; Santiago-Turla, C.M.; Akafo, S.K.; Lichter, P.R.; Gaasterland, D.E.; Moroi, S.E.; Challa, P.; Herndon, L.W.; Girkin, C.A.; Budenz, D.L.; Richards, J.E.; Allingham, R.R.; Hauser, M.A.
DNA copy number variants (CNVs) have been reported in many human diseases including autism and schizophrenia. Primary Open Angle Glaucoma (POAG) is a complex adult-onset disorder characterized by progressive optic neuropathy and vision loss. Previous studies have identified rare CNVs in POAG; however, their low frequencies prevented formal association testing. We present here the association between POAG risk and a heterozygous deletion in the galactosylceramidase gene (GALC). This CNV was initially identified in a dataset containing 71 Caucasian POAG cases and 478 ethnically matched controls obtained from dbGAP (study accession phs000126.v1.p1.) (p = 0.017, fisher's exact test). It was validated with array comparative genomic hybridization (arrayCGH) and realtime PCR, and replicated in an independent POAG dataset containing 959 cases and 1852 controls (p = 0.021, OR (odds ratio) = 3.5, 95% CI -1.1-12.0). Evidence for association was strengthened when the discovery and replication datasets were combined (p = 0.002; OR = 5.0, 95% CI 1.6-16.4). Several deletions with different endpoints were identified by array CGH of POAG patients. Homozygous deletions that eliminate GALC enzymatic activity cause Krabbe disease, a recessive Mendelian disorder of childhood displaying bilateral optic neuropathy and vision loss. Our findings suggest that heterozygous deletions that reduce GALC activity are a novel mechanism increasing risk of POAG. This is the first report of a statistically-significant association of a CNV with POAG risk, contributing to a growing body of evidence that CNVs play an important role in complex, inherited disorders. Our findings suggest an attractive biomarker and potential therapeutic target for patients with this form of POAG.
Genome-Wide Linkage Scan for Primary Open Angle Glaucoma: Influences of Ancestry and Age at Diagnosis
(2011) Crooks, Kristy R.; Allingham, R.R.; Qin, Xuejun; Yutao, Liu.; Gibson, J.R.; Santiago-Turla, C.; Larocque-Abramson, K.R.; Del Bono, E.; Challa, P.; Akafo, S.; Wiggs, J.L.; Schmidt, S.; Hauser, M.A.
Primary open-angle glaucoma (POAG) is the most common form of glaucoma and one of the leading causes of vision loss worldwide. The genetic etiology of POAG is complex and poorly understood. The purpose of this work is to identify genomic regions of interest linked to POAG. This study is the largest genetic linkage study of POAG performed to date: genomic DNA samples from 786 subjects (538 Caucasian ancestry, 248 African ancestry) were genotyped using either the Illumina GoldenGate Linkage 4 Panel or the Illumina Infinium Human Linkage-12 Panel. A total of 5233 SNPs was analyzed in 134 multiplex POAG families (89 Caucasian ancestry, 45 African ancestry). Parametric and non-parametric linkage analyses were performed on the overall dataset and within race-specific datasets (Caucasian ancestry and African ancestry). Ordered subset analysis was used to stratify the data on the basis of age of glaucoma diagnosis. Novel linkage regions were identified on chromosomes 1 and 20, and two previously described loci—GLC1D on chromosome 8 and GLC1I on chromosome 15—were replicated. These data will prove valuable in the context of interpreting results from genome-wide association studies for POAG.
Genome-Wide linkage scan for primary open angle glaucoma: Influences of ancestry and age at diagnosis
(Public Library of Science, 2013) Crooks, K.R.; Allingham, R.R.; Qin, X.; Liu, Y.; Gibson, J.R.; Santiago-Turla, C.; Larocque-Abramson, K.R.; Del Bono, E.; Challa, P.; Herndon, L.W.; Akafo, S.; Wiggs, J.L.; Schmidt, S.; Hauser, M.A.
Primary open-angle glaucoma (POAG) is the most common form of glaucoma and one of the leading causes of vision loss worldwide. The genetic etiology of POAG is complex and poorly understood. The purpose of this work is to identify genomic regions of interest linked to POAG. This study is the largest genetic linkage study of POAG performed to date: genomic DNA samples from 786 subjects (538 Caucasian ancestry, 248 African ancestry) were genotyped using either the Illumina GoldenGate Linkage 4 Panel or the Illumina Infinium Human Linkage-12 Panel. A total of 5233 SNPs was analyzed in 134 multiplex POAG families (89 Caucasian ancestry, 45 African ancestry). Parametric and non-parametric linkage analyses were performed on the overall dataset and within race-specific datasets (Caucasian ancestry and African ancestry). Ordered subset analysis was used to stratify the data on the basis of age of glaucoma diagnosis. Novel linkage regions were identified on chromosomes 1 and 20, and two previously described loci-GLC1D on chromosome 8 and GLC1I on chromosome 15-were replicated. These data will prove valuable in the context of interpreting results from genome-wide association studies for POAG.
