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Takuya Kitamoto,
Aya Kitamoto,
Masato Yoneda,
Hideyuki Hyogo,
Hidenori Ochi,
Takahiro Nakamura,
Hajime Teranishi,
Seiho Mizusawa,
Takato Ueno,
Kazuaki Chayama,
Atsushi Nakajima,
Kazuwa Nakao, Akihiro Sekine,
Kikuko Hotta
[show abstract]
[hide abstract]
ABSTRACT: We examined the genetic background of nonalcoholic fatty liver disease (NAFLD) in the Japanese population, by performing a genome-wide association study (GWAS). For GWAS, 392 Japanese NAFLD subjects and 934 control individuals were analyzed. For replication studies, 172 NAFLD and 1,012 control subjects were monitored. After quality control, 261,540 single-nucleotide polymorphisms (SNPs) in autosomal chromosomes were analyzed using a trend test. Association analysis was also performed using multiple logistic regression analysis using genotypes, age, gender and body mass index (BMI) as independent variables. Multiple linear regression analyses were performed to evaluate allelic effect of significant SNPs on biochemical traits and histological parameters adjusted by age, gender, and BMI. Rs738409 in the PNPLA3 gene was most strongly associated with NAFLD after adjustment (P = 6.8 × 10(-14), OR = 2.05). Rs2896019, and rs381062 in the PNPLA3 gene, rs738491, rs3761472, and rs2143571 in the SAMM50 gene, rs6006473, rs5764455, and rs6006611 in the PARVB gene had also significant P values (<2.0 × 10(-10)) and high odds ratios (1.84-2.02). These SNPs were found to be in the same linkage disequilibrium block and were associated with decreased serum triglycerides and increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in NAFLD patients. These SNPs were associated with steatosis grade and NAFLD activity score (NAS). Rs738409, rs2896019, rs738491, rs6006473, rs5764455, and rs6006611 were associated with fibrosis. Polymorphisms in the SAMM50 and PARVB genes in addition to those in the PNPLA3 gene were observed to be associated with the development and progression of NAFLD.
Human Genetics 03/2013; · 5.07 Impact Factor
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Kikuko Hotta,
Aya Kitamoto,
Takuya Kitamoto,
Seiho Mizusawa,
Hajime Teranishi,
Rina So,
Tomoaki Matsuo,
Yoshio Nakata,
Hideyuki Hyogo,
Hidenori Ochi, [......],
Kazuaki Chayama,
Kazuyuki Hamaguchi,
Kentaro Yamada,
Toshiaki Hanafusa,
Shinichi Oikawa,
Toshiie Sakata,
Kiyoji Tanaka,
Yuji Matsuzawa,
Kazuwa Nakao, Akihiro Sekine
[show abstract]
[hide abstract]
ABSTRACT: Aim: Visceral fat accumulation plays an integral role in morbidity and mortality rates by increasing the risk of developing metabolic disorders such as type 2 diabetes, dyslipidemia, and hypertension. New genetic loci associated with fat distribution, measured by waist-hip ratios and computed tomography (CT), have recently been identified by genome-wide association studies in European-descent populations. This study used CT to investigate whether single nucleotide polymorphisms (SNPs) that confer susceptibility to fat distribution are associated with visceral fat area (VFA) and subcutaneous fat area (SFA) in the Japanese population.Methods: We measured the VFAs and SFAs of 1424 obese Japanese subjects (BMI≥25 kg/m(2), 635 men and 789 women) that were genotyped at 15 SNPs, namely, TBX15 rs984222, DNM3 rs1011731, LYPLAL1 rs4846567, GRB14 rs10195252, NISCH rs6784615, ADAMTS9 rs6795735, CPEB4 rs6861681, LY86 rs1294421, VEGFA rs6905288, RSPO3 rs9491696, NFE2L3 rs1055144, ITPR2 rs718314, HOXC13 rs1443512, ZNRF3 rs4823006 and THNSL2 rs1659258.Results: The G-allele of LYPLAL1 rs4846567 was borderline associated with an increased ratio of VFA to SFA (V/S ratio; p= 0.0020). LYPLAL1 rs4846567 had a stronger effect on the V/S ratio in women (p= 0.0078) than in men (p= 0.12); however, neither result was significant after Bonferroni correction for multiple comparisons. NISCH rs6784615 was nominally associated with increased VFA (p=0.040) and V/S ratio (p= 0.020). The other SNPs analyzed were not significantly associated with body mass index (BMI), VFA, or SFA.Conclusion: Our results suggest that LYPLAL1 rs4846567 and NISCH rs6784615 may influence fat distribution in the Japanese population.
