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韩国生物银行阵列:与血液生化特征相关的编码变异的设计和鉴定。

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

机构信息

Division of Genome Research, Center for Genome Science, National Institute of Health, Chungcheongbuk-do, 28159, Republic of Korea.

DNA link, Incorporated, Seoul, 03759, Republic of Korea.

出版信息

Sci Rep. 2019 Feb 4;9(1):1382. doi: 10.1038/s41598-018-37832-9.

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) and alanine aminotransferase (P = 4.98 × 10). 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 and rs748547625; p.Arg143Cys, P = 1.41 × 10). These variants were successfully replicated in 6,000 individuals (P = 5.30 × 10 and P = 1.24 × 10). 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.

摘要

我们介绍了一种新的基因芯片的设计和实现,该基因芯片称为韩国生物银行基因芯片(简称 KoreanChip),针对韩国人群进行了优化,并展示了对血液生化特征进行全基因组关联研究(GWAS)的发现。KoreanChip 包含超过 833000 个标记物,其中包括从 2500 名韩国测序数据中估计的超过 247000 个稀有频率或功能变异。在 833000 个标记物中,有 208000 个功能标记物被直接进行了基因分型。特别是,有超过 89000 个标记物在东亚人中出现。由于常见和低频变异的基因组覆盖率分别高达 95.38%和 73.65%,KoreanChip 实现了更高的基因分型性能。在使用 6949 个人进行的全基因组关联研究(GWAS)中,成功地再现了 28 个关联。此外,还新鉴定了 9 个错义变异,其中我们鉴定了常见的人群特异性错义变异 rs671(p.Glu457Lys)与天冬氨酸氨基转移酶(P=5.20×10)和丙氨酸氨基转移酶(P=4.98×10)两个特征之间的新关联。此外,两种在东亚人群中罕见但在其他人群中极为罕见的新型 GPT 错义变异与丙氨酸氨基转移酶相关(rs200088103;p.Arg133Trp,P=2.02×10 和 rs748547625;p.Arg143Cys,P=1.41×10)。这些变异在 6000 个人中得到了成功的复制(P=5.30×10 和 P=1.24×10)。GWAS 结果表明,KoreanChip 具有很大数量的破坏性变异,可用于识别新的人群特异性疾病相关的稀有/功能变异,具有很好的应用前景。

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