See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/256074203 Investigation of Known Genetic Risk Factors for Primary Open Angle Glaucoma in Two Populations of African Ancestry Article  in  Investigative ophthalmology & visual science · August 2013 DOI: 10.1167/iovs.13-12779 · Source: PubMed CITATIONS READS 37 75 19 authors, including: Yutao Liu Michael A Hauser Medical College of Georgia, Augusta University, Augusta, US Duke University 146 PUBLICATIONS   2,201 CITATIONS    249 PUBLICATIONS   10,763 CITATIONS    SEE PROFILE SEE PROFILE Stephen Akafo Douglas E Gaasterland University of Ghana The EMMES Corporation 14 PUBLICATIONS   342 CITATIONS    157 PUBLICATIONS   5,080 CITATIONS    SEE PROFILE SEE PROFILE Some of the authors of this publication are also working on these related projects: Glaucoma Case Report View project Homocysteine and AMD View project All content following this page was uploaded by R Rand Allingham on 29 May 2014. The user has requested enhancement of the downloaded file. IOVS Papers in Press. Published on August 20, 2013 as Manuscript iovs.13-12779 Investigation of Known Genetic Risk Factors for Primary Open Angle Glaucoma in Two Populations of African Ancestry Yutao Liu1,2*, Michael A Hauser1,2*,Stephen K. Akafo10, Xuejun Qin1, Shiroh Miura 1, Jason R. Gibson1, Joshua Wheeler1, Douglas E. Gaasterland4, Pratap Challa2, Leon W. Herndon2, ICAARE-Glaucoma, Robert Ritch5, Sayoko E. Moroi3, Louis R. Pasquale8, Christopher A. Girkin6, Donald L. Budenz7, Janey L. Wiggs8, Julia E. Richards3,9, Allison E. Ashley-Koch1, R. Rand Allingham2 The International Consortium of African Ancestry REsearch in Glaucoma (ICAARE–Glaucoma) is led by Dr. Michael A. Hauser and Dr. R. Rand Allingham, and includes the following investigators: Stephen Akafo, Adeyinka Ashaye, Allison E. Ashley-Koch, Rupert Bourne, Donald L. Budenz, Pratap Challa, John H. Fingert, Douglas E. Gaasterland, Christopher A. Girkin, Fielding Hejtmancik, Leon Herndon, Rachel Kuchtey, Paul R. Lichter, Yutao Liu, Sayoko E. Moroi, Barbara Nemesure, Louis R. Pasquale, Julia E. Richards, Robert Ritch, Janey L. Wiggs, Susan Williams, 1Department of Medicine, 2Department of Ophthalmology, Duke University Medical Center, Durham, NC; 3Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI; 4Eye Doctors of Washington DC, Washington DC; 5 Einhorn Clinical Research Center, Department of Ophthalmology, New York Eye & Ear Infirmary, New York, NY; 6Department of Ophthalmology, University of Alabama at Birmingham, Birmingham, AL; 7Department of Ophthalmology, University of North Carolina, Chapel Hill, NC; 8Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA; 9Department of Epidemiology, University of Michigan, Ann Arbor, MI; 10Unit of Ophthalmology, Department of Surgery, University of Ghana Medical School, Accra, Ghana. Copyright 2013 by The Association for Research in Vision and Ophthalmology, Inc. *Contributed equally. Corresponding Author: R. Rand Allingham Duke University Eye Center Durham, NC 27710 Phone: (919) 684-2975 E-mail: allin002@mc.duke.edu Abstract Word Count: 245 Main Text Word Count: 2,555 Abstract 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 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 were studied. We evaluated association in the full datasets, as well as subgroups with normal pressure glaucoma (NPG, maximum IOP ≤ 21 mmHg) and high pressure glaucoma (HPG, IOP > 21 mmHg). 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. Introduction Glaucoma is the second leading cause of blindness in the world1. Primary open angle glaucoma (POAG) is the most common type and is inherited as a complex trait2-4. POAG is characterized by progressive retinal ganglion cell death, optic nerve head excavation, and visual field loss. POAG disproportionately affects individuals of African ancestry 5, 6, and is the most common cause of permanent blindness in African Americans7. The risk of POAG in persons over age 40 is four- to five-fold higher in African Americans (4-5%) than in age-matched Caucasians (1%) 5, 8-10. It is also more severe, with a 10-fold higher risk of blindness from glaucoma in African Americans 1, 11. POAG is even more common and severe in continental African populations 12-16. In a major population-based study in Ghana, West Africa, POAG was diagnosed in 6% of those over the age of 40, which is one of the highest global prevalence rates ever reported 14. In studies conducted in eye clinics serving populations of African ancestry rates of blindness in one or both eyes have been observed in excess of 40%13, 17-20. Genetics has been shown to play an important role in the pathogenesis of POAG2-4, 21, 22. Previous linkage-based studies have identified several genes with varying contribution to glaucoma, including myocilin, CYP1B1, optineurin, and WDR3623-26. It has also been reported that DNA copy number changes in TBK1 and GALC gene contribute to POAG pathogenesis27, 28. Recently, genome-wide association studies (GWAS) of POAG in Iceland, Australia, Japan, and the U.S. have successfully identified and confirmed genetic associations that are significant at the