Genome-wide meta-analysis identifies multiple novel loci associated with serum uric acid levels in Japanese individuals

Nakatochi, Masahiro; Kanai, Masahiro; Nakayama, Akiyoshi; Hishida, Asahi; Kawamura, Yusuke; Ichihara, Sahoko; Akiyama, Masato; Ikezaki, Hiroaki; Furusyo, Norihiro; Shimizu, Seiko; Yamamoto, Ken; Hirata, Makoto; Okada, Rieko; Kawai, Shinya; Kikuchi, Makoto; Nishida, Yuichiro; Shimanoe, Chisato; Ibusuki, Rie; Takezaki, Toshiro; Nakajima, Masakazu; Mitsui, Takao; Ozaki, Etsuko; Matsui, Daisuke; Nishiyama, Takeshi; Suzuki, Sadao; Takashima, Naoyuki; Kita, Yoshikuni; Endoh, Kaori; Kuriki, Kiyonori; Uemura, Hirokazu; Arisawa, Kokichi; Oze, Isao; Matsuo, Keitaro; Nakamura, Yohko; Mikami, Haruo; Tamura, Takashi; Nakashima, Hiroshi; Nakamura, Takahiro; Kato, Norihiro; Matsuda, Koichi; Murakami, Yoshinori; Matsubara, Tatsuaki; Naito, Mariko; Kubo, Michiaki; Kamatani, Yoichiro; Shinomiya, Nariyoshi; Yokota, Mitsuhiro; Wakai, Kenji; Okada, Yukinori

doi:10.1038/s42003-019-0339-0

Cited by 64 publications

(58 citation statements)

References 74 publications

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“…[4] and a new serum urate GWAS of 121,745 Japanese individuals (that encompassed all the individuals in the Kanai et al . [6] study) was published [38]. This study, the largest serum urate GWAS published to date, discovered 59 loci, of which 22 are newly reported beyond those reported in the Köttgen et al .…”

Section: Discussionmentioning

confidence: 97%

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Genomic dissection of 43 serum urate-associated loci provides multiple insights into molecular mechanisms of urate control

Boocock

Leask

Okada

et al. 2019

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69Serum urate is the end-product of purine metabolism. Elevated serum urate is causal of 70 gout and a predictor of renal disease, cardiovascular disease and other metabolic 71 conditions. Genome-wide association studies (GWAS) have reported dozens of loci 72 associated with serum urate control, however there has been little progress in 73 understanding the molecular basis of the associated loci. Here we employed trans-74 ancestral meta-analysis using data from European and East Asian populations to 75 identify ten new loci for serum urate levels. Genome-wide colocalization with cis-76 expression quantitative trait loci (eQTL) identified a further five new loci. By cis-and 77 trans-eQTL colocalization analysis we identified 24 and 20 genes respectively where 78 the causal eQTL variant has a high likelihood that it is shared with the serum urate-79 associated locus. One new locus identified was SLC22A9 that encodes organic anion 80 transporter 7 (OAT7). We demonstrate that OAT7 is a very weak urate-butyrate 81 exchanger. Newly implicated genes identified in the eQTL analysis include those 82 encoding proteins that make up the dystrophin complex, a scaffold for signaling 83 proteins and transporters at the cell membrane; MLXIP that, with the previously 84 identified MLXIPL, is a transcription factor that may regulate serum urate via the 85 pentose-phosphate pathway; and MRPS7 and IDH2 that encode proteins necessary for 86 mitochondrial function. Trans-ancestral functional fine-mapping identified six loci 87 (RREB1, INHBC, HLF, UBE2Q2, SFMBT1, HNF4G) with colocalized eQTL that 88 contained putative causal SNPs (posterior probability of causality > 0.8). This 89 systematic analysis of serum urate GWAS loci has identified candidate causal genes at 90 19 loci and a network of previously unidentified genes likely involved in control of 91 serum urate levels, further illuminating the molecular mechanisms of urate control. 92 93 Author Summary 94 High serum urate is a prerequisite for gout and a risk factor for metabolic disease. 95Previous GWAS have identified numerous loci that are associated with serum urate 96 control, however, only a small handful of these loci have known molecular 97 consequences. The majority of loci are within the non-coding regions of the genome 98 and therefore it is difficult to ascertain how these variants might influence serum urate 99 levels without tangible links to gene expression and / or protein function. We have 100 applied a novel bioinformatic pipeline where we combined population-specific GWAS 101 4 data with gene expression and genome connectivity information to identify putative 102 causal genes for serum urate associated loci. Overall, we identified 15 novel serum 103 urate loci and show that these loci along with previously identified loci are linked to 104 the expression of 44 genes. We show that some of the variants within these loci have 105 strong predicted regulatory function which can be further tested in functional analyses. 106 This study expands on previous GWAS by ident...

