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Association study on chromosome 20q11.21-13.13 locus and its contribution to type 2 diabetes susceptibility in Japanese

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Abstract

Several linkage studies have predicted that human chromosome 20q is closely related to type 2 diabetes, but there is no clear evidence that certain variant(s) or gene(s) have strong effects on the disease within this region. To examine disease susceptibility variant in Japanese, verified SNPs from the databases, with a minor allele frequency larger than 0.15, were selected at 10-kb intervals across a 19.31-Mb region (20q11.21-13.13), which contained 291 genes, including hepatocyte nuclear factor 4α (HNF4α). As a result, a total of 1,147 SNPs were genotyped with TaqMan assay using 1,818 Japanese samples. By searching for HNF4α as a representative disease-susceptible gene, no variants of HNF4α were strongly associated with disease. To identify other genetic variant related with disease, we designed an extensive two-stage association study (725 first and 1,093 second test samples). Although SNP1146 (rs220076) was selected as a landmark within the 19.31 Mb region, the magnitude of the nominal P value (P = 0.0023) was rather weak. Subsequently, a haplotype-based association study showed that two common haplotypes were weakly associated with disease. All of these tests resulted in non-significance after adjusting for Bonferroni’s correction and the false discovery rate to control for the impact of multiple testing. Contrary to the initial expectations, we could not conclude that certain SNPs had a major effect on this promising locus within the framework presented here. As a way to extend our observations, we emphasize the importance of a subsequent association study including replication and/or meta-analysis in multiple populations.

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Abbreviations

FUSION:

The Finland-United States Investigation of Non-insulin-dependent diabetes mellitus genetics

UTR:

Untranslated region

JPT:

Japanese in Tokyo

CHB:

Han Chinese in Beijing

CEU:

Utah residents with ancestry from northern and western Europe by the Centre d’Etude du Polymorphisme Humain

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Acknowledgments

We are very grateful to Dr. Naoyuki Kamatani (Division of Statistical Genetics, Department of Advanced Biomedical Engineering and Science, Tokyo Women’s Medical University) for the critical reading of the manuscript and helpful comments. We thank the members of the Institute for Genome Research for helpful discussions and assistance. This study was supported by a grant from the Cooperative Link of Unique Science and Technology for Economy Revitalization (CLUSTER) and Takeda Science Foundation (Osaka, Japan).

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Authors and Affiliations

  1. Division of Genetic Information, Institute for Genome Research, The University of Tokushima, 3-18-15, Kuramoto-cho, Tokushima, 770-8503, Japan

    Toshihito Tanahashi, Parvaneh Keshavarz, Yuka Yamaguchi, Kiyoshi Kunika, Maki Moritani, Hiroshi Inoue & Mitsuo Itakura

  2. Department of Bioinformatics, Division of Life Science Systems, Fujitsu Limited, 1-5-2, Higashishinbashi, Minato-ku, Tokyo, 105-7123, Japan

    Dai Osabe & Kyoko Nomura

  3. Division of R&D Solution, Fujitsu Nagano Systems Engineering Limited, Nagano, 380-3813, Japan

    Shuichi Shinohara

  4. Haplopharma Inc., 2-2-1, Yaesu, Chuo-ku, Tokyo, 104-0028, Japan

    Hitoshi Kato

  5. New Industry Creation Hatchery Center, Tohoku University, Aramaki, Aoba-ku, Sendai, Miyagi, 980-8579, Japan

    Eiichiro Ichiishi

  6. Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine Graduate School of Medical Sciences, 465, Kajii-cho, Hirokoji-Kawaramachi, Kamigyo-ku, Kyoto, 602-8566, Japan

    Naoto Nakamura & Toshikazu Yoshikawa

  7. Department of Orthopedics, Institute for Health Biosciences, The University of Tokushima, 3-18-15, Kuramoto-cho, Tokushima, 770-8503, Japan

    Yoichiro Takata

  8. Department of Ophthalmology and Visual Neuroscience, Institute for Health Biosciences, The University of Tokushima, 3-18-15, Kuramoto-cho, Tokushima, 770-8503, Japan

    Tatsuro Miyamoto & Hiroshi Shiota

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  1. Toshihito Tanahashi
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  2. Dai Osabe
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  12. Parvaneh Keshavarz
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  17. Mitsuo Itakura
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Correspondence to Mitsuo Itakura.

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Tanahashi, T., Osabe, D., Nomura, K. et al. Association study on chromosome 20q11.21-13.13 locus and its contribution to type 2 diabetes susceptibility in Japanese. Hum Genet 120, 527–542 (2006). https://doi.org/10.1007/s00439-006-0231-0

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