genome-wide level with multiple genes involved in the pathogenesis of POAG, including: CAV1/CAV2, CDKN2B-AS1, TMCO1, SIX1/SIX6, and an intergenic region on chromosome 8q2229-32. Multiple studies have confirmed or replicated these genetic associations in populations from Europe, the US, Japan, and Barbados33-36. However, these loci have not been examined in populations of African ancestry including African Americans and continental Africans. This study was designed to fill this significant gap. We have assembled the International Consortium of African Ancestry REsearch in Glaucoma (ICAARE-Glaucoma) with glaucoma investigators from the US and Africa (including Ghana, Nigeria, and South Africa). In this study, we used a haplotype-tagging approach to examine genetic associations in more than 3200 African American and Ghanaian (West African) glaucoma cases and controls from the ICAARE-Glaucoma. Materials and Methods Study Sample and Phenotype Description This study adhered to the tenets of the Declaration of Helsinki. Written informed consent was obtained from all participating individuals. The research was reviewed and approved by the Institutional Review Board from all participating institutions, including Duke University Medical Center (Durham, NC), the Massachusetts Eye and Ear Infirmary (Boston, MA), the University of Michigan (Ann Arbor, MI), New York Eye & Ear Infirmary (New York, NY), the University of Alabama at Birmingham (Birmingham, AL), and, for Ghanaian subjects, Noguchi Memorial Institute of Medical Research of the College of Health Sciences, University of Ghana in Accra. Subjects with POAG were unrelated and met the following inclusion criteria37 : 1) glaucomatous optic neuropathy in at least one eye; 2) visual field loss consistent with optic nerve damage in at least one eye. Glaucomatous optic neuropathy was defined as a cup-to-disc ratio greater than 0.7 or focal loss of the nerve fiber layer resulting in a notch in the neuroretinal rim, associated with a glaucomatous visual field defect. Visual fields were performed using standard automated perimetry or frequency doubling test (FDT) 1. IOP was recorded but not used as an inclusion criterion. The exclusion criteria for POAG subjects included the diagnosis or history of any secondary glaucoma, history of ocular trauma, or significant use of systemic or ocular glucocorticoids. Medical records for all POAG cases and control subjects were reviewed by professionally trained glaucoma specialists. The examined control subjects were unrelated and met the following criteria: 1) no known first-degree relative with glaucoma; 2) IOP less than 21 mmHg in both eyes without treatment; and 3) no evidence of glaucomatous optic neuropathy in either eye. POAG cases were further stratified into high pressure glaucoma (HPG) or normal pressure glaucoma (NPG) based on maximum recorded IOP > 21 mmHg or < 22 mmHg, respectively. DNA genotyping and Association Analysis Genomic DNA was extracted from peripheral blood by standard techniques (Gentra, Minneapolis, MN, USA). HaploView version 4.2 was used to design the tagging SNPs of CAV1/CAV2, CDKN2B-AS1, TMCO1, and SIX1/SIX6 in African (YRI) samples, using genotype data from the HapMap project (www.hapmap.org) with r2> 0.6 and minor allele frequency (MAF) > 0.05 14. A total of 50 tagging SNPs were selected to cover the linkage disequilibrium (LD) blocks of the selected candidate regions (Supplemental Figure 1). We also included seven additional SNPs (rs284489 on chromosome 8, rs1063192, rs4977756, rs10116277, and rs4977574 in the CDKN2B-AS1 region, rs33912345 and rs10483727 in the SIX1/SIX6 region) that were strongly associated with POAG in Caucasians 32, 38. TaqMan allelic discrimination assays were employed for genotyping these 57 SNPs by use of Assays-On- Demand products with the ViiA7 Realtime PCR system with 384-well block according to the standard protocols from the manufacturer (Applied Biosystems, Foster City, CA, USA). All 57 SNPs were genotyped in 1076 Ghanaians. Due to technical issues, 50 SNPs were genotyped on the whole set of 2149 African Americans. Seven SNPs (rs10800149 and rs7518099 in TMCO1 region, rs2151280, rs1547705, rs10738607, and rs10811658 in CDKN2B-AS1 region, and rs3759688 in SIX1/SIX6 region) were genotyped in 1593 African Americans. For quality- control (QC) purposes, two CEPH (the Centre d'Etude du Polymorphisme Humain, Foundation Jean Dausset, Paris, France) standards were included in each 96-well plate, and samples from two individuals were duplicated across all plates, with the laboratory technicians masked to their identities. Analysis of genotypes required matching QC genotypes within and across plates and at least 95% genotyping efficiency. Analysis of Hardy-Weinberg equilibrium (HWE) was performed separately for cases and controls from the two populations using GDA software.15 Within each population, genotype frequencies of POAG cases and controls were compared by logistic regression with adjustment for age and sex using SAS software (SAS Institute Inc., Cary, NC). SNP genotypes were coded according to a log-additive model, in which the