Ethnic-specific SNP arrays are becoming more important to increase the power of genome-wide association studies in diverse population. In the Tohoku Medical Megabank Project, we have been developing a series of Japonica Arrays (JPA) for genotyping participants based on reference panels constructed from whole-genome sequence data of the Japanese population. Here, we designed a novel version of the SNP array for the Japanese population, called Japonica Array NEO (JPA NEO), comprising a total of 666,883 markers. Among them, 654,246 tag SNPs of autosomes and X chromosome were selected from an expanded reference panel of 3,552 Japanese, 3.5KJPNv2, using pairwise r2 of linkage disequilibrium measures. Additionally, 28,298 markers were included for the evaluation of previously identified disease risk markers from the literature and databases, and those present in the Japanese population were extracted using the reference panel. Through genotyping 286 Japanese samples, we found that the imputation quality r2 and INFO score in the minor allele frequency bin >2.5–5% were >0.9 and >0.8, respectively, and >12 million markers were imputed with an INFO score >0.8. From these results, JPA NEO is a promising tool for genotyping the Japanese population with genome-wide coverage, contributing to the development of genetic risk scores.
Childhood glaucoma is a group of heterogeneous genetic disorders. The purpose of this study was to explore the genetic background in the Japanese population. Genomic DNA was extracted from 31 patients with childhood glaucoma from 29 families in the Japanese population. We screened the CYP1B1, FOXC1 and candidate genes using Sanger sequencing and whole-exome sequencing (WES). In the CYP1B1 gene, we identified nine mutations, of which four were novel. Almost all affected individuals had severe early-onset childhood glaucoma. In the FOXC1 gene, three novel mutations were identified in a heterozygous state. We next attempted to extract the candidate genes from the subjects showing negative results for two genes. The iterative filtering process by WES revealed 4 single-nucleotide variations (SNVs) in the PTPRF, SMPD4, VPS13B, and DHRS1 genes on autosomal chromosomes and 4 SNVs in the NHS, KCND1, BRWD3, and ENOX2 genes on the X chromosome. The CYP1B1 and FOXC1 genes are major causal genes of childhood glaucoma in Japanese families (30% and 10%, respectively), and WES results reveal the heterogeneity of the genetic background. Screening the CYP1B1 and FOXC1 genes is useful to ensure the proper diagnosis and adequate treatment of childhood glaucoma.
Background: Increasing the power of genome−wide association studies in diverse populations is important for understanding the genetic determinants of disease risks, and large−scale genotype data are collected by genome cohort and biobank projects all over the world. In particular, ethnic−specific SNP arrays are becoming more important because the use of universal SNP arrays has some limitations in terms of cost−effectiveness and throughput. As part of the Tohoku Medical Megabank Project, which integrates prospective genome cohorts into a biobank, we have been developing a series of Japonica Arrays for genotyping participants based on reference panels constructed from whole−genome sequence data of the Japanese population. Results: We designed a novel version of the SNP Array for the Japanese population, called Japonica Array NEO, comprising a total of 666,883 SNPs, including tag SNPs of autosomes and X chromosome with pseudoautosomal regions, SNPs of Y chromosome and mitochondria, and known disease risk SNPs. Among them, 654,246 tag SNPs were selected from an expanded reference panel of 3,552 Japanese using pairwise r2 of linkage disequilibrium measures. Moreover, 28,298 SNPs were included for the evaluation of previously identified disease risk SNPs from the literature and databases, and those present in the Japanese population were extracted using the reference panel. The imputation performance of Japonica Array NEO was assessed by genotyping 286 Japanese samples. We found that the imputation quality r2 and INFO score in the minor allele frequency bin >2.5%−5% were >0.9 and >0.8, respectively, and >12 million markers were imputed with an INFO score >0.8. After verification, Japonica Arrays were used to efficiently genotype cohort participants from the sample selection to perform a quality assessment of the raw data; approximately 130,000 genotyping data of >150,000 participants has already been obtained. Conclusions: Japonica Array NEO is a promising tool for genotyping the Japanese population with genome−wide coverage, contributing to the development of genetic risk scores for this population and further identifying disease risk alleles among individuals of East Asian ancestry.
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