Journal of atherosclerosis and thrombosis 12/2012; · 2.69 Impact Factor
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Kikuko Hotta,
Aya Kitamoto,
Takuya Kitamoto,
Seiho Mizusawa,
Hajime Teranishi,
Rina So,
Tomoaki Matsuo,
Yoshio Nakata,
Hideyuki Hyogo,
Hidenori Ochi, [......],
Kazuyuki Hamaguchi,
Kentaro Yamada,
Toshiaki Hanafusa,
Shinichi Oikawa,
Hironobu Yoshimatsu,
Toshiie Sakata,
Kiyoji Tanaka,
Yuji Matsuzawa,
Kazuwa Nakao, Akihiro Sekine
[show abstract]
[hide abstract]
ABSTRACT: Visceral fat accumulation has an important role in the development of several metabolic disorders, such as type 2 diabetes, dyslipidemia and hypertension. New genetic loci that contribute to the development of type 2 diabetes have been identified by genome-wide association studies. To examine the association of type 2 diabetes susceptibility loci and visceral fat accumulation, we genotyped 1279 Japanese subjects (556 men and 723 women), who underwent computed tomography for measurements of visceral fat area (VFA) and subcutaneous fat area (SFA) for the following single-nucleotide polymorphisms (SNPs): NOTCH2 rs10923931, THADA rs7578597, PPARG rs1801282, ADAMTS9 rs4607103, IGF2BP2 rs1470579, VEGFA rs9472138, JAZF1 rs864745, CDKN2A/CDKN2B rs564398 and rs10811661, HHEX rs1111875 and rs5015480, TCF7L2 rs7901695, KCNQ1 rs2237892, KCNJ11 rs5215 and rs5219, EXT2 rs1113132, rs11037909, and rs3740878, MTNR1B rs10830963, DCD rs1153188, TSPAN8/LGR5 rs7961581, and FTO rs8050136 and rs9939609. None of the above SNPs were significantly associated with VFA. The FTO rs8050136 and rs9939609 risk alleles exhibited significant associations with body mass index (BMI; P=0.00088 and P=0.0010, respectively) and SFA (P=0.00013 and P=0.00017, respectively). No other SNPs were significantly associated with BMI or SFA. Our results suggest that two SNPs in the FTO gene are associated with subcutaneous fat accumulation. The contributions of other SNPs are inconclusive because of a limitation of the sample power.
Journal of Human Genetics 03/2012; 57(5):305-10. · 2.57 Impact Factor
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Kikuko Hotta,
Aya Kitamoto,
Takuya Kitamoto,
Seiho Mizusawa,
Hajime Teranishi,
Tomoaki Matsuo,
Yoshio Nakata,
Hideyuki Hyogo,
Hidenori Ochi,
Takahiro Nakamura, [......],
Kazuyuki Hamaguchi,
Kentaro Yamada,
Toshiaki Hanafusa,
Shinichi Oikawa,
Hironobu Yoshimatsu,
Toshiie Sakata,
Kiyoji Tanaka,
Yuji Matsuzawa,
Kazuwa Nakao, Akihiro Sekine
[show abstract]
[hide abstract]
ABSTRACT: Visceral fat accumulation has an important role in increasing the morbidity and mortality rates, by increasing the risk of developing several metabolic disorders, such as type 2 diabetes, dyslipidemia and hypertension. New genetic loci that are associated with increased systolic and diastolic blood pressures have been identified by genome-wide association studies in Caucasian populations. This study investigates whether single nucleotide polymorphisms (SNPs) that confer susceptibility to high blood pressure are also associated with visceral fat obesity. We genotyped 1279 Japanese subjects (556 men and 723 women) who underwent computed tomography for measuring the visceral fat area (VFA) and subcutaneous fat area (SFA) at the following SNPs: FGF5 rs16998073, CACNB2 rs11014166, C10orf107 rs1530440, CYP17A1 rs1004467, NT5C2 rs11191548, PLEKHA7 rs381815, ATP2B1 rs2681472 and rs2681492, ARID3B rs6495112, CSK rs1378942, PLCD3 rs12946454, and ZNF652 rs16948048. In an additive model, risk alleles of the CYP17A1 rs1004467 and NT5C2 rs11191548 were found to be significantly associated with reduced SFA (P=0.00011 and 0.0016, respectively). When the analysis was performed separately in men and women, significant associations of rs1004467 (additive model) and rs11191548 (recessive model) with reduced VFA (P=0.0018 and 0.0022, respectively) and SFA (P=0.00039 and 0.00059, respectively) were observed in women, but not in men. Our results suggest that polymorphisms in the CYP17A1 and NT5C2 genes influence a reduction in both visceral and subcutaneous fat mass in Japanese women.