relative risk for carriers of two variant (minor) alleles, compared to the reference group (homozygous wild-type), was assumed to be the square of the relative risk for carriers of one variant. We also performed the association analysis based on classification of NPG or HPG. In order to correct for testing multiple SNPs in each genomic region, we calculated the effective number of independent marker loci (MeffLi) to control the experiment-wise level of significance and the false discovery rate based on the method reported by Li and Ji 39. The values of MeffLi are 6.000 for TMCO, 9.106 for CAV1/CAV2, 19.146 for CDKN2B-AS, and 7.000 for SIX1/SIX6. The experiment-wide significance threshold required to limit type 1 error rate to 5% is 0.0085 for TMCO, 0.0056 for CAV1/CAV2, 0.0027 for CDKN2B-AS1, and 0.0073 for SIX1/SIX6. Because there is only one SNP in the chromosome 8 locus, the significance for p-value cut-off is 0.05. Power calculations were performed with QUANTO software using previously described methods, assuming a population prevalence of 5% and a log-additive risk model.37, 40 To address the genetic heterogeneity between the African American and Ghanaian populations, we conducted a formal meta-analysis of the SNPs with the African American and Ghanaian datasets with PLINK 41. Results The ICAARE-Glaucoma dataset at the time of this study consisted of 2,149 African Americans and 1,076 Ghanaians (West African). The African American cohort contained 1,150 POAG cases and 999 fully ophthalmically-examined controls. The Ghanaian cohort contained 483 POAG cases and 593 examined controls. Phenotypic information is provided in Table 1. Although elevated IOP was not required for the diagnosis of POAG, the Ghanaian POAG cases essentially all demonstrated elevated IOP at examination so NPG subset analysis was not performed. All SNPs passed rigorous quality control and genotyping efficiency criteria (> 95% with all the samples). All were in Hardy-Weinberg equilibrium (HWE) in both cases and controls from both African Americans and Ghanaians (p > 0.01), except for two SNPs with minor deviations (rs1063192 in African American controls (HWE p =0.007), rs4977574 in African American cases (HWE p =0.003). SNP rs1063192 in the CDKN2B-AS1 region was monomorphic in Ghanaian controls and rare in Ghanaian POAG cases (a minor allele frequency of 0.002 for the C allele that is protective in the Caucasian POAG.) In the full African American case/control dataset, we observed a significant association of SNP rs10120688 in the CDKN2B-AS1 region with POAG risk (p=0.0020; OR [odds ratio] (95%CI) = 1.21 (1.07-1.37)). Several other SNPs reached nominal significance (p<0.05), including rs7518099 in the TMCO1 region, rs1052990 and rs4236601 in the CAV1/CAV2 region, rs7049105, rs16905597, rs16905599, rs10811658, and rs10965245 in the CDKN2B- AS1 region (Table 2). However, these associations did not survive correction for multiple testing. In the Ghanaian population, nominal associations were noted for several SNPs, including rs3807986, rs3815412, and rs8713 in the CAV1/CAV2 region. However, none of these associations remained significant after correction for multiple testing in each genomic region. The meta-analysis with these two populations identified five nominally significant SNPs (p < 0.05), including rs7518099 and rs2814471 in TMCO1, rs4236601 in CAV1/CAV2 and rs10120688 and rs16905597 in CDKN2B-AS1, that did not survive correction for multiple testing. Next, we stratified the African American cases by IOP history into normal pressure glaucoma (NPG) and high pressure glaucoma (HPG) for association analysis using logistic regression. In the HPG subgroup, we identified significant association with SNP rs10965245 (p=0.0005; OR=0.73 (0.61-0.87)) in the CDKN2B-AS1 region. Nominal associations that did not survive correction for multiple testing were noted for several SNPs including rs4236601 in the CAV1/CAV2 region, rs7049105, rs10120688, rs16905597, rs16905599, rs10965235, and rs17761446 in the CDKN2B-AS1 region (Table 2). In the NPG subgroup, we found significant association with SNP rs11849906 in the SIX1/SIX6 regions (p=0.006; OR=0.53 (0.34-0.83)). Nominal associations that did not survive correction for multiple testing were observed with several SNPs including rs7518099 and rs2814471 in the TMCO1 region, rs4236601 in the CAV1/CAV2 region, rs10120688 and rs4977756 in the CDKN2B-AS1 region (Table 2). Additional details of the association with all 57 SNPs in these five genomic regions are presented in Supplementary Table 1. The Ghanaian POAG cases were almost all classified as HPG so stratification by IOP was not performed. In order to determine the statistical power of these datasets to detect association with these genetic loci we selected an OR of 1.5 and 1.35 obtained from reports on the genetic associations in these regions. Reported ORs were 1.68 for TMCO1 32, 1.4-1.5 for CDKN2B- AS129, 32, 1.32 for SIX1/SIX629, 35, and 1.36 for CAV1/CAV2 variants. 