High-density genotyping of immune-related loci identifies new SLE risk variants in individuals with Asian ancestry

Celi Sun; Julio E. Molineros; Loren L. Looger; Xu Jie Zhou; Kwangwoo Kim; Yukinori Okada; Jianyang Ma; Yuan Yuan Qi; Xana Kim-Howard; Prasenjeet Motghare; Krishna Bhattarai; Adam Adler; So Young Bang; Hye Soon Lee; Tae Hwan Kim; Young Mo Kang; Chang Hee Suh; Won Tae Chung; Yong Beom Park; Jung Yoon Choe; Seung Cheol Shim; Yuta Kochi; Akari Suzuki; Michiaki Kubo; Takayuki Sumida; Kazuhiko Yamamoto; Shin Seok Lee; Young Jin Kim; Bok Ghee Han; Mikhail Dozmorov; Kenneth M. Kaufman; Jonathan D. Wren; John B. Harley; Nan Shen; Kek Heng Chua; Hong Zhang; Sang Cheol Bae; Swapan K. Nath

doi:10.1038/ng.3496

High-density genotyping of immune-related loci identifies new SLE risk variants in individuals with Asian ancestry

Celi Sun, Julio E. Molineros, Loren L. Looger, Xu Jie Zhou, Kwangwoo Kim, Yukinori Okada, Jianyang Ma, Yuan Yuan Qi, Xana Kim-Howard, Prasenjeet Motghare, Krishna Bhattarai, Adam Adler, So Young Bang, Hye Soon Lee, Tae Hwan Kim, Young Mo Kang, Chang Hee Suh, Won Tae Chung, Yong Beom Park, Jung Yoon ChoeSeung Cheol Shim, Yuta Kochi, Akari Suzuki, Michiaki Kubo, Takayuki Sumida, Kazuhiko Yamamoto, Shin Seok Lee, Young Jin Kim, Bok Ghee Han, Mikhail Dozmorov, Kenneth M. Kaufman, Jonathan D. Wren, John B. Harley, Nan Shen, Kek Heng Chua, Hong Zhang, Sang Cheol Bae, Swapan K. Nath

Department of Internal Medicine

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

166 Citations (Scopus)

Abstract

Systemic lupus erythematosus (SLE) has a strong but incompletely understood genetic architecture. We conducted an association study with replication in 4,478 SLE cases and 12,656 controls from six East Asian cohorts to identify new SLE susceptibility loci and better localize known loci. We identified ten new loci and confirmed 20 known loci with genome-wide significance. Among the new loci, the most significant locus was GTF2IRD1-GTF2I at 7q11.23 (rs73366469, P meta = 3.75 × 10 â '117, odds ratio (OR) = 2.38), followed by DEF6, IL12B, TCF7, TERT, CD226, PCNXL3, RASGRP1, SYNGR1 and SIGLEC6. We identified the most likely functional variants at each locus by analyzing epigenetic marks and gene expression data. Ten candidate variants are known to alter gene expression in cis or in trans. Enrichment analysis highlights the importance of these loci in B cell and T cell biology. The new loci, together with previously known loci, increase the explained heritability of SLE to 24%. The new loci share functional and ontological characteristics with previously reported loci and are possible drug targets for SLE therapeutics.

Original language	English
Pages (from-to)	323-330
Number of pages	8
Journal	Nature Genetics
Volume	48
Issue number	3
DOIs	https://doi.org/10.1038/ng.3496
Publication status	Published - 2016 Mar 1