Journal of Human Genetics 11/2011; 57(1):46-51. · 2.57 Impact Factor
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Kikuko Hotta,
Takuya Kitamoto,
Aya Kitamoto,
Seiho Mizusawa,
Tomoaki Matsuo,
Yoshio Nakata,
Seika Kamohara,
Nobuyuki Miyatake,
Kazuaki Kotani,
Ryoya Komatsu, [......],
Kazuyuki Hamaguchi,
Kiyoji Tanaka,
Kentaro Yamada,
Toshiaki Hanafusa,
Shinichi Oikawa,
Hironobu Yoshimatsu,
Toshiie Sakata,
Yuji Matsuzawa,
Kazuwa Nakao, Akihiro Sekine
[show abstract]
[hide abstract]
ABSTRACT: Metabolic syndrome is defined as a cluster of multiple risk factors, including central obesity, dyslipidemia, hypertension and impaired glucose tolerance, that increase cardiovascular disease morbidity and mortality. Genetic factors are important in the development of metabolic syndrome, as are environmental factors. However, the genetic background of metabolic syndrome is not yet fully clarified. There is evidence that obesity and obesity-related phenotypes are associated with variations in several genes, including NEGR1, SEC16B, TMEM18, ETV5, GNPDA2, BDNF, MTCH2, SH2B1, FTO, MAF, MC4R, KCTD15, SCG3, MTMR9, TFAP2B, MSRA, LYPLAL1, GCKR and FADS1. To investigate the relationship between metabolic syndrome and variations in these genes in the Japanese population, we genotyped 33 single-nucleotide polymorphisms (SNPs) in 19 genes from 1096 patients with metabolic syndrome and 581 control individuals who had no risk factors for metabolic syndrome. Four SNPs in the FTO gene were significantly related to metabolic syndrome: rs9939609 (P=0.00013), rs8050136 (P=0.00011), rs1558902 (P=6.6 × 10(-5)) and rs1421085 (P=7.4 × 10(-5)). rs3764220 in the SCG3 gene (P=0.0010) and rs2293855 in the MTMR9 gene (P=0.0015) were also significantly associated with metabolic syndrome. SNPs in the FTO, SCG3 and MTMR9 genes had no SNP × SNP epistatic effects on metabolic syndrome. Our data suggest that genetic variations in the FTO, SCG3 and MTMR9 genes independently influence the risk of metabolic syndrome.
Journal of Human Genetics 07/2011; 56(9):647-51. · 2.57 Impact Factor
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Kikuko Hotta,
Takuya Kitamoto,
Aya Kitamoto,
Seiho Mizusawa,
Tomoaki Matsuo,
Yoshio Nakata,
Hideyuki Hyogo,
Hidenori Ochi,
Seika Kamohara,
Nobuyuki Miyatake, [......],
Kazuyuki Hamaguchi,
Kentaro Yamada,
Toshiaki Hanafusa,
Shinichi Oikawa,
Hironobu Yoshimatsu,
Toshiie Sakata,
Kiyoji Tanaka,
Yuji Matsuzawa,
Kazuwa Nakao, Akihiro Sekine
[show abstract]
[hide abstract]
ABSTRACT: Visceral fat accumulation has an important role in increasing morbidity and mortality rate by increasing the risk of developing several metabolic disorders, such as type 2 diabetes, dyslipidemia and hypertension. New genetic loci that contribute to the development of obesity have been identified by genome-wide association studies in Caucasian populations. We genotyped 1279 Japanese subjects (556 men and 723 women), who underwent computed tomography (CT) for measuring visceral fat area (VFA) and subcutaneous fat area (SFA), for the following single-nucleotide polymorphisms (SNPs): NEGR1 rs2815752, SEC16B rs10913469, TMEM18 rs6548238, ETV5 rs7647305, GNPDA2 rs10938397, BDNF rs6265 and rs925946, MTCH2 rs10838738, SH2B1 rs7498665, MAF rs1424233, and KCTD15 rs29941 and rs11084753. In the additive model, none of the SNPs were significantly associated with body mass index (BMI). The SH2B1 rs7498665 risk allele was found to be significantly associated with VFA (P=0.00047) but not with BMI or SFA. When the analysis was performed in men and women separately, no significant associations with VFA were observed (P=0.0099 in men and P=0.022 in women). None of the other SNPs were significantly associated with SFA. Our results suggest that there is a VFA-specific genetic factor and that a polymorphism in the SH2B1 gene influences the risk of visceral fat accumulation.