33, 42 Statistical power to detect association with these genomic loci was calculated using Quanto software 40. Assuming population risk α=0.05 and allele frequency of 0.10, our African American dataset has 98.9% power for OR of 1.5 and 87.2% power for OR of 1.35. The Ghanaian dataset has 85% power for OR of 1.5 and 59% power for OR of 1.35. In summary, our African American and Ghanaian datasets were well-powered to detect associations in these regions. Discussion Our study represents the largest association study of glaucoma to date in populations of African ancestry. We replicated the association of POAG with the CDKN2B-AS1 locus in the African Americans first reported in populations of European ancestry 6, 29, 32, 34, 35, 43, 44. After stratification for IOP this association remained significant in the HPG subgroup. We also found significant association of the SIX1/SIX6 locus in African American cases in the NPG subgroup. Interestingly, we did not observed significant association with any of the previously reported genes and loci in POAG cases from the West African population of Ghana. This may be due to the relatively limited sample size of the Ghanaian dataset. Several studies have reported the association of CDKN2B-AS1 SNPs, and upon stratification by IOP history, this association is restricted to the NPG but not the HPG subpopulation29, 32, 38, 43-46. In African Americans, we see significant association with CDKN2B- AS1 SNPs in the full dataset and in the HPG subgroup. This difference in pattern may be due to the small sample size of our NPG dataset (280 cases and 999 controls), which reflects the smaller proportion of African Americans with NPG. Cao et al reported the association of rs1063192 in this region in the Afro-Caribbean populations of Barbados, West Indies 47. Consistent with our other findings, we do not observe this association in either African Americans or Ghanaians. The protective C allele of this SNP is rare in the Ghanaian population (MAF=0.002 in cases vs. 0 in controls). In addition, the mean IOP of POAG cases in the Barbados dataset was 22.5mmHg, significantly lower than the 26.2mmHg observed in our African American cases. These facts may contribute to the lack of association with the CDKN2B-AS1 locus in Ghanaians and African Americans. We have also identified a significant association of rs11849906 in the SIX1/SIX6 region in African American NPG subgroup (p=0.006; OR=0.53±0.34-0.83). This SNP is monomorphic in the Caucasian and Asian populations from the International HapMap Project (http://hapmap.ncbi.nlm.nih.gov) and is polymorphic only in populations of African ancestry, including African Americans and Africans in Nigeria, Kenya. Additional studies in populations of African ancestry are required to replicate this finding. The lack of association with TMCO1, CAV1/CAV2, or the chromosome 8q22 intergenic region may be secondary to the limited sample size or perhaps due to smaller effect sizes in populations of African ancestry compared with Caucasians. The lack of associations with specific variants previously identified in Caucasian populations may be explained by the rarity of those alleles in African populations. Several associated SNPs common in Caucasians were rare in the Ghanaians, including rs10483727 and rs33912345 in the SIX1/SIX6 region, rs10116277 and rs1063192 in the CDKN2B-AS1 region, potentially limiting the effect that these alleles could have on POAG risk. Admixture in the African Americans and genetic heterogeneity between the African American and Ghanaian populations may also influence our association findings. Our meta- analysis of these loci with the African American and Ghanaian data sets indicates that five SNPs were nominally significant (p<0.05) in the meta-analysis (rs7518099 and rs2814471 in TMCO1, rs4236601 in CAV1/CAV2 and rs10120688 and rs16905597 in CDKN2B-AS1). Interestingly, for the SNPs in TMCO1 and CAV1/CAV2, the odds ratios and risk alleles were consistent between populations, while, for CDKN2B-AS1, the odds ratios and risk allele were opposite in the two populations (Table 2 and Supplemental Table 1). This suggests that some of the risk for POAG in the African American population may be explained by Caucasian admixture (CDKN2B-AS1), while other POAG risk factors may be driven by African-derived risk alleles. Mutations in myocilin and optineurin have been documented in POAG cases. Previous studies 14, 48-52 found that, despite the high prevalence of POAG in the populations of African ancestry, the mutations in these two genes play a relatively limited role. The increased prevalence of glaucoma in the African populations is not due to a higher prevalence of myocilin mutations. In this study, approximately 573 African American and 100 Ghanaian POAG cases have been screened for myocilin mutations 49, 50. Patients carrying any known mutations were excluded in our analysis. Given the relatively rare frequency of myocilin mutations in these African populations, we expect that the association results will not be affected by the lack of myocilin screening in the remaining POAG cases. In addition, several studies have confirmed the lack of significant association of common variants in myocilin with POAG in the Caucasians 38, 