OBJECTIVES: Genome-wide meta-analyses of clinically defined gout were performed to identify subtype-specific susceptibility loci. Evaluation using selection pressure analysis with these loci was also conducted to investigate genetic risks characteristic of the Japanese population over the last 2000-3000 years. METHODS: Two genome-wide association studies (GWASs) of 3053 clinically defined gout cases and 4554 controls from Japanese males were performed using the Japonica Array and Illumina Array platforms. About 7.2 million single-nucleotide polymorphisms were meta-analysed after imputation. Patients were then divided into four clinical subtypes (the renal underexcretion type, renal overload type, combined type and normal type), and meta-analyses were conducted in the same manner. Selection pressure analyses using singleton density score were also performed on each subtype. RESULTS: In addition to the eight loci we reported previously, two novel loci, PIBF1 and ACSM2B, were identified at a genome-wide significance level (p<5.0×10-8) from a GWAS meta-analysis of all gout patients, and other two novel intergenic loci, CD2-PTGFRN and SLC28A3-NTRK2, from normal type gout patients. Subtype-dependent patterns of Manhattan plots were observed with subtype GWASs of gout patients, indicating that these subtype-specific loci suggest differences in pathophysiology along patients' gout subtypes. Selection pressure analysis revealed significant enrichment of selection pressure on ABCG2 in addition to ALDH2 loci for all subtypes except for normal type gout. CONCLUSIONS: Our findings on subtype GWAS meta-analyses and selection pressure analysis of gout will assist elucidation of the subtype-dependent molecular targets and evolutionary involvement among genotype, phenotype and subtype-specific tailor-made medicine/prevention of gout and hyperuricaemia.

Akasaka Central Clinic Tokyo Japan

Cancer Prevention Center Chiba Cancer Center Research Institute Chiba Japan

Department of Biochemisty University of Otago Dunedin New Zealand

Department of Bioinformatics and Genomics Graduate School of Advanced Preventive Medical Sciences Kanazawa University Kanazawa Japan

Department of Epidemiology for Community Health and Medicine Kyoto Prefectural University of Medicine Kyoto Japan

Department of Health Science Shiga University of Medical Science Otsu Japan Department of Public Health Faculty of Medicine Kindai University Osaka Sayama Japan

Department of Integrative Physiology and Bio Nano Medicine National Defense Medical College Tokorozawa Japan

Department of Integrative Physiology and Bio Nano Medicine National Defense Medical College Tokorozawa Japan Department of General Medicine National Defense Medical College Tokorozawa Japan

Department of Integrative Physiology and Bio Nano Medicine National Defense Medical College Tokorozawa Japan Department of Surgery National Defense Medical College Tokorozawa Japan

Department of Integrative Physiology and Bio Nano Medicine National Defense Medical College Tokorozawa Japan Department of Urology National Defense Medical College Tokorozawa Japan

Department of Integrative Physiology and Bio Nano Medicine National Defense Medical College Tokorozawa Japan Graduate School of Information Science and Technology Hokkaido University Sapporo Japan

Department of Integrative Physiology and Bio Nano Medicine National Defense Medical College Tokorozawa Japan Medical Squadron Air Base Group Western Aircraft Control and Warning Wing Japan Air Self Defense Force Kasuga Japan

Department of International Island and Community Medicine Kagoshima University Graduate School of Medical and Dental Sciences Kagoshima Japan

Department of Medical Biochemistry Kurume University School of Medicine Kurume Japan

Department of Pediatrics and Adolescent Medicine 1st Faculty of Medicine Charles University and General University Hospital Prague Czech Republic Institute of Rheumatology Prague Czech Republic

Department of Pharmacy The University of Tokyo Hospital Tokyo Japan

Department of Preventive Medicine and Epidemiology Tohoku Medical Megabank Organization Tohoku University Sendai Japan

Department of Preventive Medicine and Public Health National Defense Medical College Tokorozawa Japan

Department of Preventive Medicine Faculty of Medicine Saga University Saga Japan Clinical Research Center Saga University Hospital Saga Japan

Department of Preventive Medicine Institute of Biomedical Sciences Tokushima University Graduate School Tokushima Japan

