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

Research output: Contribution to journalArticlepeer-review

128 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 languageEnglish
Pages (from-to)323-330
Number of pages8
JournalNature Genetics
Volume48
Issue number3
DOIs
Publication statusPublished - 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

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