Investigation of known genetic risk factors for primary open angle glaucoma in two populations of African ancestry
(Investigative Ophthalmology and Visual Science, 2013-08) Liu, Y.; Hauser, M.A.; Akafo, S.K.; Qin, X.; Miura, S.; Gibson, J.R.; Wheeler, J.; Gaasterland, D.E.; Challa, P.; Herndon, L.W.; Ritch, R.; Moroi, S.E.; Pasquale, L.R.; Girkin, C.A.; Budenz, D.L.; Wiggs, J.L.; Richards, J.E.; Ashley-Koch, A.E.; Allingham, R.R.
Purpose. Multiple genes have been associated with primary open angle glaucoma (POAG) in Caucasian populations. We now examine the association of these loci in populations of African ancestry, populations at particularly high risk for POAG. Methods. We genotyped DNA samples from two populations: African American (1150 cases and 999 controls) and those from Ghana, West Africa (483 cases and 593 controls). Our analysis included 57 single nucleotide polymorphisms (SNPs) in five loci previously associated with POAG at the genome-wide level, including CDKN2B-AS1, TMCO1, CAV1/CAV2, chromosome 8q22 intergenic region, and SIX1/SIX6. We evaluated association in the full datasets, as well as subgroups with normal pressure glaucoma (NPG, maximum IOP ≤21 mm Hg) and high pressure glaucoma (HPG, IOP >21 mm Hg). Results. In African Americans, we identified an association of rs10120688 in the CDNK2B-AS1 region with POAG (P = 0.0020). Several other SNPs were nominally associated, but did not survive correction for multiple testing. In the subgroup analyses, significant associations were identified for rs10965245 (P = 0.0005) in the CDKN2B-AS1 region with HPG and rs11849906 in the SIX1/SIX6 region with NPG (P = 0.006). No significant association was identified with any loci in the Ghanaian samples. Conclusions. POAG genetic susceptibility alleles associated in Caucasians appear to play a greatly reduced role in populations of African ancestry. Thus, the major genetic components of POAG of African origin remain to be identified. This finding underscores the critical need to pursue large-scale genome-wide association studies in this understudied, yet disproportionately affected population. © 2013 The Association for Research in Vision and Ophthalmology, Inc.
Lack of Association between LOXL1 Variants and Primary Open- Angle Glaucoma in Three Different Populations
(Investigative Ophthalmology & Visual Science, 2008) Yutao, L.; Schmidt, S.; Qin, X.; Gibson, J.; Hutchins, K.; Santiago-Turla, C.; Wiggs, J.L.; Budenz, D.L.; Akafo, S.; Challa, P.; Herndon, L.W.; Hauser, M.A.; Allingham, R.R.
Purpose—Significant association has recently been reported between pseudoexfoliation glaucoma (XFG) and two single-nucleotide polymorphisms (SNPs), rs3825942, and rs1048661, in the lysyl oxidase-like 1 gene (LOXL1). The purpose of this study was to investigate whether XFG-associated variants of LOXL1 play a significant role in primary open-angle glaucoma in the Caucasian, African- American, and Ghanaian (West-African) populations. Methods—POAG was defined as the presence of glaucomatous optic nerve damage, associated visual field loss, and elevated intraocular pressure (>22 mm Hg in both eyes). Thirteen tagging SNPs were genotyped by allelic discrimination assays in the Caucasian (279 cases and 227 controls), African-American (193 cases and 97 controls), and Ghanaian (170 cases and 138 controls) populations. Allele and genotype frequencies were compared between the cases and controls from each population. Results—None of the SNPs associated with XFG in LOXL1 were significantly associated with POAG in these populations. The risk allele frequencies for rs2165241 and rs3825942 were significantly lower in the African-American and Ghanaian populations, compared with Caucasian individuals. Conclusions—There was no association between SNPs in the LOXL1 gene and POAG. This is the first analysis of the LOXL1 gene in African-American and West-African populations. LOXL1 gene variants do not appear to play a significant role in the pathogenesis of POAG in populations of either Caucasian or West-African ancestry. Primary open-angle glaucoma (POAG, OMIM 137760