Department of Preventive Medicine Nagoya University Graduate School of Medicine Nagoya Japan

Department of Public Health Nagoya City University Graduate School Medical Science Nagoya Japan

Department of Statistical Genetics Osaka University Graduate School of Medicine Suita Japan Department of Respiratory Medicine and Clinical Immunology Osaka University Graduate School of Medicine Suita Japan

Department of Statistical Genetics Osaka University Graduate School of Medicine Suita Japan Laboratory of Statistical Immunology Immunology Frontier Research Center Osaka University Suita Japan

Division of Cancer Epidemiology and Prevention Aichi Cancer Center Research Institute Nagoya Japan Department of Epidemiology Nagoya University Graduate School of Medicine Nagoya Japan

Division of Department of Nursing Nagoya University Graduate School of Medicine Nagoya Japan

Division of Human Genetics Department of Integrated Genetics National Institute of Genetics Mishima Japan

Division of Kidney and Hypertension Department of Internal Medicine Jikei University School of Medicine Tokyo Japan Department of Pathophysiology and Therapy in Chronic Kidney Disease Jikei University School of Medicine Tokyo Japan

Division of Kidney and Hypertension Department of Internal Medicine Jikei University School of Medicine Tokyo Japan Department of Pathophysiology Tokyo University of Pharmacy and Life Science Hachioji Japan

Faculty of Medical Science Teikyo University of Science Tokyo Japan

Group of Privacy Controls Tohoku Medical Megabank Organization Sendai Japan

Laboratory for Mathematics National Defense Medical College Tokorozawa Japan

Laboratory for Statistical Analysis RIKEN Center for Integrative Medical Sciences Yokohama Japan Center for Genomic Medicine Kyoto University Graduate School of Medicine Kyoto Japan

Laboratory of Public Health School of Food and Nutritional Sciences University of Shizuoka Shizuoka Japan

Midorigaoka Hospital Takatsuki Japan Kyoto Industrial Health Association Kyoto Japan

Nagase Clinic Tokyo Japan

RIKEN Center for Integrative Medical Sciences Yokohama Japan

Ryougoku East Gate Clinic Tokyo Japan

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$a Nakayama, Akiyoshi $u Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Japan. Medical Squadron, Air Base Group, Western Aircraft Control and Warning Wing, Japan Air Self-Defense Force, Kasuga, Japan.

245    10

$a Subtype-specific gout susceptibility loci and enrichment of selection pressure on ABCG2 and ALDH2 identified by subtype genome-wide meta-analyses of clinically defined gout patients / $c A. Nakayama, M. Nakatochi, Y. Kawamura, K. Yamamoto, H. Nakaoka, S. Shimizu, T. Higashino, T. Koyama, A. Hishida, K. Kuriki, M. Watanabe, T. Shimizu, K. Ooyama, H. Ooyama, M. Nagase, Y. Hidaka, D. Matsui, T. Tamura, T. Nishiyama, C. Shimanoe, S. Katsuura-Kamano, N. Takashima, Y. Shirai, M. Kawaguchi, M. Takao, R. Sugiyama, Y. Takada, T. Nakamura, H. Nakashima, M. Tsunoda, I. Danjoh, A. Hozawa, K. Hosomichi, Y. Toyoda, Y. Kubota, T. Takada, H. Suzuki, B. Stiburkova, TJ. Major, TR. Merriman, N. Kuriyama, H. Mikami, T. Takezaki, K. Matsuo, S. Suzuki, T. Hosoya, Y. Kamatani, M. Kubo, K. Ichida, K. Wakai, I. Inoue, Y. Okada, N. Shinomiya, H. Matsuo, Japan Gout Genomics Consortium (Japan Gout),

