对东亚个体的关联分析以及与欧洲个体的跨祖先分析揭示了与胆固醇和甘油三酯水平相关的新基因座。

Association analyses of East Asian individuals and trans-ancestry analyses with European individuals reveal new loci associated with cholesterol and triglyceride levels.

作者信息

Spracklen Cassandra N, Chen Peng, Kim Young Jin, Wang Xu, Cai Hui, Li Shengxu, Long Jirong, Wu Ying, Wang Ya Xing, Takeuchi Fumihiko, Wu Jer-Yuarn, Jung Keum-Ji, Hu Cheng, Akiyama Koichi, Zhang Yonghong, Moon Sanghoon, Johnson Todd A, Li Huaixing, Dorajoo Rajkumar, He Meian, Cannon Maren E, Roman Tamara S, Salfati Elias, Lin Keng-Hung, Guo Xiuqing, Sheu Wayne H H, Absher Devin, Adair Linda S, Assimes Themistocles L, Aung Tin, Cai Qiuyin, Chang Li-Ching, Chen Chien-Hsiun, Chien Li-Hsin, Chuang Lee-Ming, Chuang Shu-Chun, Du Shufa, Fan Qiao, Fann Cathy S J, Feranil Alan B, Friedlander Yechiel, Gordon-Larsen Penny, Gu Dongfeng, Gui Lixuan, Guo Zhirong, Heng Chew-Kiat, Hixson James, Hou Xuhong, Hsiung Chao Agnes, Hu Yao, Hwang Mi Yeong, Hwu Chii-Min, Isono Masato, Juang Jyh-Ming Jimmy, Khor Chiea-Chuen, Kim Yun Kyoung, Koh Woon-Puay, Kubo Michiaki, Lee I-Te, Lee Sun-Ju, Lee Wen-Jane, Liang Kae-Woei, Lim Blanche, Lim Sing-Hui, Liu Jianjun, Nabika Toru, Pan Wen-Harn, Peng Hao, Quertermous Thomas, Sabanayagam Charumathi, Sandow Kevin, Shi Jinxiu, Sun Liang, Tan Pok Chien, Tan Shu-Pei, Taylor Kent D, Teo Yik-Ying, Toh Sue-Anne, Tsunoda Tatsuhiko, van Dam Rob M, Wang Aili, Wang Feijie, Wang Jie, Wei Wen Bin, Xiang Yong-Bing, Yao Jie, Yuan Jian-Min, Zhang Rong, Zhao Wanting, Chen Yii-Der Ida, Rich Stephen S, Rotter Jerome I, Wang Tzung-Dau, Wu Tangchun, Lin Xu, Han Bok-Ghee, Tanaka Toshihiro, Cho Yoon Shin, Katsuya Tomohiro, Jia Weiping, Jee Sun-Ha, Chen Yuan-Tsong, Kato Norihiro, Jonas Jost B, Cheng Ching-Yu, Shu Xiao-Ou, He Jiang, Zheng Wei, Wong Tien-Yin, Huang Wei, Kim Bong-Jo, Tai E-Shyong, Mohlke Karen L, Sim Xueling

机构信息

Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.

Saw Swee Hock School of Public Health, National University Health System, National University of Singapore, Singapore, Singapore.

出版信息

Hum Mol Genet. 2017 May 1;26(9):1770-1784. doi: 10.1093/hmg/ddx062.

Abstract

Large-scale meta-analyses of genome-wide association studies (GWAS) have identified >175 loci associated with fasting cholesterol levels, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG). With differences in linkage disequilibrium (LD) structure and allele frequencies between ancestry groups, studies in additional large samples may detect new associations. We conducted staged GWAS meta-analyses in up to 69,414 East Asian individuals from 24 studies with participants from Japan, the Philippines, Korea, China, Singapore, and Taiwan. These meta-analyses identified (P < 5 × 10-8) three novel loci associated with HDL-C near CD163-APOBEC1 (P = 7.4 × 10-9), NCOA2 (P = 1.6 × 10-8), and NID2-PTGDR (P = 4.2 × 10-8), and one novel locus associated with TG near WDR11-FGFR2 (P = 2.7 × 10-10). Conditional analyses identified a second signal near CD163-APOBEC1. We then combined results from the East Asian meta-analysis with association results from up to 187,365 European individuals from the Global Lipids Genetics Consortium in a trans-ancestry meta-analysis. This analysis identified (log10Bayes Factor ≥6.1) eight additional novel lipid loci. Among the twelve total loci identified, the index variants at eight loci have demonstrated at least nominal significance with other metabolic traits in prior studies, and two loci exhibited coincident eQTLs (P < 1 × 10-5) in subcutaneous adipose tissue for BPTF and PDGFC. Taken together, these analyses identified multiple novel lipid loci, providing new potential therapeutic targets.

摘要

全基因组关联研究(GWAS)的大规模荟萃分析已确定超过175个与空腹胆固醇水平相关的基因座,包括总胆固醇(TC)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)和甘油三酯(TG)。由于不同祖先群体之间的连锁不平衡(LD)结构和等位基因频率存在差异,在更多大样本中开展的研究可能会发现新的关联。我们对来自24项研究的多达69414名东亚个体进行了分阶段GWAS荟萃分析,这些研究的参与者来自日本、菲律宾、韩国、中国、新加坡和台湾。这些荟萃分析确定了(P < 5×10−8)三个与HDL-C相关的新基因座,分别位于CD163-APOBEC1附近(P = 7.4×10−9)、NCOA2附近(P = 1.6×10−8)和NID2-PTGDR附近(P = 4.2×10−8),以及一个与TG相关的新基因座,位于WDR11-FGFR2附近(P = 2.7×10−10)。条件分析在CD163-APOBEC1附近确定了第二个信号。然后,我们将东亚荟萃分析的结果与全球脂质遗传学联盟中多达187365名欧洲个体的关联结果进行了跨祖先荟萃分析。该分析确定了(log10贝叶斯因子≥6.1)另外八个新的脂质基因座。在总共确定的12个基因座中,8个基因座的索引变体在先前的研究中已显示出与其他代谢性状至少具有名义上的显著性,并且两个基因座在皮下脂肪组织中表现出与BPTF和PDGFC一致的表达数量性状基因座(P <

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