Journal of Human Genetics 07/2011; 56(10):716-9. · 2.57 Impact Factor
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Kazuki Yasuda,
Kazuaki Miyake,
Yukio Horikawa,
Kazuo Hara,
Haruhiko Osawa,
Hiroto Furuta,
Yushi Hirota,
Hiroyuki Mori,
Anna Jonsson,
Yoshifumi Sato, [......], Akihiro Sekine,
Yusuke Nakamura,
Ken Yamamoto,
Teruhiko Yoshida,
Katsushi Tokunaga,
Mitsuo Itakura,
Hideichi Makino,
Kishio Nanjo,
Takashi Kadowaki,
Masato Kasuga
[show abstract]
[hide abstract]
ABSTRACT: We carried out a multistage genome-wide association study of type 2 diabetes mellitus in Japanese individuals, with a total of 1,612 cases and 1,424 controls and 100,000 SNPs. The most significant association was obtained with SNPs in KCNQ1, and dense mapping within the gene revealed that rs2237892 in intron 15 showed the lowest Pvalue (6.7 x 10(-13), odds ratio (OR) = 1.49). The association of KCNQ1 with type 2 diabetes was replicated in populations of Korean, Chinese and European ancestry as well as in two independent Japanese populations, and meta-analysis with a total of 19,930 individuals (9,569 cases and 10,361 controls) yielded a P value of 1.7 x 10(-42) (OR = 1.40; 95% CI = 1.34-1.47) for rs2237892. Among control subjects, the risk allele of this polymorphism was associated with impairment of insulin secretion according to the homeostasis model assessment of beta-cell function or the corrected insulin response. Our data thus implicate KCNQ1 as a diabetes susceptibility gene in groups of different ancestries.
Nature Genetics 09/2008; 40(9):1092-7. · 35.53 Impact Factor
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Hiromi Sakamoto,
Kimio Yoshimura,
Norihisa Saeki,
Hitoshi Katai,
Tadakazu Shimoda,
Yoshihiro Matsuno,
Daizo Saito,
Haruhiko Sugimura,
Fumihiko Tanioka,
Shunji Kato, [......],
Kazuyoshi Yanagihara,
Kyong-Ah Yoon,
Myeong-Cherl Kook,
Yeon-Su Lee,
Sook Ryun Park,
Chan Gyoo Kim,
Il Ju Choi,
Teruhiko Yoshida,
Yusuke Nakamura,
Setsuo Hirohashi
[show abstract]
[hide abstract]
ABSTRACT: Gastric cancer is classified into intestinal and diffuse types, the latter including a highly malignant form, linitis plastica. A two-stage genome-wide association study (stage 1: 85,576 SNPs on 188 cases and 752 references; stage 2: 2,753 SNPs on 749 cases and 750 controls) in Japan identified a significant association between an intronic SNP (rs2976392) in PSCA (prostate stem cell antigen) and diffuse-type gastric cancer (allele-specific odds ratio (OR) = 1.62, 95% CI = 1.38-1.89, P = 1.11 x 10(-9)). The association was far less significant in intestinal-type gastric cancer. We found that PSCA is expressed in differentiating gastric epithelial cells, has a cell-proliferation inhibition activity in vitro and is frequently silenced in gastric cancer. Substitution of the C allele with the risk allele T at a SNP in the first exon (rs2294008, which has r(2) = 0.995, D' = 0.999 with rs2976392) reduces transcriptional activity of an upstream fragment of the gene. The same risk allele was also significantly associated with diffuse-type gastric cancer in 457 cases and 390 controls in Korea (allele-specific OR = 1.90, 95% CI = 1.56-2.33, P = 8.01 x 10(-11)). The polymorphism of the PSCA gene, which is possibly involved in regulating gastric epithelial-cell proliferation, influences susceptibility to diffuse-type gastric cancer.
Nature Genetics 07/2008; 40(6):730-40. · 35.53 Impact Factor
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Norihiro Kato,
Toshiyuki Miyata,
Yasuharu Tabara,
Tomohiro Katsuya,
Kazuyuki Yanai,
Hironori Hanada,
Kei Kamide,
Jun Nakura,
Katsuhiko Kohara,
Fumihiko Takeuchi, [......],
Yuhei Kawano,
Kazuwa Nakao, Akihiro Sekine,
Teruhiko Yoshida,
Yusuke Nakamura,
Takao Saruta,
Toshio Ogihara,
Sumio Sugano,
Tetsuro Miki,
Hitonobu Tomoike
[show abstract]
[hide abstract]
ABSTRACT: Essential hypertension is one of the most common, complex diseases, of which considerable efforts have been made to unravel the pathophysiological mechanisms. Over the last decade, multiple genome-wide linkage analyses have been conducted using 300-900 microsatellite markers but no single study has yielded definitive evidence for 'principal' hypertension susceptibility gene(s). Here, we performed a three-tiered, high-density association study of hypertension, which has been recently made possible. For tier 1, we genotyped 80 795 SNPs distributed throughout the genome in 188 male hypertensive subjects and two general population control groups (752 subjects per group). For tier 2 (752 hypertensive and 752 normotensive subjects), we genotyped a panel of 2676 SNPs selected (odds ratio >or= 1.4 and P <or= 0.015 in tier 1) and identified 75 SNPs that showed similar tendency of association in tier 1 and tier 2 samples (P <or= 0.05 for allele frequency and P <or= 0.01 for genotype distribution tests). For tier 3 (619 hypertensive and 1406 normotensive subjects), we genotyped the 75 SNPs and found nine SNPs from seven genomic loci to be associated with hypertension (P <or= 0.05). In three of these loci, the lowest P-values were observed for rs3755351 (P = 1.7 x 10(-5)) in ADD2, rs3794260 (P = 0.0001) in KIAA0789 and rs1805762 (P = 0.0003) in M6PR when case-control comparison was made in the combined data. An SNP (rs3755351) within ADD2 had the lowest P-value and its experiment-wide significance level is 0.13. Thus, these results have nominated several susceptibility genes for hypertension, and independent replication will clarify their etiological relevance.