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$a OBJECTIVES: Genome-wide meta-analyses of clinically defined gout were performed to identify subtype-specific susceptibility loci. Evaluation using selection pressure analysis with these loci was also conducted to investigate genetic risks characteristic of the Japanese population over the last 2000-3000 years. METHODS: Two genome-wide association studies (GWASs) of 3053 clinically defined gout cases and 4554 controls from Japanese males were performed using the Japonica Array and Illumina Array platforms. About 7.2 million single-nucleotide polymorphisms were meta-analysed after imputation. Patients were then divided into four clinical subtypes (the renal underexcretion type, renal overload type, combined type and normal type), and meta-analyses were conducted in the same manner. Selection pressure analyses using singleton density score were also performed on each subtype. RESULTS: In addition to the eight loci we reported previously, two novel loci, PIBF1 and ACSM2B, were identified at a genome-wide significance level (p<5.0×10-8) from a GWAS meta-analysis of all gout patients, and other two novel intergenic loci, CD2-PTGFRN and SLC28A3-NTRK2, from normal type gout patients. Subtype-dependent patterns of Manhattan plots were observed with subtype GWASs of gout patients, indicating that these subtype-specific loci suggest differences in pathophysiology along patients' gout subtypes. Selection pressure analysis revealed significant enrichment of selection pressure on ABCG2 in addition to ALDH2 loci for all subtypes except for normal type gout. CONCLUSIONS: Our findings on subtype GWAS meta-analyses and selection pressure analysis of gout will assist elucidation of the subtype-dependent molecular targets and evolutionary involvement among genotype, phenotype and subtype-specific tailor-made medicine/prevention of gout and hyperuricaemia.

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$a Nakatochi, Masahiro $u Division of Department of Nursing, Nagoya University Graduate School of Medicine, Nagoya, Japan.

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$a Kawamura, Yusuke $u Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Japan. Department of General Medicine, National Defense Medical College, Tokorozawa, Japan.

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$a Yamamoto, Ken $u Department of Medical Biochemistry, Kurume University School of Medicine, Kurume, Japan.

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$a Nakaoka, Hirofumi $u Division of Human Genetics, Department of Integrated Genetics, National Institute of Genetics, Mishima, Japan.

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$a Koyama, Teruhide $u Department of Epidemiology for Community Health and Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.

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$a Shimizu, Toru $u Midorigaoka Hospital, Takatsuki, Japan. Kyoto Industrial Health Association, Kyoto, Japan.

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$a Ooyama, Keiko $u Ryougoku East Gate Clinic, Tokyo, Japan.

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$a Ooyama, Hiroshi $u Ryougoku East Gate Clinic, Tokyo, Japan.

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$a Nishiyama, Takeshi $u Department of Public Health, Nagoya City University Graduate School Medical Science, Nagoya, Japan.

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$a Shimanoe, Chisato $u Department of Preventive Medicine, Faculty of Medicine, Saga University, Saga, Japan. Clinical Research Center, Saga University Hospital, Saga, Japan.

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$a Katsuura-Kamano, Sakurako $u Department of Preventive Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.

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$a Takashima, Naoyuki $u Department of Health Science, Shiga University of Medical Science, Otsu, Japan. Department of Public Health, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan.

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$a Shirai, Yuya $u Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan. Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Japan.

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$a Kawaguchi, Makoto $u Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Japan. Department of Urology, National Defense Medical College, Tokorozawa, Japan.

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$a Takada, Yuzo $u Faculty of Medical Science, Teikyo University of Science, Tokyo, Japan.

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$a Nakamura, Takahiro $u Laboratory for Mathematics, National Defense Medical College, Tokorozawa, Japan.

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$a Tsunoda, Masashi $u Department of Preventive Medicine and Public Health, National Defense Medical College, Tokorozawa, Japan.

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$a Danjoh, Inaho $u Group of Privacy Controls, Tohoku Medical Megabank Organization, Sendai, Japan.

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$a Hozawa, Atsushi $u Department of Preventive Medicine and Epidemiology, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.

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$a Takezaki, Toshiro $u Department of International Island and Community Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.

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$a Kamatani, Yoichiro $u Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.

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$a Ichida, Kimiyoshi $u Division of Kidney and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan. Department of Pathophysiology, Tokyo University of Pharmacy and Life Science, Hachioji, Japan.

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$a Okada, Yukinori $u Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan. Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Japan.

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$a Shinomiya, Nariyoshi $u Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Japan.

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$a Matsuo, Hirotaka $u Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Japan hmatsuo@ndmc.ac.jp.

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