53. Collectively, these results suggest that other currently unknown genetic risk factors contribute to POAG in these African populations. Our findings suggest that genetic associations for POAG found in Caucasian populations appear to play a much smaller role in populations of African ancestry, leaving a large portion of genetic architecture of African POAG to be determined. This is not surprising since Africa in general, and Sub Saharan Africa in particular, contains the anthropologically oldest and most heterogeneous populations on Earth who have experienced environmental conditions that have historically contributed unique selection pressures. In the long term, multiple genome-wide association studies of POAG in populations of African descent will be required to not only validate the known glaucoma loci, but also to identify novel variants and loci in specific populations of African ancestry that contribute to POAG pathogenesis and related blindness. Acknowledgement We are grateful to the study participants, without whom this work would not have been possible. 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Association between genetic variants associated with vertical cup-to-disc ratio and phenotypic features of primary open-angle glaucoma. Ophthalmology 2012;119:1819-1825. 46. Nakano M, Ikeda Y, Tokuda Y, et al. Common variants in CDKN2B-AS1 associated with optic- nerve vulnerability of glaucoma identified by genome-wide association studies in Japanese. PloS one 2012;7:e33389. 47. Cao D, Jiao X, Liu X, et al. CDKN2B polymorphism is associated with primary open-angle glaucoma (POAG) in the Afro-Caribbean population of Barbados, West Indies. PloS one 2012;7:e39278. 48. Liu Y, Akafo S, Santiago-Turla C, et al. Optineurin coding variants in Ghanaian patients with primary open-angle glaucoma. Molecular vision 2008;14:2367-2372. 49. Challa P, Herndon LW, Hauser MA, et al. Prevalence of myocilin mutations in adults with primary open-angle glaucoma in Ghana, West Africa. Journal of glaucoma 2002;11:416-420. 50. Liu W, Liu Y, Challa P, et al. Low prevalence of myocilin mutations in an African American population with primary open-angle glaucoma. Molecular vision 2012;18:2241-2246. 51. Fingert JH, Heon E, Liebmann JM, et al. Analysis of myocilin mutations in 1703 glaucoma patients from five different populations. Human molecular genetics 1999;8:899-905. 52. Whigham BT, Williams SE, Liu Y, et al. Myocilin mutations in black South Africans with POAG. Molecular vision 2011;17:1064-1069. 53. Ramdas WD, van Koolwijk LM, Cree AJ, et al. Clinical implications of old and new genes for open- angle glaucoma. Ophthalmology 2011;118:2389-2397. Table 1. Clinical characteristics of individuals in ICAARE-Glaucoma (International Consortium of African Ancestry REsearch in Glaucoma). Affection status N % Female Age Maximal IOP (years) (mmHg) African American Total 2,149 51.9 58.1±13.4 22.2±9.0 African American Cases 1150 49.5 57.0±13.0 26.2±8.8 African American HPG 870 48.7 56.0±12.7 30.0±7.4 African American NPG 280 49.8 58.9±13.3 16.9±3.6 African American Controls 999 54.6 59.4±13.8 15.2±3.1 Ghanaians Total 1,076 51.3 63.3±11.8 31.2±12.6 Ghanaian Cases 483 43.9 63.4±12.4 35.1±11.6 Ghanaian Controls 593 57.3 63.3±9.6 18.4±5.6 Age: age at diagnosis for cases and age of examination for controls. HPG: high pressure glaucoma. NPG: normal pressure glaucoma; IOP: intraocular pressure. Table 2. The genetic association of 57 SNPs with POAG in the ICAARE-Glaucoma samples of African Americans and Ghanaians (West Africans) using logistic regression with additive model. African American (n=1150 AA HPG (n=870 case/ AA NPG (n=280 Ghanaian (n=483 Genomic SNP Allele case/999 control) 999 control) case/999 control) case/593 control) Region P OR (95%CI) P OR (95%CI) P OR (95%CI) P OR (95%CI) TMCO1 rs10800149 A 0.66 1.04 (0.89-1.21) 0.74 0.97 (0.82-1.15) 0.09 1.21 (0.97-1.51) 0.10 1.19 (0.97-1.46) TMCO1 rs10800150 C 0.49 0.96 (0.85-1.08) 0.74 0.98 (0.86-1.11) 0.29 0.90 (0.75-1.09) 0.24 0.90 (0.76-1.07) TMCO1 rs4656461 C 0.74 1.02 (0.89-1.18) 0.82 1.02 (0.87-1.19) 0.62 1.06 (0.85-1.32) 0.19 1.14 (0.94-1.40) TMCO1 rs1913845 C 0.74 1.03 (0.88-1.20) 0.40 1.08 (0.91-1.27) 0.31 0.89 (0.71-1.12) 0.76 0.97 (0.78-1.20) TMCO1 rs12059327 C 0.71 0.97 (0.80-1.16) 0.93 1.01 (0.83-1.23) 0.28 0.85 (0.63-1.15) 0.22 1.17 (0.91-1.51) TMCO1 rs6426940 C 0.94 1.00 (0.89-1.13) 0.98 1.00 (0.88-1.14) 0.92 1.01 (0.84-1.22) 0.31 0.91 (0.77-1.09) TMCO1 rs7518099 C 0.048 1.27 (1.00-1.62) 0.12 1.23 (0.95-1.59) 0.05 1.39 (0.99-1.93) 0.11 1.29 (0.94-1.75) TMCO1 rs2814471 C 0.27 1.11 (0.93-1.32) 0.80 1.03 (0.85-1.24) 0.019 1.37 (1.05-1.77) 0.76 1.04 (0.81-1.34) CAV1/CAV2 rs8940 C 0.051 0.86 (0.74-1.00) 0.08 0.86 (0.73-1.02) 0.15 0.84 (0.66-1.06) 0.10 0.83 (0.67-1.04) CAV1/CAV2 rs1052990 A 0.029 0.87 (0.77-0.99) 0.06 0.88 (0.77-1.00) 0.08 0.85 (0.70-1.02) 0.11 0.87 (0.73-1.03) CAV1/CAV2 rs6466578 C 0.23 0.91 (0.78-1.06) 0.52 0.95 (0.80-1.12) 0.08 0.80 (0.62-1.03) 0.19 0.86 (0.70-1.07) CAV1/CAV2 rs3919515 C 0.41 0.95 (0.84-1.08) 0.44 0.95 (0.83-1.09) 0.59 0.95 (0.78-1.15) 0.56 0.95 (0.79-1.13) CAV1/CAV2 rs10227696 A 0.13 1.13 (0.97-1.31) 0.20 1.11 (0.94-1.32) 0.18 1.17 (0.93-1.49) 0.09 1.21 (0.97-1.51) CAV1/CAV2 rs4236601 A 0.020 1.16 (1.02-1.31) 0.050 1.14 (1.00-1.31) 0.05 1.21 (1.00-1.47) 0.06 1.19 (0.99-1.42) CAV1/CAV2 rs917664 A 0.72 1.02 (0.91-1.16) 0.75 1.02 (0.90-1.16) 0.79 1.03 (0.85-1.25) 0.98 1.00 (0.84-1.19) CAV1/CAV2 rs3779512 A 0.43 1.05 (0.93-1.20) 0.28 1.08 (0.94-1.24) 0.90 0.99 (0.81-1.21) 0.74 1.03 (0.86-1.24) CAV1/CAV2 rs3807986 C 0.97 1.00 (0.88-1.13) 0.93 1.01 (0.88-1.15) 0.84 0.98 (0.81-1.19) 0.015 0.80 (0.66-0.96) CAV1/CAV2 rs3807989 C 0.97 1.00 (0.88-1.13) 0.56 0.96 (0.84-1.10) 0.28 1.12 (0.92-1.36) 0.35 0.91 (0.76-1.10) CAV1/CAV2 rs3779514 A 0.69 1.03 (0.89-1.19) 0.41 1.07 (0.92-1.24) 0.47 0.92 (0.73-1.16) 0.84 0.98 (0.80-1.20) CAV1/CAV2 rs3815412 A 0.51 1.04 (0.92-1.18) 0.63 1.03 (0.90-1.18) 0.54 1.06 (0.88-1.29) 0.03 0.82 (0.69-0.98) CAV1/CAV2 rs8713 A 0.85 1.01 (0.89-1.16) 0.89 1.01 (0.87-1.17) 0.79 1.03 (0.83-1.27) 0.04 0.82 (0.68-0.99) Chr 8q22 rs284489 C 0.69 0.98 (0.86-1.10) 0.92 0.99 (0.87-1.13) 0.44 0.93 (0.77-1.12) 0.66 1.04 (0.86-1.27) CDKN2B-AS1 rs2069422 G 0.96 1.01 (0.82-1.23) 0.86 0.98 (0.79-1.22) 0.57 1.09 (0.80-1.49) 0.75 0.95 (0.71-1.28) CDKN2B-AS1 rs7049105 A 0.009 0.84 (0.73-0.96) 0.013 0.83 (0.72-0.96) 0.12 0.85 (0.69-1.05) 0.75 1.03 (0.85-1.25) CDKN2B-AS1 rs2151280 A 0.19 1.11 (0.95-1.29) 0.38 1.08 (0.91-1.27) 0.11 1.19 (0.96-1.48) 0.25 0.89 (0.73-1.08) CDKN2B-AS1 rs7851706 C 0.26 1.11 (0.92-1.34) 0.24 1.13 (0.92-1.38) 0.66 1.07 (0.80-1.43) 0.06 0.80 (0.64-1.01) CDKN2B-AS1 rs10120688 A 0.0020 1.21 (1.07-1.37) 0.012 1.18 (1.04-1.35) 0.004 1.32 (1.09-1.60) 0.10 0.86 (0.72-1.03) CDKN2B-AS1 rs16905597 A 0.010 0.78 (0.64-0.94) 0.006 0.74 (0.60-0.92) 0.38 0.88 (0.66-1.18) 0.57 1.07 (0.85-1.36) CDKN2B-AS1 rs16905599 C 0.04 0.86 (0.75-1.00) 0.04 0.85 (0.73-0.99) 0.33 0.90 (0.72-1.12) 0.28 1.12 (0.92-1.36) CDKN2B-AS1 rs16923583 A 0.47 0.94 (0.80-1.11) 0.44 0.93 (0.78-1.11) 0.71 0.95 (0.73-1.24) 0.94 1.01 (0.81-1.25) CDKN2B-AS1 rs1547705 A 0.43 1.07 (0.91-1.27) 0.33 1.10 (0.91-1.31) 0.97 1.01 (0.79-1.28) 0.89 1.01 (0.84-1.23) CDKN2B-AS1 rs1537370 C 0.06 0.88 (0.77-1.00) 0.11 0.89 (0.77-1.03) 0.09 0.84 (0.68-1.03) 0.24 1.12 (0.93-1.36) CDKN2B-AS1 rs10738607 C 0.32 0.92 (0.78-1.09) 0.16 0.88 (0.73-1.05) 0.82 1.03 (0.81-1.30) 0.95 0.99 (0.80-1.23) CDKN2B-AS1 rs10965235 A 0.06 1.13 (1.00-1.27) 0.03 1.16 (1.01-1.32) 0.70 1.04 (0.86-1.25) 0.43 0.93 (0.79-1.11) CDKN2B-AS1 rs4990722 G 0.55 1.05 (0.89-1.25) 0.65 1.04 (0.87-1.25) 0.41 1.12 (0.85-1.47) 0.79 0.97 (0.79-1.20) CDKN2B-AS1 rs17761446 G 0.08 0.79 (0.60-1.03) 0.05 0.74 (0.55-1.00) 0.76 0.94 (0.63-1.41) 0.86 1.04 (0.70-1.53) CDKN2B-AS1 rs1333049 C 0.10 0.89 (0.78-1.02) 0.07 0.87 (0.75-1.01) 0.78 0.97 (0.78-1.20) 0.68 1.05 (0.84-1.31) CDKN2B-AS1 rs1333050 C 0.37 1.07 (0.92-1.24) 0.43 1.07 (0.91-1.26) 0.53 1.08 (0.85-1.36) 0.10 1.28 (0.95-1.73) CDKN2B-AS1 rs10811658 A 0.04 1.17 (1.01-1.35) 0.07 1.16 (0.99-1.35) 0.08 1.21 (0.98-1.49) 0.48 1.07 (0.90-1.27) CDKN2B-AS1 rs12347779 C 0.97 1.00 (0.78-1.27) 0.89 1.02 (0.79-1.32) 0.73 0.94 (0.65-1.35) 0.28 0.82 (0.57-1.18) CDKN2B-AS1 rs10965245 A 0.006 0.80 (0.68-0.94) 0.0005 0.73 (0.61-0.87) 0.97 1.00 (0.78-1.27) 0.38 1.10 (0.89-1.35) CDKN2B-AS1 rs2383208 A 0.24 0.91 (0.78-1.06) 0.42 0.94 (0.79-1.10) 0.18 0.85 (0.67-1.08) 0.47 1.09 (0.87-1.35) CDKN2B-AS1 rs1063192 C 0.15 0.85 (0.67-1.06) 0.39 0.90 (0.70-1.15) 0.06 0.68 (0.46-1.01) 0.98 N/A CDKN2B-AS1 rs4977756 C 0.16 0.91 (0.81-1.04) 0.41 0.95 (0.83-1.08) 0.04 0.82 (0.67-1.00) 0.44 1.07 (0.90-1.29) CDKN2B-AS1 rs10116277 G 0.88 0.99 (0.81-1.20) 0.89 1.02 (0.82-1.26) 0.43 0.88 (0.64-1.21) 0.23 1.82 (0.68-4.85) CDKN2B-AS1 rs4977574 A 0.48 1.05 (0.91-1.22) 0.41 1.07 (0.91-1.26) 0.99 1.00 (0.80-1.26) 0.48 1.10 (0.85-1.41) SIX1/SIX6 rs2350890 C 0.31 1.07 (0.94-1.20) 0.42 1.06 (0.93-1.21) 0.36 1.09 (0.90-1.32) 0.65 1.04 (0.87-1.24) SIX1/SIX6 rs4901977 A 0.99 1.00 (0.88-1.13) 0.79 0.98 (0.86-1.12) 0.67 1.04 (0.86-1.26) 0.28 1.10 (0.92-1.32) SIX1/SIX6 rs8012339 A 0.56 0.95 (0.82-1.12) 0.31 0.92 (0.77-1.09) 0.64 1.06 (0.83-1.36) 0.69 0.96 (0.78-1.17) SIX1/SIX6 rs1266416 C 0.50 0.96 (0.85-1.08) 0.74 0.98 (0.86-1.12) 0.24 0.90 (0.74-1.08) 0.14 1.14 (0.96-1.35) SIX1/SIX6 rs3759688 A 0.88 1.01 (0.86-1.20) 0.97 1.00 (0.83-1.20) 0.63 1.06 (0.83-1.35) 0.86 0.98 (0.82-1.18) SIX1/SIX6 rs11849906 G 0.43 0.91 (0.72-1.15) 0.77 1.04 (0.81-1.32) 0.006 0.53 (0.34-0.83) 0.18 1.23 (0.91-1.67) SIX1/SIX6 rs10148202 A 0.13 0.88 (0.74-1.04) 0.18 0.88 (0.74-1.06) 0.24 0.85 (0.65-1.12) 0.72 1.04 (0.84-1.30) SIX1/SIX6 rs7156317 A 0.73 1.02 (0.90-1.16) 0.61 1.04 (0.90-1.19) 0.87 0.98 (0.81-1.20) 0.52 1.06 (0.89-1.26) SIX1/SIX6 rs7146104 A 0.17 1.24 (0.91-1.68) 0.23 1.22 (0.88-1.69) 0.25 1.32 (0.82-2.11) 0.70 0.93 (0.66-1.32) SIX1/SIX6 rs10483727 C 0.67 0.96 (0.78-1.18) 0.97 0.99 (0.77-1.28) 0.66 0.92 (0.64-1.32) 0.76 1.13 (0.52-2.44) SIX1/SIX6 rs33912345 A 0.25 0.88 (0.71-1.10) 0.91 0.99 (0.77-1.27) 0.57 0.90 (0.62-1.30) 0.93 0.96 (0.42-2.23) SNP: single nucleotide polymorphism; POAG: primary open-angle glaucoma; ICAARE-Glaucoma: International Consortium of African Ancestry REsearch in Glaucoma; HPG: high pressure glaucoma; NPG: normal