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Section: Discussionmentioning

confidence: 97%

“…[6] and Nakatochi et al . [38] studies reported this segment of Chr11 as a single locus. Here we dissected the Chr11 63.2-64.4 Mb segment and identified four loci in this region, including SLC22A9 (encoding OAT7), the locus with the largest effect size on serum urate in the Japanese population (Table 1).…”

Section: Discussionmentioning

confidence: 99%

Genomic dissection of 43 serum urate-associated loci provides multiple insights into molecular mechanisms of urate control

Boocock

Leask

Okada

et al. 2019

Preprint

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“…The association between rs2544390 and SUA was first identified by a GWAS of SUA in a Japanese population by Kamatani et al [3]; this was also confirmed by the recent genome-wide meta-analysis of SUA [15]. Since the association between LRP2 and SUA was reported, several association studies for the Japanese population have been conducted, because gout is a consequence of hyperuricemia.…”

Section: Discussionmentioning

confidence: 77%

A common variant of LDL receptor related protein 2 (LRP2) gene is associated with gout susceptibility: a meta-analysis in a Japanese population

et al. 2020

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Gout, which results from elevated serum uric acid (SUA), is a common form of arthritis that is induced by urate crystals. A single nucleotide polymorphism, rs2544390, of LDL receptor related protein 2 (LRP2/Megalin), has previously been reported to be associated with SUA by a genome-wide association study in a Japanese population. However, it was controversial as to whether rs2544390 is associated with gout in a Japanese population, since previous studies with Japanese populations have reported an association between gout and rs2544390 both with and without significance. This prompted us to investigate the association between gout and rs2544390 of LRP2. Using 1208 clinically diagnosed gout patients and 1223 controls in a Japanese male population, our results showed that while rs2544390 did not show a significant association with gout susceptibility in the present study (p = 0.0793, odds ratio [OR] with 95% confidential interval [CI] 1.11 [0.99-1.24]). However, a meta-analysis using previous studies on Japanese populations revealed a significant association with gout (p meta = 0.0314, OR with 95% CI 1.09 [1.01-1.18]). We have therefore for the first time confirmed a positive association between rs2544390 and gout with only a Japanese male population. Our study provides clues to a better understanding of the pathogenesis of gout and has the potential to lead to novel therapeutic strategies against gout using LRP2 as a molecular target.

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“…As suggestive loci for gout, seven loci: PDZK1 , TACR1-EVA1A , LOC100128993 , ARID5B , TOLLIP-AS1-BRSK2 , SLC38A1 and MLXIP , were detected (see online supplementary table S4). Of these, PDZK1 , a gene encoding a scaffolding protein22 23 such as for urate transporters SLC22A12/URAT1 and ABCG2, was reported to have an association with SUA by a GWAS approach24 25 and with gout as a result of candidate gene approach studies 26–28…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2020

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ObjectivesGenome-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.MethodsTwo 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.ResultsIn 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.ConclusionsOur 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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Genome-wide meta-analysis identifies multiple novel loci associated with serum uric acid levels in Japanese individuals

Cited by 64 publications

References 74 publications

Genomic dissection of 43 serum urate-associated loci provides multiple insights into molecular mechanisms of urate control

Genomic dissection of 43 serum urate-associated loci provides multiple insights into molecular mechanisms of urate control

A common variant of LDL receptor related protein 2 (LRP2) gene is associated with gout susceptibility: a meta-analysis in a Japanese population

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

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