OBJECTIVE: A genome-wide association study (GWAS) of gout and its subtypes was performed to identify novel gout loci, including those that are subtype-specific. METHODS: Putative causal association signals from a GWAS of 945 clinically defined gout cases and 1213 controls from Japanese males were replicated with 1396 cases and 1268 controls using a custom chip of 1961 single nucleotide polymorphisms (SNPs). We also first conducted GWASs of gout subtypes. Replication with Caucasian and New Zealand Polynesian samples was done to further validate the loci identified in this study. RESULTS: In addition to the five loci we reported previously, further susceptibility loci were identified at a genome-wide significance level (p<5.0×10-8): urate transporter genes (SLC22A12 and SLC17A1) and HIST1H2BF-HIST1H4E for all gout cases, and NIPAL1 and FAM35A for the renal underexcretion gout subtype. While NIPAL1 encodes a magnesium transporter, functional analysis did not detect urate transport via NIPAL1, suggesting an indirect association with urate handling. Localisation analysis in the human kidney revealed expression of NIPAL1 and FAM35A mainly in the distal tubules, which suggests the involvement of the distal nephron in urate handling in humans. Clinically ascertained male patients with gout and controls of Caucasian and Polynesian ancestries were also genotyped, and FAM35A was associated with gout in all cases. A meta-analysis of the three populations revealed FAM35A to be associated with gout at a genome-wide level of significance (p meta =3.58×10-8). CONCLUSIONS: Our findings including novel gout risk loci provide further understanding of the molecular pathogenesis of gout and lead to a novel concept for the therapeutic target of gout/hyperuricaemia.

1st Faculty of Medicine Charles University Prague and General University Hospital Prague Institute of Inherited Metabolic Disorders Prague Czech Republic

Department of Biochemisty University of Otago Dunedin New Zealand

Department of Biopharmaceutics Graduate School of Pharmaceutical Sciences Nagoya City University Nagoya Aichi Japan

Department of Biopharmaceutics School of Pharmacy Tokyo University of Pharmacy and Life Sciences Tokyo Japan

Department of Dermatology National Defense Medical College Tokorozawa Saitama Japan

Department of Human Genetics and Disease Diversity Graduate School of Medical and Dental Sciences Tokyo Medical and Dental University Tokyo Japan

Department of Human Physiology and Pathology Faculty of Pharma Sciences Teikyo University Tokyo Japan

Department of Integrative Genomics Tohoku Medical Megabank Organization Tohoku University Sendai Miyagi Japan

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

Department of Internal Medicine Self Defense Forces Central Hospital Tokyo Japan

Department of Internal Medicine Teikyo University School of Medicine Tokyo Japan

Department of Medical Chemistry Kurume University School of Medicine Kurume Fukuoka Japan

Department of Medicine University of Auckland Grafton Auckland New Zealand

Department of Medicine University of Otago Christchurch New Zealand

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

Department of Pathophysiology Tokyo University of Pharmacy and Life Sciences Tokyo Japan

Department of Pharmacy The University of Tokyo Hospital Tokyo Japan

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

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

Department of Statistical Genetics Osaka University Graduate School of Medicine Osaka Japan

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

Division of Kidney and Hypertension Department of Internal Medicine Jikei University School of Medicine Tokyo Japan

Division of Transcriptomics Research Center for Transomics Medicine Medical Institute of Bioregulation Kyushu University Fukuoka Japan

Institute of Rheumatology Prague Czech Republic

Kyoto Industrial Health Association Kyoto Japan

Laboratory for Genotyping Development Center for Integrative Medical Sciences RIKEN Yokohama Kanagawa Japan

Laboratory for Mathematics National Defense Medical College Tokorozawa Saitama Japan

Laboratory for Statistical Analysis RIKEN Center for Integrative Medical Sciences Yokohama Kanagawa Japan

Midorigaoka Hospital Takatsuki Osaka Japan

Omics Research Center National Cerebral and Cardiovascular Center Suita Osaka Japan

Program in Radiological and Medical Laboratory Sciences Pathophysiological Laboratory Sciences Nagoya University Graduate School of Medicine Nagoya Aichi Japan

Ryougoku East Gate Clinic Tokyo Japan

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