Identification of independent risk loci for Graves disease within the MHC in the Japanese population

Kazuhiko Nakabayashi, Atsushi Tajima, Ken Yamamoto, Atsushi Takahashi, Kenichiro Hata, Yasuo Takashima, Midori Koyanagi, Hirofumi Nakaoka, Takashi Akamizu, Naofumi Ishikawa, Sumihisa Kubota, Shiro Maeda, Tatsuhiko Tsunoda, Michiaki Kubo, Naoyuki Kamatani, Yusuke Nakamura, Takehiko Sasazuki, Senji Shirasawa

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Abstract

To identify genetic variants that confer the risk of Graves disease (GD) in the Japanese population, we conducted a two-stage genome-wide association study (GWAS) using 1119 Japanese individuals with GD and 2718 unrelated controls, and a subsequent replication study using independent 432 GD cases and 1157 controls. We identified 34 single nucleotide polymorphisms (SNPs) to be significantly associated with GD in the GWAS phase. Twenty-two out of 34 SNPs remained positive in the replication study. All 22 SNPs were located within the major histocompatibility complex (MHC) locus on chromosome 6p21. No strong long-range linkage disequilibrium (LD) was observed among the 22 SNPs, indicating independent involvement of multiple loci within the MHC with the risk of GD. Multivariate stepwise logistic regression analysis selected rs3893464, rs4313034, rs3132613, rs4248154, rs2273017, rs9394159 and rs4713693, as markers for independent risk loci for GD. The analysis of LD between these seven SNPs and tagging SNPs for GD-associated human leukocyte antigen (HLA) alleles in the Japanese population (HLA-DPB1 0501 and HLA-A 0206) demonstrated that all of and five of seven SNPs were not in strong LD with HLA-DPB1 0501 and HLA-A 0206, respectively. Although causal variants remain to be identified, our results demonstrate the existence of multiple GD susceptibility loci within the MHC region.

Original languageEnglish
Pages (from-to)772-778
Number of pages7
JournalJournal of Human Genetics
Volume56
Issue number11
DOIs
Publication statusPublished - 01-11-2011

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Graves Disease
Major Histocompatibility Complex
Single Nucleotide Polymorphism
HLA Antigens
Population
Linkage Disequilibrium
Genome-Wide Association Study
Disease Susceptibility
Chromosomes
Logistic Models
Alleles
Regression Analysis

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Nakabayashi, K., Tajima, A., Yamamoto, K., Takahashi, A., Hata, K., Takashima, Y., ... Shirasawa, S. (2011). Identification of independent risk loci for Graves disease within the MHC in the Japanese population. Journal of Human Genetics, 56(11), 772-778. https://doi.org/10.1038/jhg.2011.99
Nakabayashi, Kazuhiko ; Tajima, Atsushi ; Yamamoto, Ken ; Takahashi, Atsushi ; Hata, Kenichiro ; Takashima, Yasuo ; Koyanagi, Midori ; Nakaoka, Hirofumi ; Akamizu, Takashi ; Ishikawa, Naofumi ; Kubota, Sumihisa ; Maeda, Shiro ; Tsunoda, Tatsuhiko ; Kubo, Michiaki ; Kamatani, Naoyuki ; Nakamura, Yusuke ; Sasazuki, Takehiko ; Shirasawa, Senji. / Identification of independent risk loci for Graves disease within the MHC in the Japanese population. In: Journal of Human Genetics. 2011 ; Vol. 56, No. 11. pp. 772-778.
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Nakabayashi, K, Tajima, A, Yamamoto, K, Takahashi, A, Hata, K, Takashima, Y, Koyanagi, M, Nakaoka, H, Akamizu, T, Ishikawa, N, Kubota, S, Maeda, S, Tsunoda, T, Kubo, M, Kamatani, N, Nakamura, Y, Sasazuki, T & Shirasawa, S 2011, 'Identification of independent risk loci for Graves disease within the MHC in the Japanese population', Journal of Human Genetics, vol. 56, no. 11, pp. 772-778. https://doi.org/10.1038/jhg.2011.99

Identification of independent risk loci for Graves disease within the MHC in the Japanese population. / Nakabayashi, Kazuhiko; Tajima, Atsushi; Yamamoto, Ken; Takahashi, Atsushi; Hata, Kenichiro; Takashima, Yasuo; Koyanagi, Midori; Nakaoka, Hirofumi; Akamizu, Takashi; Ishikawa, Naofumi; Kubota, Sumihisa; Maeda, Shiro; Tsunoda, Tatsuhiko; Kubo, Michiaki; Kamatani, Naoyuki; Nakamura, Yusuke; Sasazuki, Takehiko; Shirasawa, Senji.

In: Journal of Human Genetics, Vol. 56, No. 11, 01.11.2011, p. 772-778.

Research output: Contribution to journalArticle

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T1 - Identification of independent risk loci for Graves disease within the MHC in the Japanese population

AU - Nakabayashi, Kazuhiko

AU - Tajima, Atsushi

AU - Yamamoto, Ken

AU - Takahashi, Atsushi

AU - Hata, Kenichiro

AU - Takashima, Yasuo

AU - Koyanagi, Midori

AU - Nakaoka, Hirofumi

AU - Akamizu, Takashi

AU - Ishikawa, Naofumi

AU - Kubota, Sumihisa

AU - Maeda, Shiro

AU - Tsunoda, Tatsuhiko

AU - Kubo, Michiaki

AU - Kamatani, Naoyuki

AU - Nakamura, Yusuke

AU - Sasazuki, Takehiko

AU - Shirasawa, Senji

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N2 - To identify genetic variants that confer the risk of Graves disease (GD) in the Japanese population, we conducted a two-stage genome-wide association study (GWAS) using 1119 Japanese individuals with GD and 2718 unrelated controls, and a subsequent replication study using independent 432 GD cases and 1157 controls. We identified 34 single nucleotide polymorphisms (SNPs) to be significantly associated with GD in the GWAS phase. Twenty-two out of 34 SNPs remained positive in the replication study. All 22 SNPs were located within the major histocompatibility complex (MHC) locus on chromosome 6p21. No strong long-range linkage disequilibrium (LD) was observed among the 22 SNPs, indicating independent involvement of multiple loci within the MHC with the risk of GD. Multivariate stepwise logistic regression analysis selected rs3893464, rs4313034, rs3132613, rs4248154, rs2273017, rs9394159 and rs4713693, as markers for independent risk loci for GD. The analysis of LD between these seven SNPs and tagging SNPs for GD-associated human leukocyte antigen (HLA) alleles in the Japanese population (HLA-DPB1 0501 and HLA-A 0206) demonstrated that all of and five of seven SNPs were not in strong LD with HLA-DPB1 0501 and HLA-A 0206, respectively. Although causal variants remain to be identified, our results demonstrate the existence of multiple GD susceptibility loci within the MHC region.

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Nakabayashi K, Tajima A, Yamamoto K, Takahashi A, Hata K, Takashima Y et al. Identification of independent risk loci for Graves disease within the MHC in the Japanese population. Journal of Human Genetics. 2011 Nov 1;56(11):772-778. https://doi.org/10.1038/jhg.2011.99