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

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

doi:10.1093/hmg/ddx062

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

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

Research output: Contribution to journal › Article › peer-review

111 Citations (Scopus)

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 metaanalyses 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^-10), 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.

Original language	English
Pages (from-to)	1770-1784
Number of pages	15
Journal	Human molecular genetics
Volume	26
Issue number	9
DOIs	https://doi.org/10.1093/hmg/ddx062
Publication status	Published - 01-05-2017
Externally published	Yes

All Science Journal Classification (ASJC) codes

Molecular Biology
Genetics
Genetics(clinical)

Access to Document

10.1093/hmg/ddx062

Cite this

Spracklen, C. N., Chen, P., Kim, Y. J., Wang, X., Cai, H., Li, S., Long, J., Wu, Y., Wang, Y. X., Takeuchi, F., Wu, J. Y., Jung, K. J., Hu, C., Akiyama, K., Zhang, Y., Moon, S., Johnson, T. A., Li, H., Dorajoo, R., ... Sim, X. (2017). Association analyses of East Asian individuals and trans-ancestry analyses with European individuals reveal new loci associated with cholesterol and triglyceride levels. Human molecular genetics, 26(9), 1770-1784. https://doi.org/10.1093/hmg/ddx062

@article{64e4645a7eaa402692dd3b4532eb53b8,

title = "Association analyses of East Asian individuals and trans-ancestry analyses with European individuals reveal new loci associated with cholesterol and triglyceride levels",

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 metaanalyses 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=7.4×10-10), 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.",

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

year = "2017",

month = may,

day = "1",

doi = "10.1093/hmg/ddx062",

language = "English",

volume = "26",

pages = "1770--1784",

journal = "Human molecular genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "9",

}

Spracklen, CN, Chen, P, Kim, YJ, Wang, X, Cai, H, Li, S, Long, J, Wu, Y, Wang, YX, Takeuchi, F, Wu, JY, Jung, KJ, Hu, C, Akiyama, K, Zhang, Y, Moon, S, Johnson, TA, Li, H, Dorajoo, R, He, M, Cannon, ME, Roman, TS, Salfati, E, Lin, KH, Guo, X, Sheu, WHH, Absher, D, Adair, LS, Assimes, TL, Aung, T, Cai, Q, Chang, LC, Chen, CH, Chien, LH, Chuang, LM, Chuang, SC, Du, S, Fan, Q, Fann, CSJ, Feranil, AB, Friedlander, Y, Gordon-Larsen, P, Gu, D, Gui, L, Guo, Z, Heng, CK, Hixson, J, Hou, X, Hsiung, CA, Hu, Y, Hwang, MY, Hwu, CM, Isono, M, Jimmy Juang, JM, Khor, CC, Kim, YK, Koh, WP, Kubo, M, Lee, IT, Lee, SJ, Lee, WJ, Liang, KW, Lim, B, Lim, SH, Liu, J, Nabika, T, Pan, WH, Peng, H, Quertermous, T, Sabanayagam, C, Sandow, K, Shi, J, Sun, L, Tan, PC, Tan, SP, Taylor, KD, Teo, YY, Toh, SA, Tsunoda, T, van Dam, RM, Wang, A, Wang, F, Wang, J, Wei, WB, Xiang, YB, Yao, J, Yuan, JM, Zhang, R, Zhao, W, Ida Chen, YD, Rich, SS, Rotter, JI, Wang, TD, Wu, T, Lin, X, Han, BG, Tanaka, T, Cho, YS, Katsuya, T, Jia, W, Jee, SH, Chen, YT, Kato, N, Jonas, JB, Cheng, CY, Shu, XO, He, J, Zheng, W, Wong, TY, Huang, W, Kim, BJ, Tai, ES, Mohlke, KL & Sim, X 2017, 'Association analyses of East Asian individuals and trans-ancestry analyses with European individuals reveal new loci associated with cholesterol and triglyceride levels', Human molecular genetics, vol. 26, no. 9, pp. 1770-1784. https://doi.org/10.1093/hmg/ddx062

Association analyses of East Asian individuals and trans-ancestry analyses with European individuals reveal new loci associated with cholesterol and triglyceride levels. / Spracklen, Cassandra N.; Chen, Peng; Kim, Young Jin et al.
In: Human molecular genetics, Vol. 26, No. 9, 01.05.2017, p. 1770-1784.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Association analyses of East Asian individuals and trans-ancestry analyses with European individuals reveal new loci associated with cholesterol and triglyceride levels

AU - Spracklen, Cassandra N.