Human Molecular Genetics 02/2008; 17(4):617-27. · 7.64 Impact Factor
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Yoshihiro Onouchi,
Tomohiko Gunji,
Jane C Burns,
Chisato Shimizu,
Jane W Newburger,
Mayumi Yashiro,
Yoshikazu Nakamura,
Hiroshi Yanagawa,
Keiko Wakui,
Yoshimitsu Fukushima, [......],
Takeo Tanaka,
Toshiro Nagai,
Hideo Cho,
Akihiro Fujino, Akihiro Sekine,
Reiichiro Nakamichi,
Tatsuhiko Tsunoda,
Tomisaku Kawasaki,
Yusuke Nakamura,
Akira Hata
[show abstract]
[hide abstract]
ABSTRACT: Kawasaki disease is a pediatric systemic vasculitis of unknown etiology for which a genetic influence is suspected. We identified a functional SNP (itpkc_3) in the inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) gene on chromosome 19q13.2 that is significantly associated with Kawasaki disease susceptibility and also with an increased risk of coronary artery lesions in both Japanese and US children. Transfection experiments showed that the C allele of itpkc_3 reduces splicing efficiency of the ITPKC mRNA. ITPKC acts as a negative regulator of T-cell activation through the Ca2+/NFAT signaling pathway, and the C allele may contribute to immune hyper-reactivity in Kawasaki disease. This finding provides new insights into the mechanisms of immune activation in Kawasaki disease and emphasizes the importance of activated T cells in the pathogenesis of this vasculitis.
Nature Genetics 02/2008; 40(1):35-42. · 35.53 Impact Factor
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Takahiro Yanagiya,
Atsushi Tanabe,
Aritoshi Iida,
Susumu Saito, Akihiro Sekine,
Atsushi Takahashi,
Tatsuhiko Tsunoda,
Seika Kamohara,
Yoshio Nakata,
Kazuaki Kotani, [......],
Kentaro Yamada,
Toshiaki Hanafusa,
Shinichi Oikawa,
Hironobu Yoshimatsu,
Kazuwa Nakao,
Toshiie Sakata,
Yuji Matsuzawa,
Naoyuki Kamatani,
Yusuke Nakamura,
Kikuko Hotta
[show abstract]
[hide abstract]
ABSTRACT: Genetic factors are clearly involved in the development of obesity, but the genetic background of obesity remains largely unclear. Starting from 62 663 gene-based single-nucleotide polymorphisms (SNPs) in three sequential case-control association studies, we identified a replicated association between the obesity phenotype (BMI > or =30 kg/m(2)) and a SNP (rs2293855) located in the myotublarin-related protein 9 (MTMR9) gene in the chromosomal segment 8p23-p22. P-values (minor allele dominant model) of the first set (93 cases versus 649 controls) and the second set (564 cases versus 562 controls) were 0.008 and 0.0002, respectively. The association was replicated in the third set [394 cases versus 958 controls, P = 0.005, odds ratio (95% CI) =1.40 (1.11-1.78)]. The global P-value was 0.0000005. A multiple regression analysis revealed that gender, age BMI and rs2293855 genotype (minor allele dominant model) were significantly associated with both systolic and diastolic blood pressures. MTMR9 was shown to be the only gene within the haplotype block that contained SNPs associated with obesity. Both the transcript and protein of MTMR9 were detected in the rodent lateral hypothalamic area as well as in the arcuate nucleus, and the protein co-existed with orexin, melanin concentrating hormone, neuropeptide Y and proopiomelanocortin. The levels of MTMR9 transcript in the murine hypothalamic region increased after fasting and were decreased by a high-fat diet. Our data suggested that genetic variations in MTMR9 may confer a predisposition towards obesity and hypertension through regulation of hypothalamic neuropeptides.