Bibliographical note

Funding Information:
We are grateful to the affected and unaffected individuals who participated in this study. We thank the research assistants, coordinators and physicians who helped in the recruitment of subjects, including the individuals in the coordinating projects. A part of the Korean control data was provided from the Korean Biobank Project supported by the Korea Center for Disease Control and Prevention at the Korea National Institute of Health. Genomic DNA from ~100 Korean patients with SLE was obtained from the Korean National Biobank at Wonkwang University Hospital, which is supported by the Ministry of Health and Welfare, Republic of Korea. This work was supported by grants from the US National Institutes of Health (AR060366, MD007909, AI103399, AI024717, AI083194, AI107176, TR001425, HG008666 and HG006828), the US Department of Defense (PR094002), the US Department of Veterans Affairs, the National Basic Research Program of China (973 program) (2014CB541902), the Research Fund of Beijing Municipal Science and Technology for the Outstanding PhD Program (20121000110), the National Natural Science Foundation of China (81200524, 81230072) and High-Impact Research Ministry of Education Grant UM.C/625/1/HIR/MoE/E000044-20001, Malaysia. This study was also supported by a grant from the Korea Healthcare Technology R&D Project (HI13C2124), Ministry for Health and Welfare, Republic of Korea.

Funding Information:
We are grateful to the affected and unaffected individuals who participated in this study. We thank the research assistants, coordinators and physicians who helped in the recruitment of subjects, including the individuals in the coordinating projects. A part of the Korean control data was provided from the Korean Biobank Project supported by the Korea Center for Disease Control and Prevention at the Korea National Institute of Health. Genomic DNA from ~100 Korean patients with SLE was obtained from the Korean National Biobank at Wonkwang University Hospital, which is supported by the Ministry of Health and Welfare, Republic of Korea. This work was supported by grants from the US National Institutes of Health (AR060366, MD007909, AI103399, AI024717, AI083194, AI107176, TR001425, HG008666 and HG006828), the US Department of Defense (PR094002), the US Department of Veterans Affairs, the National Basic Research Program of China (973 program) (2014CB541902), the Research Fund of Beijing Municipal Science and Technology for the Outstanding PhD Program (20121000110), the National Natural Science Foundation of China (81200524, 81230072) and High-Impact Research Ministry of Education Grant UM.C/625/1/HIR/MoE/E000044-20001, Malaysia. This study was also supported by a grant from the Korea Healthcare Technology R&D Project (HI13C2124), Ministry for Health and Welfare, Republic of Korea.

Publisher Copyright:
© 2016 Nature America, Inc.

All Science Journal Classification (ASJC) codes

Genetics

Access to Document

10.1038/ng.3496

Cite this

Sun, C., Molineros, J. E., Looger, L. L., Zhou, X. J., Kim, K., Okada, Y., Ma, J., Qi, Y. Y., Kim-Howard, X., Motghare, P., Bhattarai, K., Adler, A., Bang, S. Y., Lee, H. S., Kim, T. H., Kang, Y. M., Suh, C. H., Chung, W. T., Park, Y. B., ... Nath, S. K. (2016). High-density genotyping of immune-related loci identifies new SLE risk variants in individuals with Asian ancestry. Nature Genetics, 48(3), 323-330. https://doi.org/10.1038/ng.3496

@article{f5a89b91fde9486fad5896b96409c389,

title = "High-density genotyping of immune-related loci identifies new SLE risk variants in individuals with Asian ancestry",

abstract = "Systemic lupus erythematosus (SLE) has a strong but incompletely understood genetic architecture. We conducted an association study with replication in 4,478 SLE cases and 12,656 controls from six East Asian cohorts to identify new SLE susceptibility loci and better localize known loci. We identified ten new loci and confirmed 20 known loci with genome-wide significance. Among the new loci, the most significant locus was GTF2IRD1-GTF2I at 7q11.23 (rs73366469, P meta = 3.75 × 10 {\^a} '117, odds ratio (OR) = 2.38), followed by DEF6, IL12B, TCF7, TERT, CD226, PCNXL3, RASGRP1, SYNGR1 and SIGLEC6. We identified the most likely functional variants at each locus by analyzing epigenetic marks and gene expression data. Ten candidate variants are known to alter gene expression in cis or in trans. Enrichment analysis highlights the importance of these loci in B cell and T cell biology. The new loci, together with previously known loci, increase the explained heritability of SLE to 24%. The new loci share functional and ontological characteristics with previously reported loci and are possible drug targets for SLE therapeutics.",