AU - Chen, Peng

AU - Kim, Young Jin

AU - Wang, Xu

AU - Cai, Hui

AU - Li, Shengxu

AU - Long, Jirong

AU - Wu, Ying

AU - Wang, Ya Xing

AU - Takeuchi, Fumihiko

AU - Wu, Jer Yuarn

AU - Jung, Keum Ji

AU - Hu, Cheng

AU - Akiyama, Koichi

AU - Zhang, Yonghong

AU - Moon, Sanghoon

AU - Johnson, Todd A.

AU - Li, Huaixing

AU - Dorajoo, Rajkumar

AU - He, Meian

AU - Cannon, Maren E.

AU - Roman, Tamara S.

AU - Salfati, Elias

AU - Lin, Keng Hung

AU - Guo, Xiuqing

AU - Sheu, Wayne H.H.

AU - Absher, Devin

AU - Adair, Linda S.

AU - Assimes, Themistocles L.

AU - Aung, Tin

AU - Cai, Qiuyin

AU - Chang, Li Ching

AU - Chen, Chien Hsiun

AU - Chien, Li Hsin

AU - Chuang, Lee Ming

AU - Chuang, Shu Chun

AU - Du, Shufa

AU - Fan, Qiao

AU - Fann, Cathy S.J.

AU - Feranil, Alan B.

AU - Friedlander, Yechiel

AU - Gordon-Larsen, Penny

AU - Gu, Dongfeng

AU - Gui, Lixuan

AU - Guo, Zhirong

AU - Heng, Chew Kiat

AU - Hixson, James

AU - Hou, Xuhong

AU - Hsiung, Chao Agnes

AU - Hu, Yao

AU - Hwang, Mi Yeong

AU - Hwu, Chii Min

AU - Isono, Masato

AU - Jimmy Juang, Jyh Ming

AU - Khor, Chiea Chuen

AU - Kim, Yun Kyoung

AU - Koh, Woon Puay

AU - Kubo, Michiaki

AU - Lee, I. Te

AU - Lee, Sun Ju

AU - Lee, Wen Jane

AU - Liang, Kae Woei

AU - Lim, Blanche

AU - Lim, Sing Hui

AU - Liu, Jianjun

AU - Nabika, Toru

AU - Pan, Wen Harn

AU - Peng, Hao

AU - Quertermous, Thomas

AU - Sabanayagam, Charumathi

AU - Sandow, Kevin

AU - Shi, Jinxiu

AU - Sun, Liang

AU - Tan, Pok Chien

AU - Tan, Shu Pei

AU - Taylor, Kent D.

AU - Teo, Yik Ying

AU - Toh, Sue Anne

AU - Tsunoda, Tatsuhiko

AU - van Dam, Rob M.

AU - Wang, Aili

AU - Wang, Feijie

AU - Wang, Jie

AU - Wei, Wen Bin

AU - Xiang, Yong Bing

AU - Yao, Jie

AU - Yuan, Jian Min

AU - Zhang, Rong

AU - Zhao, Wanting

AU - Ida Chen, Yii Der

AU - Rich, Stephen S.

AU - Rotter, Jerome I.

AU - Wang, Tzung Dau

AU - Wu, Tangchun

AU - Lin, Xu

AU - Han, Bok Ghee

AU - Tanaka, Toshihiro

AU - Cho, Yoon Shin

AU - Katsuya, Tomohiro

AU - Jia, Weiping

AU - Jee, Sun Ha

AU - Chen, Yuan Tsong

AU - Kato, Norihiro

AU - Jonas, Jost B.

AU - Cheng, Ching Yu

AU - Shu, Xiao Ou

AU - He, Jiang

AU - Zheng, Wei

AU - Wong, Tien Yin

AU - Huang, Wei

AU - Kim, Bong Jo

AU - Tai, E. Shyong

AU - Mohlke, Karen L.

AU - Sim, Xueling

PY - 2017/5/1

Y1 - 2017/5/1

N2 - 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 metaanalyses 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=7.4×10-10), 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.

AB - 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 metaanalyses 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=7.4×10-10), 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.

UR - http://www.scopus.com/inward/record.url?scp=85019161150&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85019161150&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddx062

DO - 10.1093/hmg/ddx062

M3 - Article

C2 - 28334899

AN - SCOPUS:85019161150

SN - 0964-6906

VL - 26

SP - 1770

EP - 1784

JO - Human molecular genetics

JF - Human molecular genetics

IS - 9

ER -

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

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