Human Molecular Genetics 01/2008; 16(24):3017-26. · 7.64 Impact Factor
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Kelly A Frazer,
Dennis G Ballinger,
David R Cox,
David A Hinds,
Laura L Stuve,
Richard A Gibbs,
John W Belmont,
Andrew Boudreau,
Paul Hardenbol,
Suzanne M Leal, [......],
Vivian Ota Wang,
Jane L Peterson,
Michael Shi,
Jack Spiegel,
Lawrence M Sung,
Lynn F Zacharia,
Francis S Collins,
Karen Kennedy,
Ruth Jamieson,
John Stewart
[show abstract]
[hide abstract]
ABSTRACT: We describe the Phase II HapMap, which characterizes over 3.1 million human single nucleotide polymorphisms (SNPs) genotyped in 270 individuals from four geographically diverse populations and includes 25-35% of common SNP variation in the populations surveyed. The map is estimated to capture untyped common variation with an average maximum r2 of between 0.9 and 0.96 depending on population. We demonstrate that the current generation of commercial genome-wide genotyping products captures common Phase II SNPs with an average maximum r2 of up to 0.8 in African and up to 0.95 in non-African populations, and that potential gains in power in association studies can be obtained through imputation. These data also reveal novel aspects of the structure of linkage disequilibrium. We show that 10-30% of pairs of individuals within a population share at least one region of extended genetic identity arising from recent ancestry and that up to 1% of all common variants are untaggable, primarily because they lie within recombination hotspots. We show that recombination rates vary systematically around genes and between genes of different function. Finally, we demonstrate increased differentiation at non-synonymous, compared to synonymous, SNPs, resulting from systematic differences in the strength or efficacy of natural selection between populations.
Nature 11/2007; 449(7164):851-61. · 36.28 Impact Factor
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Pardis C Sabeti,
Patrick Varilly,
Ben Fry,
Jason Lohmueller,
Elizabeth Hostetter,
Chris Cotsapas,
Xiaohui Xie,
Elizabeth H Byrne,
Steven A McCarroll,
Rachelle Gaudet, [......],
Vivian Ota Wang,
Jane L Peterson,
Michael Shi,
Jack Spiegel,
Lawrence M Sung,
Lynn F Zacharia,
Francis S Collins,
Karen Kennedy,
Ruth Jamieson,
John Stewart
[show abstract]
[hide abstract]
ABSTRACT: With the advent of dense maps of human genetic variation, it is now possible to detect positive natural selection across the human genome. Here we report an analysis of over 3 million polymorphisms from the International HapMap Project Phase 2 (HapMap2). We used 'long-range haplotype' methods, which were developed to identify alleles segregating in a population that have undergone recent selection, and we also developed new methods that are based on cross-population comparisons to discover alleles that have swept to near-fixation within a population. The analysis reveals more than 300 strong candidate regions. Focusing on the strongest 22 regions, we develop a heuristic for scrutinizing these regions to identify candidate targets of selection. In a complementary analysis, we identify 26 non-synonymous, coding, single nucleotide polymorphisms showing regional evidence of positive selection. Examination of these candidates highlights three cases in which two genes in a common biological process have apparently undergone positive selection in the same population:LARGE and DMD, both related to infection by the Lassa virus, in West Africa;SLC24A5 and SLC45A2, both involved in skin pigmentation, in Europe; and EDAR and EDA2R, both involved in development of hair follicles, in Asia.
Nature 11/2007; 449(7164):913-8. · 36.28 Impact Factor
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Pardis C. Sabeti,
Patrick Varilly,
Ben Fry,
Jason Lohmueller,
Elizabeth Hostetter,
Chris Cotsapas,
Xiaohui Xie,
Elizabeth H. Byrne,
Steven A. McCarroll,
Rachelle Gaudet, [......],
Vivian Ota Wang,
Jane L. Peterson,
Michael Shi,
Jack Spiegel,
Lawrence M. Sung,
Lynn F. Zacharia,
Francis S. Collins,
Karen Kennedy,
Ruth Jamieson,
John Stewart
[show abstract]
[hide abstract]
ABSTRACT: With the advent of dense maps of human genetic variation, it is now possible to detect positive natural selection across the human genome. Here we report an analysis of over 3 million polymorphisms from the International HapMap Project Phase 2 (HapMap2)
Nature 10/2007; 449(7164):913-918. · 36.28 Impact Factor
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Atsushi Tanabe,
Takahiro Yanagiya,
Aritoshi Iida,
Susumu Saito, Akihiro Sekine,
Atsushi Takahashi,
Takahiro Nakamura,
Tatsuhiko Tsunoda,
Seika Kamohara,
Yoshio Nakata, [......],
Kiyoji Tanaka,
Kentaro Yamada,
Toshiaki Hanafusa,
Shinichi Oikawa,
Hironobu Yoshimatsu,
Toshiie Sakata,
Yuji Matsuzawa,
Naoyuki Kamatani,
Yusuke Nakamura,
Kikuko Hotta
[show abstract]
[hide abstract]
ABSTRACT: Genetic factors are important for the development of obesity. However, the genetic background of obesity still remains unclear.
