Association between obesity and polymorphisms in SEC16B, TMEM18, GNPDA2, BDNF, FAIM2 and MC4R in a Japanese population

Hotta, Kikuko; Nakamura, Michihiro; Nakamura, Takahiro; Matsuo, Tomoaki; Nakata, Yoshio; Kamohara, Seika; Miyatake, Nobuyuki; Kotani, Kazuaki; Komatsu, Ryoya; Itoh, Naoto; Mineo, Ikuo; Wada, Jun; Masuzaki, Hiroaki; Yoneda, Masato; Nakajima, Atsushi; Funahashi, Tohru; Miyazaki, Shigeru; Tokunaga, Katsuto; Kawamoto, Manabu; Ueno, Takato; Hamaguchi, Kazuyuki; Tanaka, Kiyoji; Yamada, Kentaro; Hanafusa, Toshiaki; Oikawa, Shinichi; Yoshimatsu, Hironobu; Nakao, Kazuwa; Sakata, Toshiie; Matsuzawa, Yūji; Kamatani, Naoyuki; Nakamura, Yusuke

doi:10.1038/jhg.2009.106

Cited by 120 publications

(108 citation statements)

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“…We also detected associations of Z-BMI with SNPs at the GNPDA2, MC4R, SEC16B, TMEM18, ETV5 and the BDNF loci, which is in line with previous replication attempts in East-Asians. [11][12][13][14] Replication of index SNPs at QPCTL/GIPR, MAP2K5/SKOR1 and TNKS/MSRA represents novel findings in Asians. In addition, three SNPs showed significant associations in subgroups, including rs13078807 at the CADM2 (Asian-Indians only); rs1555543 at PTBP2 (Chinese type 2 diabetics only); and rs7138803 at FAIM2 (Chinese children and Chinese type 2 diabetics) loci.…”

Section: Discussionmentioning

confidence: 99%

Replication of 13 obesity loci among Singaporean Chinese, Malay and Asian-Indian populations

et al. 2011

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Objective: Recent genome-wide association studies (GWAS) have identified 38 obesity-associated loci among European populations. However, their contribution to obesity in other ethnicities is largely unknown. Methods: We utilised five GWAS (N ¼ 10 482) from Chinese (three cohorts, including one with type 2 diabetes and another one of children), Malay and Indian ethnic groups from Singapore. Data sets were analysed individually and subsequently in combined meta-analysis for Z-score body-mass index (BMI) associations. Results: Variants at the FTO locus showed the strongest associations with BMI Z-score after meta-analysis (P-values 1.16 Â 10 À7 -7.95 Â 10 À7 ). We further detected associations with nine other index obesity variants close to the MC4R, GNPDA2, TMEM18, QPCTL/GIPR, BDNF, ETV5, MAP2K5/SKOR1, SEC16B and TNKS/MSRA loci (meta-analysis P-values ranging from 3.58 Â 10 À4 -1.44 Â 10 À2 ). Three other single-nucleotide polymorphisms (SNPs) from CADM2, PTBP2 and FAIM2 were associated with BMI (Pvalue p0.0418) in at least one dataset. The neurotrophin/TRK pathway (P-value ¼ 0.029) was highlighted by pathway-based analysis of loci that had statistically significant associations among Singaporean populations. Conclusion: Our data confirm the role of FTO in obesity predisposition among Chinese, Malays and Indians, the three major Asian ethnic groups. We additionally detected associations for 12 obesity-associated SNPs among Singaporeans. Thus, it is likely that Europeans and Asians share some of the genetic predisposition to obesity. Furthermore, the neurotrophin/TRK signalling may have a central role for common obesity among Asians.

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Section: Discussionmentioning

confidence: 99%

Replication of 13 obesity loci among Singaporean Chinese, Malay and Asian-Indian populations

et al. 2011

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“…11,39 The TMEM18 and GNPDA2 associations have also been validated in East Asian studies. 40,41 Figure 1. Effects of rs9939609 and rs6548238 on obesity-related indices for overall sample, boys and girls.…”

Section: Discussionmentioning

confidence: 99%

Study of eight GWAS-identified common variants for association with obesity-related indices in Chinese children at puberty

