Patterns of OAG risk alleles among populations
A total of 135 OAG-related SNPs was obtained from 24 GWAS studies. Among these, 15 studies were performed in Europeans, 13 in East Asians, 4 in South Asians, 7 in Africans, and 2 in Americans (9 studies were performed in mixed ethnic populations). Clearly, populations except Europeans were understudied. However, there was no significant difference in the SNP frequency among these populations with the Kruskal-Wallis rank-sum test (Figure 1). This result suggests that many SNPs found in Europeans are also applicable to other populations. Following collecting the OAG-associated SNPs, we obtained their effect allele frequencies (EAFs) in each of the continental groups and Koreans based on genotype information from the 1000 Genomes Project and KRGDB (Supplementary Table 1). A heatmap showed how significantly the effect allele was enriched or depleted across the Korean and continental groups (SupplementaryFigure S1) with a log scale among 135 OAG-related SNPs. For Koreans, 63 OAG-related SNPs were significantly enriched, 63 SNPs were depleted, and 9 SNPs were similar to global EAF. The heatmap visualized the proportion of effect alleles in each continental group compared to the global average. There were certain patterns of risk allele frequencies depending on continental groups. The hierarchical clustering tree showed the differences among the populations; Europeans, Americans, and South Asians were in one cluster, and Africans, East Asians, and Koreans were in another cluster. In addition, we compared the EAFs of East Asians and Koreans (Supplementary Table S2and Figure S2). Although the EAF was not much different among East Asians, 25 SNPs were enriched, 26 SNPs were depleted, and 84 SNPs were similar to those in Koreans. Moreover, the heatmap clearly showed that the main pattern of the allele frequency in East Asians in the 1000 Genomes Project was very similar to that in Koreans, while few alleles showed the opposite pattern in allele frequency between East Asians and Koreans.
Patterns of IOP elevation-related OAG risk alleles among populations
Fifty-two IOP-related SNP traits were selected from 135 OAG-related SNPs (Table 1), and a heatmap showing how significantly the EAF was enriched or depleted across the Koreans and continental groups (Figure 2) with a log scale among 52 IOP-related SNPs was generated. For Koreans, 23 OAG-related SNPs were significantly enriched, 27 SNPs depleted, and 2 SNPs were similar to global EAF. For example, rs2024211, located in the intergenic of CAV2; CAV1 that is expressed in the trabecular meshwork cells cultured from OAG eyes and encoding Caveolins [34], has T/C alleles in which the C allele was tested in European populations to identify the risk of OAG with high IOP [25]. The C allele frequencies were 26%, 36%, and 0.7% in European, African, and Korean populations, respectively. Further, rs1579050, located in FMNL2 gene belongs to the formin-related family of proteins that acts as a downstream effector of CDC42 (Rho family member) [33], has A/G alleles in which the G allele frequencies were 58%, 10%, and 2.5% in European, African, and Korean populations. The rs8141433, located in the intergenic of GNB1L; TXNRD2, TXNRD2 gene encodes a mitochondrial protein required for redox homeostasis [35], revealed the G allele frequencies of 15%, 69%, and 4% in European, African, and Korean populations. A hierarchical clustering tree showed the differences among the populations; Europeans, Americans, and South Asians were in one cluster, and Africans, East Asians, and Koreans were in another cluster. These allele frequencies may be related to a difference in the NTG proportion of OAG among the populations. In addition, a heatmap showed how significantly the EAF was enriched or depleted across the Koreans and East Asians (Table 2, Figure 3). For Koreans, rs12377624, LMX1B gene had G/C alleles in which the C allele frequencies were 14%, 12.5%, and 7.9% in Chinese, Japanese, and Koreans, respectively, whereas, rs2073006, EXOC2 gene had C/T alleles in which the T allele frequencies were 11.8%, 8.1%, and 22.0% in Chinese, Vietnamese, and Koreans, respectively. However, the EAF was not much different among East Asians; for Koreans, 13 SNPs were enriched, 7 SNPs were depleted, and 32 SNPs were similar to those in Global East Asians. A hierarchical clustering tree showed the differences among East Asians, KOR, Japanese, and Han Chinese in Beijing in one cluster, and Southern Han Chinese and Chinese Dai in Xishuangbanna in another cluster.
Composite genetic risk scores calculated using SNPs related to OAG as whole and OAG with high IOP
We calculated the composite genetic risk scores based on copies of effect alleles at OAG-associated SNPs, with the assumption that allelic associations from a significant majority of GWAS-identified variants can be replicated in non-European populations [36]. The genetic risk score of OAG was highest in Africans, followed by Europeans, South Asians, and East Asians (Figure 4). The prevalence of OAG was correlated with the population average genetic risk score (R=0.293, Figure 4). In addition, the genetic risk score of OAG with high IOP was highest in Europeans, followed by South Asians, Africans, and East Asians (Figure 5). The prevalence of OAG with elevated IOP was positively correlated with the population average genetic risk score (R=0.699, Figure 5).