author = "Celi Sun and Molineros, {Julio E.} and Looger, {Loren L.} and Zhou, {Xu Jie} and Kwangwoo Kim and Yukinori Okada and Jianyang Ma and Qi, {Yuan Yuan} and Xana Kim-Howard and Prasenjeet Motghare and Krishna Bhattarai and Adam Adler and Bang, {So Young} and Lee, {Hye Soon} and Kim, {Tae Hwan} and Kang, {Young Mo} and Suh, {Chang Hee} and Chung, {Won Tae} and Park, {Yong Beom} and Choe, {Jung Yoon} and Shim, {Seung Cheol} and Yuta Kochi and Akari Suzuki and Michiaki Kubo and Takayuki Sumida and Kazuhiko Yamamoto and Lee, {Shin Seok} and Kim, {Young Jin} and Han, {Bok Ghee} and Mikhail Dozmorov and Kaufman, {Kenneth M.} and Wren, {Jonathan D.} and Harley, {John B.} and Nan Shen and Chua, {Kek Heng} and Hong Zhang and Bae, {Sang Cheol} and Nath, {Swapan K.}",

note = "Funding Information: We are grateful to the affected and unaffected individuals who participated in this study. We thank the research assistants, coordinators and physicians who helped in the recruitment of subjects, including the individuals in the coordinating projects. A part of the Korean control data was provided from the Korean Biobank Project supported by the Korea Center for Disease Control and Prevention at the Korea National Institute of Health. Genomic DNA from ~100 Korean patients with SLE was obtained from the Korean National Biobank at Wonkwang University Hospital, which is supported by the Ministry of Health and Welfare, Republic of Korea. This work was supported by grants from the US National Institutes of Health (AR060366, MD007909, AI103399, AI024717, AI083194, AI107176, TR001425, HG008666 and HG006828), the US Department of Defense (PR094002), the US Department of Veterans Affairs, the National Basic Research Program of China (973 program) (2014CB541902), the Research Fund of Beijing Municipal Science and Technology for the Outstanding PhD Program (20121000110), the National Natural Science Foundation of China (81200524, 81230072) and High-Impact Research Ministry of Education Grant UM.C/625/1/HIR/MoE/E000044-20001, Malaysia. This study was also supported by a grant from the Korea Healthcare Technology R&D Project (HI13C2124), Ministry for Health and Welfare, Republic of Korea. Funding Information: We are grateful to the affected and unaffected individuals who participated in this study. We thank the research assistants, coordinators and physicians who helped in the recruitment of subjects, including the individuals in the coordinating projects. A part of the Korean control data was provided from the Korean Biobank Project supported by the Korea Center for Disease Control and Prevention at the Korea National Institute of Health. Genomic DNA from ~100 Korean patients with SLE was obtained from the Korean National Biobank at Wonkwang University Hospital, which is supported by the Ministry of Health and Welfare, Republic of Korea. This work was supported by grants from the US National Institutes of Health (AR060366, MD007909, AI103399, AI024717, AI083194, AI107176, TR001425, HG008666 and HG006828), the US Department of Defense (PR094002), the US Department of Veterans Affairs, the National Basic Research Program of China (973 program) (2014CB541902), the Research Fund of Beijing Municipal Science and Technology for the Outstanding PhD Program (20121000110), the National Natural Science Foundation of China (81200524, 81230072) and High-Impact Research Ministry of Education Grant UM.C/625/1/HIR/MoE/E000044-20001, Malaysia. This study was also supported by a grant from the Korea Healthcare Technology R&D Project (HI13C2124), Ministry for Health and Welfare, Republic of Korea. Publisher Copyright: {\textcopyright} 2016 Nature America, Inc.",