pressure glaucoma; AA: African American; P: p value from the logistic regression using additive model with the justification of age and gender; OR: odds ratio; CI: confidence interval. Supplemental Figure 1. Fifty seven tagging and previously reported SNPs were selected to cover the reported five genomic regions, including TMCO1 (panel A), CAV1/CAV2 (panel B), chromosome 8q22 intergenic region (panel C), CDKN2B-AS1 (panel D), and SIX1/SIX6 (panel E), in the African population (YRI). These tagging SNPs were selected using HaploView software with r2>0.6 and MAF > 0.05. TaqMan allelic discrimination assays were employed for genotyping these 57 SNPs by use of Assays-On-Demand products with the ViiA7 Realtime PCR system with 384-well block according to the standard protocols from the manufacturer (Applied Biosystems, Foster City, CA, USA). Supplemental Table 1.The genetic association of all 57 genotyped SNPs with POAG in the ICAARE-Glaucoma samples of African Americans and Ghanaians (West Africans). African American African American HPG African American NPG Ghanaian Genomic SNP Allele (n=1150 case/999 control) (n=870 case/ 999 control) (n=280 case/999 control) (n=483 case/593 control) Regions FU FA P OR FU FA P OR FU FA P OR FU FA P OR TMCO1 rs10800149 A 25.4 26.1 0.66 1.04 (0.89-1.21) 25.4 24.8 0.74 0.97 25.4 29.2 0.09 1.21 19.1 22.1 0.10 1.19 (0.82-1.15) (0.97-1.51) (0.97-1.46) TMCO1 rs10800150 C 42.7 41.8 0.49 0.96 0.98 0.90 0.90 (0.85-1.08) 42.7 42.3 0.74 (0.86-1.11) 42.7 40.1 0.29 (0.75-1.09) 47.0 44.7 0.24 (0.76-1.07) TMCO1 rs4656461 C 22.6 23.3 0.74 1.02 (0.89-1.18) 22.6 23.2 0.82 1.02 22.6 23.7 0.62 1.06 22.6 25.6 0.19 1.14 (0.87-1.19) (0.85-1.32) (0.94-1.40) TMCO1 rs1913845 C 81.7 82.1 0.74 1.03 1.08 0.89 0.97 (0.88-1.20) 81.7 82.9 0.40 (0.91-1.27) 81.7 79.7 0.31 (0.71-1.12) 81.4 81.0 0.76 (0.78-1.20) TMCO1 rs12059327 C 12.9 12.6 0.71 0.97 1.01 0.85 1.17 (0.80-1.16) 12.9 13.1 0.93 (0.83-1.23) 12.9 11.2 0.28 (0.63-1.15) 13.1 15.1 0.22 (0.91-1.51) TMCO1 rs6426940 C 42.4 42.3 0.94 1.00 (0.89-1.13) 42.4 42.1 0.98 1.00 1.01 0.91 (0.88-1.14) 42.4 42.6 0.92 (0.84-1.22) 40.5 38.2 0.31 (0.77-1.09) TMCO1 rs7518099 C 8.3 10.3 0.048 1.27 (1.00-1.62) 8.3 10.0 0.12 1.23 1.39 1.29 (0.95-1.59) 8.3 11.0 0.05 (0.99-1.93) 7.0 9.1 0.11 (0.94-1.75) TMCO1 rs2814471 C 12.0 13.3 0.27 1.11 (0.93-1.32) 12.0 12.4 0.80 1.03 1.37 1.04 (0.85-1.24) 12.0 15.9 0.019 (1.05-1.77) 12.5 13.4 0.76 (0.81-1.34) CAV1/CAV 2 rs8940 C 81.4 79.1 0.051 0.86 81.4 79.2 0.08 0.86 81.4 78.8 0.15 0.84 (0.74-1.00) (0.73-1.02) (0.66-1.06) 82.3 79.4 0.10 0.83 (0.67-1.04) CAV1/CAV 2 rs1052990 A 61.2 58.0 0.029 0.87 (0.77-0.99) 61.2 58.2 0.06 0.88 (0.77-1.00) 61.2 57.2 0.08 0.85 61.3 57.8 0.11 0.87 (0.70-1.02) (0.73-1.03) CAV1/CAV 2 rs6466578 C 19.6 18.1 0.23 0.91 (0.78-1.06) 19.6 18.7 0.52 0.95 (0.80-1.12) 19.6 16.3 0.08 0.80 (0.62-1.03) 21.4 18.8 0.19 0.86 (0.70-1.07) CAV1/CAV 2 rs3919515 C 38.4 37.3 0.41 0.95 (0.84-1.08) 38.4 37.3 0.44 0.95 0.95 0.95 (0.83-1.09) 38.4 37.2 0.59 (0.78-1.15) 37.4 36.2 0.56 (0.79-1.13) CAV1/CAV rs10227696 A 18.7 20.5 0.13 1.13 1.11 1.17 1.21 2 (0.97-1.31) 18.7 20.2 0.20 (0.94-1.32) 18.7 21.1 0.18 (0.93-1.49) 17.3 20.3 0.09 (0.97-1.51) CAV1/CAV rs4236601 A 36.2 39.5 0.020 1.16 36.2 39.2 0.050 1.14 36.2 40.7 0.05 1.21 1.19 2 (1.02-1.31) (1.00-1.31) (1.00-1.47) 37.6 41.7 0.06 (0.99-1.42) CAV1/CAV 2 rs917664 A 48.7 49.1 0.72 1.02 1.02 1.03 1.00 (0.91-1.16) 48.7 49.1 0.75 (0.90-1.16) 48.7 49.3 0.79 (0.85-1.25) 51.4 51.5 0.98 (0.84-1.19) CAV1/CAV 2 rs3779512 A 66.5 67.6 0.43 1.05 1.08 0.99 1.03 (0.93-1.20) 66.5 68.0 0.28 (0.94-1.24) 66.5 66.3 0.90 (0.81-1.21) 71.5 72.4 0.74 (0.86-1.24) CAV1/CAV 2 rs3807986 C 55.8 55.8 0.97 1.00 1.01 0.98 0.80 (0.88-1.13) 55.8 55.9 0.93 (0.88-1.15) 55.8 55.4 0.84 (0.81-1.19) 68.1 63.5 0.015 (0.66-0.96) CAV1/CAV 2 rs3807989 C 34.2 34.4 0.97 1.00 0.96 1.12 0.91 (0.88-1.13) 34.2 33.7 0.56 (0.84-1.10) 34.2 36.7 0.28 (0.92-1.36) 29.5 27.5 0.35 (0.76-1.10) CAV1/CAV 2 rs3779514 A 23.8 24.2 0.69 1.03 1.07 0.92 0.98 (0.89-1.19) 23.8 24.8 0.41 (0.92-1.24) 23.8 22.4 0.47 (0.73-1.16) 27.9 27.9 0.84 (0.80-1.20) CAV1/CAV 2 rs3815412 A 61.4 62.5 0.51 1.04 1.03 1.06 0.82 (0.92-1.18) 61.4 62.4 0.63 (0.90-1.18) 61.4 62.8 0.54 (0.88-1.29) 62.7 58.5 0.03 (0.69-0.98) CAV1/CAV 2 rs8713 A 70.7 70.9 0.85 1.01 1.01 1.03 0.82 (0.89-1.16) 70.7 70.8 0.89 (0.87-1.17) 70.7 71.2 0.79 (0.83-1.27) 70.9 67.0 0.04 (0.68-0.99) Chr8q22 rs284489 C 63.2 62.3 0.69 0.98 0.99 0.93 1.04 (0.86-1.10) 63.2 62.6 0.92 (0.87-1.13) 63.2 61.2 0.44 (0.77-1.12) 71.6 72.2 0.66 (0.86-1.27) CDKN2B- AS1 rs2069422 G 9.8 9.8 0.96 1.01 0.98 (0.82-1.23) 9.8 9.5 0.86 (0.79-1.22) 9.8 10.6 0.57 1.09 9.8 9.2 0.75 0.95 (0.80-1.49) (0.71-1.28) CDKN2B- AS1 rs7049105 A 29.6 26.0 0.009 0.84 (0.73-0.96) 29.6 25.9 0.013 0.83 (0.72-0.96) 29.6 26.3 0.12 0.85 (0.69-1.05) 25.0 25.5 0.75 1.03 (0.85-1.25) CDKN2B- AS1 rs2151280 A 30.9 33.1 0.19 1.11 30.9 32.5 0.38 1.08 30.9 34.5 0.11 1.19 (0.95-1.29) (0.91-1.27) (0.96-1.48) 28.5 26.4 0.25 0.89 (0.73-1.08) CDKN2B- 1.11 1.13 1.07 0.80 AS1 rs7851706 C 87.9 89.0 0.26 (0.92-1.34) 87.9 89.1 0.24 (0.92-1.38) 87.9 88.5 0.66 (0.80-1.43) 84.9 82.1 0.06 (0.64-1.01) CDKN2B- AS1 rs10120688 A 