The Korea Biobank Array: Design and Identification of Coding Variants Associated with Blood Biochemical Traits

Abstract

We introduce the design and implementation of a new array, the Korea Biobank Array (referred to as KoreanChip), optimized for the Korean population and demonstrate findings from GWAS of blood biochemical traits. KoreanChip comprised >833,000 markers including >247,000 rare-frequency or functional variants estimated from >2,500 sequencing data in Koreans. Of the 833 K markers, 208 K functional markers were directly genotyped. Particularly, >89 K markers were presented in East Asians. KoreanChip achieved higher imputation performance owing to the excellent genomic coverage of 95.38% for common and 73.65% for low-frequency variants. From GWAS (Genome-wide association study) using 6,949 individuals, 28 associations were successfully recapitulated. Moreover, 9 missense variants were newly identified, of which we identified new associations between a common population-specific missense variant, rs671 (p.Glu457Lys) of ALDH2, and two traits including aspartate aminotransferase (P = 5.20 × 10^-13) and alanine aminotransferase (P = 4.98 × 10^-8). Furthermore, two novel missense variants of GPT with rare frequency in East Asians but extreme rarity in other populations were associated with alanine aminotransferase (rs200088103; p.Arg133Trp, P = 2.02 × 10^-9 and rs748547625; p.Arg143Cys, P = 1.41 × 10^-6). These variants were successfully replicated in 6,000 individuals (P = 5.30 × 10^-8 and P = 1.24 × 10^-6). GWAS results suggest the promising utility of KoreanChip with a substantial number of damaging variants to identify new population-specific disease-associated rare/functional variants.

Figure 1

Overall scheme of KoreanChip evaluation process. Evaluation of KoreanChip consisted of 5 steps: reproducibility, accuracy, content comparison, genomic coverage, and application to GWAS. All subjects were selected from three independent cohorts: Ansan and Ansung study, Health EXAminee (HEXA), and CArdioVascular disease Association Study (CAVAS). Datasets for the test are shown in colored squares with number. The number in parentheses indicates the number of subjects genotyped with the corresponding platform.