year = "2016",

month = mar,

day = "1",

doi = "10.1038/ng.3496",

language = "English",

volume = "48",

pages = "323--330",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "3",

}

Sun, C, Molineros, JE, Looger, LL, Zhou, XJ, Kim, K, Okada, Y, Ma, J, Qi, YY, Kim-Howard, X, Motghare, P, Bhattarai, K, Adler, A, Bang, SY, Lee, HS, Kim, TH, Kang, YM, Suh, CH, Chung, WT, Park, YB, Choe, JY, Shim, SC, Kochi, Y, Suzuki, A, Kubo, M, Sumida, T, Yamamoto, K, Lee, SS, Kim, YJ, Han, BG, Dozmorov, M, Kaufman, KM, Wren, JD, Harley, JB, Shen, N, Chua, KH, Zhang, H, Bae, SC & Nath, SK 2016, 'High-density genotyping of immune-related loci identifies new SLE risk variants in individuals with Asian ancestry', Nature Genetics, vol. 48, no. 3, pp. 323-330. https://doi.org/10.1038/ng.3496

TY - JOUR

T1 - High-density genotyping of immune-related loci identifies new SLE risk variants in individuals with Asian ancestry

AU - Sun, Celi

AU - Molineros, Julio E.

AU - Looger, Loren L.

AU - Zhou, Xu Jie

AU - Kim, Kwangwoo

AU - Okada, Yukinori

AU - Ma, Jianyang

AU - Qi, Yuan Yuan

AU - Kim-Howard, Xana

AU - Motghare, Prasenjeet

AU - Bhattarai, Krishna

AU - Adler, Adam

AU - Bang, So Young

AU - Lee, Hye Soon

AU - Kim, Tae Hwan

AU - Kang, Young Mo

AU - Suh, Chang Hee

AU - Chung, Won Tae

AU - Park, Yong Beom

AU - Choe, Jung Yoon

AU - Shim, Seung Cheol

AU - Kochi, Yuta

AU - Suzuki, Akari

AU - Kubo, Michiaki

AU - Sumida, Takayuki

AU - Yamamoto, Kazuhiko

AU - Lee, Shin Seok

AU - Kim, Young Jin

AU - Han, Bok Ghee

AU - Dozmorov, Mikhail

AU - Kaufman, Kenneth M.

AU - Wren, Jonathan D.

AU - Harley, John B.

AU - Shen, Nan

AU - Chua, Kek Heng

AU - Zhang, Hong

AU - Bae, Sang Cheol

AU - Nath, Swapan K.

N1 - Funding Information: We are grateful to the affected and unaffected individuals who participated in this study. We thank the research assistants, coordinators and physicians who helped in the recruitment of subjects, including the individuals in the coordinating projects. A part of the Korean control data was provided from the Korean Biobank Project supported by the Korea Center for Disease Control and Prevention at the Korea National Institute of Health. Genomic DNA from ~100 Korean patients with SLE was obtained from the Korean National Biobank at Wonkwang University Hospital, which is supported by the Ministry of Health and Welfare, Republic of Korea. This work was supported by grants from the US National Institutes of Health (AR060366, MD007909, AI103399, AI024717, AI083194, AI107176, TR001425, HG008666 and HG006828), the US Department of Defense (PR094002), the US Department of Veterans Affairs, the National Basic Research Program of China (973 program) (2014CB541902), the Research Fund of Beijing Municipal Science and Technology for the Outstanding PhD Program (20121000110), the National Natural Science Foundation of China (81200524, 81230072) and High-Impact Research Ministry of Education Grant UM.C/625/1/HIR/MoE/E000044-20001, Malaysia. This study was also supported by a grant from the Korea Healthcare Technology R&D Project (HI13C2124), Ministry for Health and Welfare, Republic of Korea. Funding Information: We are grateful to the affected and unaffected individuals who participated in this study. We thank the research assistants, coordinators and physicians who helped in the recruitment of subjects, including the individuals in the coordinating projects. A part of the Korean control data was provided from the Korean Biobank Project supported by the Korea Center for Disease Control and Prevention at the Korea National Institute of Health. Genomic DNA from ~100 Korean patients with SLE was obtained from the Korean National Biobank at Wonkwang University Hospital, which is supported by the Ministry of Health and Welfare, Republic of Korea. This work was supported by grants from the US National Institutes of Health (AR060366, MD007909, AI103399, AI024717, AI083194, AI107176, TR001425, HG008666 and HG006828), the US Department of Defense (PR094002), the US Department of Veterans Affairs, the National Basic Research Program of China (973 program) (2014CB541902), the Research Fund of Beijing Municipal Science and Technology for the Outstanding PhD Program (20121000110), the National Natural Science Foundation of China (81200524, 81230072) and High-Impact Research Ministry of Education Grant UM.C/625/1/HIR/MoE/E000044-20001, Malaysia. This study was also supported by a grant from the Korea Healthcare Technology R&D Project (HI13C2124), Ministry for Health and Welfare, Republic of Korea. Publisher Copyright: © 2016 Nature America, Inc.

