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

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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 - 01-03-2016

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All Science Journal Classification (ASJC) codes

Genetics

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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

Sun, Celi ; Molineros, Julio E. ; Looger, Loren L. ; Zhou, Xu Jie ; Kim, Kwangwoo ; Okada, Yukinori ; Ma, Jianyang ; Qi, Yuan Yuan ; Kim-Howard, Xana ; Motghare, Prasenjeet ; Bhattarai, Krishna ; Adler, Adam ; Bang, So Young ; Lee, Hye Soon ; Kim, Tae Hwan ; Kang, Young Mo ; Suh, Chang Hee ; Chung, Won Tae ; Park, Yong Beom ; Choe, Jung Yoon ; Shim, Seung Cheol ; Kochi, Yuta ; Suzuki, Akari ; Kubo, Michiaki ; Sumida, Takayuki ; Yamamoto, Kazuhiko ; Lee, Shin Seok ; Kim, Young Jin ; Han, Bok Ghee ; Dozmorov, Mikhail ; Kaufman, Kenneth M. ; Wren, Jonathan D. ; Harley, John B. ; Shen, Nan ; Chua, Kek Heng ; Zhang, Hong ; Bae, Sang Cheol ; Nath, Swapan K. / High-density genotyping of immune-related loci identifies new SLE risk variants in individuals with Asian ancestry. In: Nature Genetics. 2016 ; Vol. 48, No. 3. pp. 323-330.

@article{b86bcccc6346404cba81f833a48afa02,

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.}",

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doi = "10.1038/ng.3496",

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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

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

In: Nature Genetics, Vol. 48, No. 3, 01.03.2016, p. 323-330.

Research output: Contribution to journal › Article

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.

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.

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