In this study, the stratification analysis revealed different associations across populations. SNPs rs10483727 and rs33912345 were significantly associated with POAG in East Asian and Caucasian populations under all genetic models. Meanwhile, rs10483727 was associated with POAG in Saudi Arabian populations
25 in West Asia, and rs33912345 had association in Mexican populations (Latino).
17 However, there was only one study reported in each one of these populations, and further validation is therefore required to confirm the associations. In contrast, SNPs rs10483727 and rs33912345 were not associated with POAG in South Asians (Indian and Pakistani)
33,36,37 and the populations with African ancestry (Ghanaian, African American, and Barbadian).
32,34 These findings suggested that the association of the SNPs in
SIX1-SIX6 with POAG could be specific in certain ethnic populations, such as Caucasians and East Asians. Population-specific effects of these SNPs might be the result of different genetic architectures and interactions with local environmental factors. Minor allele frequencies of both SNPs were low in African (0.032 and 0.034; 1000 Genomes Project Phase 3 v5); therefore, a larger sample size is needed for sufficient statistical power to detect a significant association. Boundaries of haplotype blocks may vary across different populations; in particular, the block size (>22 kb) in African cohorts is small, whereas the block sizes in Caucasian and Asian cohorts are relatively large and comparable (>44 kb).
53 This implies that the linkage in this region might be weaker in African compared to Caucasian and Asian cohorts. Similarly, the associations of the SNPs, such as rs4977756, in the
CDKN2B-AS1 gene reported by GWASs
13,18,19,22,52 could not be replicated in some African cohorts,
32,34,46 but another two SNPs (rs1063192 and rs10120688) in this locus showed significant associations in Africans.
32,34 Both rs1063192 and rs10120688 have stronger LD with the GWAS SNP rs4977756 in European (
R2 = 0.778 and 0.643, respectively) than in African cohorts (
R2 = 0.0264 and 0.327, respectively; 1000 Genomes Project Phase 3 v5). Therefore, different LD block structures in different ethnic groups might have altered the proxies for the causal variants for the disease, leading to different association patterns. Moreover, environmental factors linked to POAG risk might vary regionally and have different interaction with the genetic locus in glaucoma pathogenesis. Clinical assessment variabilities might lead to the differential association across the studies. Two of the South Asian studies
36,37 recruited only POAG cases with IOP > 21 mm Hg, while the other included studies had both high- and normal-tension glaucoma patients. Besides POAG, population-specific genetic effects among Caucasian, Asian, and African populations have also been reported in other diseases (e.g., type 2 diabetes
54 and asthma
55,56) and quantitative traits (e.g., body mass index
57 and plasma B12 concentration
58). However, there could be other reasons for such discrepancies, including sampling or selection bias and/or limited sample sizes with insufficient power. Further studies in those populations showing negative results are warranted to confirm the ethnic diversities of SNPs in
SIX1-SIX6 in POAG.