Our objective was to search for obesity-related genes using a large number of gene-based single-nucleotide polymorphisms (SNPs).
We conducted case-control association analyses using 94 obese patients and 658 controls with 62,663 SNPs selected from the SNP database. SNPs that possessed P < or = 0.02 were further analyzed using 796 obese and 711 control subjects. One SNP (rs3764220) in the secretogranin III (SCG3) gene showed the lowest P value (P = 0.0000019). We sequenced an approximately 300-kb genomic region around rs3764220 and discovered SNPs for haplotype analyses. SCG3 was the only gene within a haplotype block that contained rs3764220. The functions of SCG3 were studied.
Obese subjects (body mass index > or = 30 kg/m(2), n = 890) and control subjects (general population; n = 658, body mass index < or = 25 kg/m(2); n = 711) were recruited for this study.
Twelve SNPs in the SCG3 gene including rs3764220 were in almost complete linkage disequilibrium and significantly associated with an obesity phenotype. Two SNPs (rs16964465, rs16964476) affected the transcriptional activity of SCG3, and subjects with the minor allele seemed to be resistant to obesity (odds ratio, 9.23; 95% confidence interval, 2.77-30.80; chi(2) = 19.2; P = 0.0000067). SCG3 mRNA and immunoreactivity were detected in the paraventricular nucleus, lateral hypothalamic area, and arcuate nucleus, and the protein coexisted with orexin, melanin-concentrating hormone, neuropeptide Y, and proopiomelanocortin. SCG3 formed a granule-like structure together with these neuropeptides.
Genetic variations in the SCG3 gene may influence the risk of obesity through possible regulation of hypothalamic neuropeptide secretion.
Journal of Clinical Endocrinology & Metabolism 04/2007; 92(3):1145-54. · 6.50 Impact Factor
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[show abstract]
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ABSTRACT: To establish 'personalized medicines' that can provide the right drug at the appropriate dose for each individual patient on the basis of genetic background, we have been building the infrastructure for a Japanese single nucleotide polymorphism (SNP) database of the genes encoding various enzymes, transporters and receptors that are involved in the metabolism, transportation and action of drugs. We have so far screened a genomic region of 4,068.3 kb, and identified a total of 7,552 genetic variations, including 6,733 SNP and 819 genetic variations of other types among 267 genes in Japanese populations. Interestingly, among the 212 non-synonymous substitutions we found, six would be considered to be nonsense mutations. In this review, we focused on the molecular features of the non-synonymous substitutions and insertion/deletion polymorphisms within coding regions detected in drug-related gene loci. The database established in this study makes us confident of achieving one of our goals, which is establishment of personalized medicine.
Cancer Science 02/2006; 97(1):16-24. · 3.33 Impact Factor
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ABSTRACT: The strong linkage disequilibrium (LD) recently found in genic or exonic regions of the human genome demonstrated that LD can be increased by evolutionary mechanisms that select for functionally important loci. This suggests that LD might be stronger in regions conserved among species than in non-conserved regions, since regions exposed to natural selection tend to be conserved. To assess this hypothesis, we used genome-wide polymorphism data from the HapMap project and investigated LD within DNA sequences conserved between the human and mouse genomes.
Unexpectedly, we observed that LD was significantly weaker in conserved regions than in non-conserved regions. To investigate why, we examined sequence features that may distort the relationship between LD and conserved regions. We found that interspersed repeats, and not other sequence features, were associated with the weak LD tendency in conserved regions. To appropriately understand the relationship between LD and conserved regions, we removed the effect of repetitive elements and found that the high degree of sequence conservation was strongly associated with strong LD in coding regions but not with that in non-coding regions.
Our work demonstrates that the degree of sequence conservation does not simply increase LD as predicted by the hypothesis. Rather, it implies that purifying selection changes the polymorphic patterns of coding sequences but has little influence on the patterns of functional units such as regulatory elements present in non-coding regions, since the former are generally restricted by the constraint of maintaining a functional protein product across multiple exons while the latter may exist more as individually isolated units.