PY - 2016/3/1

Y1 - 2016/3/1

N2 - Systemic lupus erythematosus (SLE) has a strong but incompletely understood genetic architecture. We conducted an association study with replication in 4,478 SLE cases and 12,656 controls from six East Asian cohorts to identify new SLE susceptibility loci and better localize known loci. We identified ten new loci and confirmed 20 known loci with genome-wide significance. Among the new loci, the most significant locus was GTF2IRD1-GTF2I at 7q11.23 (rs73366469, P meta = 3.75 × 10 â '117, odds ratio (OR) = 2.38), followed by DEF6, IL12B, TCF7, TERT, CD226, PCNXL3, RASGRP1, SYNGR1 and SIGLEC6. We identified the most likely functional variants at each locus by analyzing epigenetic marks and gene expression data. Ten candidate variants are known to alter gene expression in cis or in trans. Enrichment analysis highlights the importance of these loci in B cell and T cell biology. The new loci, together with previously known loci, increase the explained heritability of SLE to 24%. The new loci share functional and ontological characteristics with previously reported loci and are possible drug targets for SLE therapeutics.

AB - Systemic lupus erythematosus (SLE) has a strong but incompletely understood genetic architecture. We conducted an association study with replication in 4,478 SLE cases and 12,656 controls from six East Asian cohorts to identify new SLE susceptibility loci and better localize known loci. We identified ten new loci and confirmed 20 known loci with genome-wide significance. Among the new loci, the most significant locus was GTF2IRD1-GTF2I at 7q11.23 (rs73366469, P meta = 3.75 × 10 â '117, odds ratio (OR) = 2.38), followed by DEF6, IL12B, TCF7, TERT, CD226, PCNXL3, RASGRP1, SYNGR1 and SIGLEC6. We identified the most likely functional variants at each locus by analyzing epigenetic marks and gene expression data. Ten candidate variants are known to alter gene expression in cis or in trans. Enrichment analysis highlights the importance of these loci in B cell and T cell biology. The new loci, together with previously known loci, increase the explained heritability of SLE to 24%. The new loci share functional and ontological characteristics with previously reported loci and are possible drug targets for SLE therapeutics.

UR - http://www.scopus.com/inward/record.url?scp=84959530680&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84959530680&partnerID=8YFLogxK

U2 - 10.1038/ng.3496

DO - 10.1038/ng.3496

M3 - Article

C2 - 26808113

AN - SCOPUS:84959530680

SN - 1061-4036

VL - 48

SP - 323

EP - 330

JO - Nature Genetics

JF - Nature Genetics

IS - 3

ER -

High-density genotyping of immune-related loci identifies new SLE risk variants in individuals with Asian ancestry

Abstract

Bibliographical note

All Science Journal Classification (ASJC) codes

Access to Document

Other files and links

Fingerprint

Cite this