et al. 2011

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OBJECTIVE: Genome-wide association studies (GWAS) have identified some common variants associated with obesity risk in European descents. However, their influences on obesity-related indices for the Chinese children at puberty are not widely clear yet. To address this question, we conducted a study that aims to examine effects of eight previously reported GWAS singlenucleotide polymorphisms (SNPs) on four obesity-related indices in a sample of Chinese children aged 10 --12 years. METHODS: Anthropometric indices were measured in 1688 children (10.8 ± 0.4 years, boys ¼ 877, girls ¼ 811) from Shanghai Children's Sleep Project. Eight SNPs within the NEGR1, TMEM18, GNPDA2, MTCH2, SH2B1, FTO, MC4R and KCTD15 genes were genotyped using matrix-assisted laser desorption/ionization --time of flight mass spectrometry. Linear regression and genetic additive model were used to test for the association betweens SNPs and obesity-related indices (weight, body mass index (BMI), waist-to-height ratio and body fat). RESULTS: Only two SNPs, rs6548238 (TMEM18) and rs9939609 (FTO), were associated with all obesity-related indices with Po0.05. After adjusting for multiple tests, rs9939609 is the only one significantly associated with the indices. SNPs, rs6548238 and rs9939609 explained 0.28% (P ¼ 0.03) and 0.54% (P ¼ 0.002) variance of BMI, respectively, that are almost two-fold of the previously GWAS-reported effects. In addition, rs6548238 was associated with four indices in boys, but not in girls. In contrast, rs9939609 showed a strong association only in girls. Six other SNPs, rs2815752 (NEGR1), rs10938397 (GNPDA2), rs10838738 (MTCH2), rs7498665 (SH2B1), rs17782313 (MC4R) and rs11084753 (KCTD15), were not associated with obesity (P40.05). CONCLUSIONS: Variants of TMEM18 and FTO are associated with obesity indices during puberty in Chinese children, but candidate SNPs of NEGR1, GNPDA2, MTCH2, SH2B1, MC4R and KCTD15 have no significant effects on obesity indices. The findings also suggest that obesity susceptibility genes may exert more obvious effects during children's puberty. In addition, gender differences may exist in various obesity-related genes.

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“…13 In a Japanese adult cohort of 1129 obese and 1736 normal weight controls, the TMEM18-associated SNPs, rs2867125, rs6548238, rs4854344 and rs7561317, were all observed to be associated to obesity. 14 The near-TMEM18 SNP rs7561317 was also tested for association to phenotypes of metabolic disorder in this study, owing to its previous association to type II diabetes. BMI, blood pressure, fasting plasma glucose, triglycerides, total cholesterol and HDL cholesterol were compared in obese and controls, but no association to rs7561317 genotype was observed.…”

Section: Introductionmentioning

confidence: 99%

Association of TMEM18 variants with BMI and waist circumference in children and correlation of mRNA expression in the PFC with body weight in rats

et al. 2011

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Genome-wide association studies have shown a strong association of single-nucleotide polymorphisms (SNPs) in the near vicinity of the TMEM18 gene. The effects of the TMEM18-associated variants are more readily observed in children. TMEM18 encodes a 3TM protein, which locates to the nuclear membrane. The functional context of TMEM18 and the effects of its associated variants are as of yet undetermined. To further explore the effects of near-TMEM18 variants, we have genotyped two TMEM18-associated SNPs, rs6548238 and rs4854344, in a cohort of 2352 Greek children (Healthy Growth Study). Included in this study are data on anthropomorphic traits body weight, BMI z-score and waist circumference. Also included are dietary energy and macronutrient intake as measured via 24-h recall interviews. Major alleles of rs6548238 and rs4854344 were significantly associated with an increased risk of obesity (odds ratio¼1.489 (1.161-1.910) and 1.494 (1.165-1.917), respectively), and positively correlated to body weight (P¼0.017, P¼0.010) and waist circumference (P¼0.003, P¼0.003). An association to energy and macronutrient intake was not observed in this cohort. We also correlated food intake and body weight in a food choice model in rats to Tmem18 expression in central regions involved in feeding behavior. We observed a strong positive correlation between TMEM18 expression and body weight in the prefrontal cortex (PFC) (r¼0.5694, P¼0.0003) indicating a potential role for TMEM18 in higher functions related to feeding involving the PFC. Keywords: obesity; TMEM18; FTO INTRODUCTION Genome-wide association (GWA) studies have led to the identification of several loci in the human genome containing genetic variants conferring an increased risk of developing overweight and obesity. 1-2 One such gene to be associated with a higher BMI, the fat mass and obesity-associated gene (FTO) was identified by Frayling et al in 2007. 3 FTO has since been shown to be involved in regulation of feeding behavior via homeostatic hypothalamic pathways, 4-6 and its obesityassociated variants to confer gain-of-function by increasing gene transcription. 7 The most recent meta analyses of GWA studies on obesity, which included genetic information from 249 796 individuals, identified variants at a total of 32 genetic loci affecting the development of BMI. 2 Single-nucleotide polymorphisms (SNPs) in the FTO gene, followed by SNPs in the proximity of TMEM18 and MC4R, have consistently given the strongest associations to obesity in large-scale GWA studies. TMEM18-associated SNPs were first found to be associated with a higher BMI in 2009 by the GIANT consortium, 1 and this was confirmed in the same year by an independent group. 8 Results from child cohorts have shown stronger effects of near-TMEM18 SNPs to obesity, compared with adults. Zhao et al 9 found near-TMEM18 SNPs to confer the strongest effect on pediatric BMI out of 25 studied obesity-associated variants in a cohort of 6078

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Association between obesity and polymorphisms in SEC16B, TMEM18, GNPDA2, BDNF, FAIM2 and MC4R in a Japanese population

Cited by 120 publications

References 30 publications

Replication of 13 obesity loci among Singaporean Chinese, Malay and Asian-Indian populations

Replication of 13 obesity loci among Singaporean Chinese, Malay and Asian-Indian populations

Study of eight GWAS-identified common variants for association with obesity-related indices in Chinese children at puberty

Association of TMEM18 variants with BMI and waist circumference in children and correlation of mRNA expression in the PFC with body weight in rats

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