40.9 45.6 0.002 1.21 (1.07-1.37) 40.9 44.9 0.012 1.18 (1.04-1.35) 40.9 47.7 0.004 1.32 (1.09-1.60) 39.5 36.1 0.10 0.86 (0.72-1.03) CDKN2B- AS1 rs16905597 A 12.2 9.9 0.010 0.78 (0.64-0.94) 12.2 9.5 0.006 0.74 (0.60-0.92) 12.2 11.0 0.38 0.88 (0.66-1.18) 15.1 16.1 0.57 1.07 (0.85-1.36) CDKN2B- 0.86 0.85 0.90 1.12 AS1 rs16905599 C 77.8 75.2 0.04 (0.75-1.00) 77.8 74.9 0.04 (0.73-0.99) 77.8 76.0 0.33 (0.72-1.12) 73.6 75.7 0.28 (0.92-1.36) CDKN2B- rs16923583 A 16.0 15.3 0.47 0.94 16.0 15.3 0.44 0.93 16.0 15.5 0.71 0.95 1.01 AS1 (0.80-1.11) (0.78-1.11) (0.73-1.24) 20.1 20.2 0.94 (0.81-1.25) CDKN2B- rs1547705 A 75.8 77.0 0.43 1.07 75.8 77.4 0.33 1.10 75.8 76.1 0.97 1.01 1.01 AS1 (0.91-1.27) (0.91-1.31) (0.79-1.28) 72.1 72.2 0.89 (0.84-1.23) CDKN2B- rs1537370 C 32.5 29.7 0.06 0.88 32.5 30.0 0.11 0.89 AS1 (0.77-1.00) (0.77-1.03) 32.5 28.5 0.09 0.84 (0.68-1.03) 25.2 27.8 0.24 1.12 (0.93-1.36) CDKN2B- AS1 rs10738607 C 24.2 22.7 0.32 0.92 (0.78-1.09) 24.2 21.9 0.16 0.88 24.2 24.5 0.82 1.03 0.99 (0.73-1.05) (0.81-1.30) 19.0 18.8 0.95 (0.80-1.23) CDKN2B- AS1 rs10965235 A 45.8 48.7 0.06 1.13 (1.00-1.27) 45.8 49.4 0.03 1.16 (1.01-1.32) 45.8 46.6 0.70 1.04 0.93 (0.86-1.25) 57.3 55.8 0.43 (0.79-1.11) CDKN2B- rs4990722 G 84.6 85.3 0.55 1.05 84.6 85.0 0.65 1.04 84.6 86.2 0.41 1.12 81.5 80.9 0.79 0.97 AS1 (0.89-1.25) (0.87-1.25) (0.85-1.47) (0.79-1.20) CDKN2B- AS1 rs17761446 G 5.7 4.6 0.08 0.79 (0.60-1.03) 5.7 4.4 0.05 0.74 0.94 (0.55-1.00) 5.7 5.4 0.76 (0.63-1.41) 5.2 5.4 0.86 1.04 (0.70-1.53) CDKN2B- AS1 rs1333049 C 25.7 23.5 0.10 0.89 (0.78-1.02) 25.7 23.0 0.07 0.87 (0.75-1.01) 25.7 25.2 0.78 0.97 (0.78-1.20) 18.5 19.0 0.68 1.05 (0.84-1.31) CDKN2B- AS1 rs1333050 C 79.9 81.1 0.37 1.07 (0.92-1.24) 79.9 81.1 0.43 1.07 (0.91-1.26) 79.9 81.1 0.53 1.08 (0.85-1.36) 89.6 91.6 0.10 1.28 (0.95-1.73) CDKN2B- rs10811658 A 43.0 46.8 0.04 1.17 43.0 46.5 0.07 1.16 43.0 47.6 0.08 1.21 43.8 45.5 0.48 1.07 AS1 (1.01-1.35) (0.99-1.35) (0.98-1.49) (0.90-1.27) CDKN2B- AS1 rs12347779 C 93.2 93.3 0.97 1.00 (0.78-1.27) 93.2 93.4 0.89 1.02 0.94 0.82 (0.79-1.32) 93.2 92.9 0.73 (0.65-1.35) 94.1 92.8 0.28 (0.57-1.18) CDKN2B- AS1 rs10965245 A 18.6 15.5 0.006 0.80 0.000 0.73 1.00 (0.68-0.94) 18.6 14.5 5 (0.61-0.87) 18.6 18.6 0.97 (0.78-1.27) 19.6 21.2 0.38 1.10 (0.89-1.35) CDKN2B- AS1 rs2383208 A 82.3 81.0 0.24 0.91 0.94 0.85 (0.78-1.06) 82.3 81.4 0.42 (0.79-1.10) 82.3 79.8 0.18 (0.67-1.08) 80.8 82.1 0.47 1.09 (0.87-1.35) CDKN2B- AS1 rs1063192 C 7.7 6.4 0.15 0.85 (0.67-1.06) 7.7 6.8 0.39 0.90 (0.70-1.15) 7.7 5.2 0.06 0.68 (0.46-1.01) 0 0.2 0.98 N/A CDKN2B- AS1 rs4977756 C 35.3 33.0 0.16 0.91 0.95 0.82 1.07 (0.81-1.04) 35.3 33.9 0.41 (0.83-1.08) 35.3 30.4 0.04 (0.67-1.00) 34.6 36.3 0.44 (0.90-1.29) CDKN2B- rs10116277 G 10.2 9.9 0.88 0.99 10.2 10.2 0.89 1.02 10.2 9.0 0.43 0.88 1.82 AS1 (0.81-1.20) (0.82-1.26) (0.64-1.21) 0.6 1.0 0.23 (0.68-4.85) VViieeww ppuubblliiccaattiioonn ssttaattss CDKN2B- AS1 rs4977574 A 80.0 80.9 0.48 1.05 (0.91-1.22) 80.0 81.2 0.41 1.07 1.00 1.10 (0.91-1.26) 80.0 79.9 0.99 (0.80-1.26) 87.1 88.1 0.48 (0.85-1.41) SIX1/SIX6 rs2350890 C 57.3 58.9 0.31 1.07 1.06 1.09 (0.94-1.20) 57.3 58.7 0.42 (0.93-1.21) 57.3 59.6 0.36 (0.90-1.32) 57.6 58.7 0.65 1.04 (0.87-1.24) SIX1/SIX6 rs4901977 A 58.1 58.3 0.99 1.00 58.1 58.0 0.79 0.98 58.1 59.2 0.67 1.04 (0.88-1.13) (0.86-1.12) (0.86-1.26) 63.3 65.9 0.28 1.10 (0.92-1.32) SIX1/SIX6 rs8012339 A 82.2 81.8 0.56 0.95 0.92 1.06 0.96 (0.82-1.12) 82.2 81.4 0.31 (0.77-1.09) 82.2 83.3 0.64 (0.83-1.36) 78.3 77.8 0.69 (0.78-1.17) SIX1/SIX6 rs1266416 C 53.5 52.4 0.50 0.96 0.98 (0.85-1.08) 53.5 53.0 0.74 (0.86-1.12) 53.5 50.7 0.24 0.90 1.14 (0.74-1.08) 44.5 47.8 0.14 (0.96-1.35) SIX1/SIX6 rs3759688 A 22.0 22.1 0.88 1.01 1.00 1.06 0.98 (0.86-1.20) 22.0 21.9 0.97 (0.83-1.20) 22.0 22.6 0.63 (0.83-1.35) 29.4 28.6 0.86 (0.82-1.18) SIX1/SIX6 rs11849906 G 7.3 6.8 0.43 0.91 7.3 7.7 0.77 1.04 7.3 3.9 0.006 0.53 8.4 10.1 0.18 1.23 (0.72-1.15) (0.81-1.32) (0.34-0.83) (0.91-1.67) SIX1/SIX6 rs10148202 A 15.8 14.3 0.13 0.88 (0.74-1.04) 15.8 14.5 0.18 0.88 (0.74-1.06) 15.8 13.9 0.24 0.85 1.04 (0.65-1.12) 17.0 17.3 0.72 (0.84-1.30) SIX1/SIX6 rs7156317 A 65.5 65.9 0.73 1.02 (0.90-1.16) 65.5 66.2 0.61 1.04 (0.90-1.19) 65.5 65.0 0.87 0.98 (0.81-1.20) 58.0 59.7 0.52 1.06 (0.89-1.26) SIX1/SIX6 rs7146104 A 3.7 4.4 0.17 1.24 3.7 4.3 0.23 1.22 3.7 4.7 0.25 1.32 0.93 (0.91-1.68) (0.88-1.69) (0.82-2.11) 6.8 6.5 0.70 (0.66-1.32) SIX1/SIX6 rs10483727 C 12.4 11.9 0.67 0.96 0.99 (0.78-1.18) 12.4 11.9 0.97 (0.77-1.28) 12.4 11.8 0.66 0.92 1.13 (0.64-1.32) 1.2 1.4 0.76 (0.52-2.44) SIX1/SIX6 rs33912345 A 12.5 11.2 0.25 0.88 0.99 (0.71-1.10) 12.5 11.1 0.91 (0.77-1.27) 12.5 11.6 0.57 0.90 (0.62-1.30) 1.1 1.1 0.93 0.96 (0.42-2.23) SNP: single nucleotide polymorphism; POAG: primary open-angle glaucoma; ICAARE-Glaucoma: International Consortium of African Ancestry REsearch in Glaucoma; HPG: high pressure glaucoma; NPG: normal pressure glaucoma; AA: African American; FU: Allele frequency in controls; FA: allele frequency in POAG cases; P: p value from the logistic regression using additive model with the justification of age and gender; OR: odds ratio with 95% confidence interval in the parenthesis.