BMC Genomics 02/2006; 7:326. · 4.07 Impact Factor
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Keiko Yamazaki,
Dermot McGovern,
Jiannis Ragoussis,
Marta Paolucci,
Helen Butler,
Derek Jewell,
Lon Cardon,
Masakazu Takazoe,
Torao Tanaka,
Toshiki Ichimori,
Susumu Saito, Akihiro Sekine,
Aritoshi Iida,
Atsushi Takahashi,
Tatsuhiko Tsunoda,
Mark Lathrop,
Yusuke Nakamura
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ABSTRACT: The inflammatory bowel diseases (IBDs), Crohn's disease (CD) and ulcerative colitis, are chronic inflammatory disorders of the digestive tract. The pathogenesis of IBD is complicated, and it is widely accepted that immunologic, environmental and genetic components contribute to its etiology. To identify genetic susceptibility factors in CD, we performed a genome-wide association study in Japanese patients and controls using nearly 80,000 gene-based single nucleotide polymorphism (SNP) markers and investigated the haplotype structure of the candidate locus in Japanese and European patients. We identified highly significant associations (P = 1.71 x 10(-14) with odds ratio of 2.17) of SNPs and haplotypes within the TNFSF15 (the gene encoding tumor necrosis factor superfamily, member 15) genes in Japanese CD patients. The association was confirmed in the study of two European IBD cohorts. Interestingly, a core TNFSF15 haplotype showing association with increased risk to the disease was common in the two ethnic groups. Our results suggest that the genetic variations in the TNFSF15 gene contribute to the susceptibility to IBD in the Japanese and European populations.
Human Molecular Genetics 12/2005; 14(22):3499-506. · 7.64 Impact Factor
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Yuta Kochi,
Ryo Yamada,
Akari Suzuki,
John B Harley,
Senji Shirasawa,
Tetsuji Sawada,
Sang-Cheol Bae,
Shinya Tokuhiro,
Xiaotian Chang, Akihiro Sekine, [......],
Kenneth M Kaufman,
Changsoo Paul Kang,
Changwon Kang,
Shigeru Otsubo,
Wako Yumura,
Akio Mimori,
Takao Koike,
Yusuke Nakamura,
Takehiko Sasazuki,
Kazuhiko Yamamoto
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ABSTRACT: Rheumatoid arthritis is a common autoimmune disease with a complex genetic etiology. Here we identify a SNP in the promoter region of FCRL3, a member of the Fc receptor-like family, that is associated with susceptibility to rheumatoid arthritis (odds ratio = 2.15, P = 0.00000085). This polymorphism alters the binding affinity of nuclear factor-kappaB and regulates FCRL3 expression. We observed high FCRL3 expression on B cells and augmented autoantibody production in individuals with the disease-susceptible genotype. We also found associations between the SNP and susceptibility to autoimmune thyroid disease and systemic lupus erythematosus. FCRL3 may therefore have a pivotal role in autoimmunity.
Nature Genetics 06/2005; 37(5):478-85. · 35.53 Impact Factor
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Hideyuki Mototani,
Akihiko Mabuchi,
Susumu Saito,
Mikihiro Fujioka,
Aritoshi Iida,
Yoshio Takatori,
Akihiro Kotani,
Toshikazu Kubo,
Kozo Nakamura, Akihiro Sekine,
Yoshinori Murakami,
Tatsuhiko Tsunoda,
Kohei Notoya,
Yusuke Nakamura,
Shiro Ikegawa
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ABSTRACT: Osteoarthritis (OA), a common skeletal disease, is a leading cause of disability among the elderly populations. OA is characterized by gradual loss of articular cartilage, but the etiology and pathogenesis of OA are largely unknown. Epidemiological and genetic studies have demonstrated that genetic factors play an important role in OA. To identify susceptibility genes for OA, we performed a large-scale, case-control association study using gene-based single nucleotide polymorphisms (SNPs). In two independent case-control populations, we found significant association (P=9.8x10(-7)) between hip OA and a SNP (IVS3-293C>T) located in intron 3 of the calmodulin (CaM) 1 gene (CALM1). CALM1 was expressed in cultured chondrocytes and articular cartilage, and its expression was increased in OA. Subsequent linkage-disequilibrium mapping identified five SNPs showing significant association equivalent to IVS3-293C>T. One of these (-16C>T) is located in the core promoter region of CALM1. Functional analyses indicate that the susceptibility -16T allele decreases CALM1 transcription in vitro and in vivo. Inhibition of CaM in chondrogenic cells reduced the expression of the major cartilage matrix genes Col2a1 and Agc1. These results suggest that the transcriptional level of CALM1 is associated with susceptibility for hip OA through modulation of chondrogenic activity. Our findings reveal the CALM1-mediated signaling pathway in chondrocytes as a novel potential target for treatment of OA.
Human Molecular Genetics 05/2005; 14(8):1009-17. · 7.64 Impact Factor
