Investigation of the Locus Near <i>MC4R</i> With Childhood Obesity in Americans of European and African Ancestry

Grant, Struan F.A.; Bradfield, Jonathan P.; Zhang, Haitao; Wang, Kai; Kim, Chong; Annaiah, Kiran; Santa, Erin; Glessner, Joseph T.; Thomas, Kelly; Garris, Maria; Frackelton, Edward C.; Otieno, F. George; Shaner, Julie L.; Smith, Ryan M.; Imieliński, Marcin; Chiavacci, Rosetta M.; Li, Mingyao; Berkowitz, Robert I.; Hákonarson, Hákon

doi:10.1038/oby.2009.53

Cited by 72 publications

(53 citation statements)

References 19 publications

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“…35,36 However, there is controversial data in African-American youth populations. 37 Interestingly, we did not entirely replicate the association between obesity and the SNP rs17782313 among Chinese children, as this SNP was only associated with WHtR in girls.…”

Section: Discussionmentioning

confidence: 59%

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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Section: Discussionmentioning

confidence: 59%

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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“…Nevertheless, consistent with there being some kind of association, a weak main effect on lean body mass was found when considering possible interactive effects with birth weight. Most studies of rs17782313 appear to assume that it functions through altering MC4R activity [1,2,6,7,23,24,25]. Therefore, given that increases in lean body mass are observed in people with rare MC4R mutations [5], our weak interactive association with lean body mass, rather than being due to a type 1 statistical error, may reflect rs17782313 not being causal in the relationship and only being in weak linkage disequilibrium with the polymorphism that is.…”

Section: Discussionmentioning

confidence: 99%

Association between a Common Variant near MC4R and Change in Body Mass Index Develops by Two Weeks of Age

Petry

López‐Bermejo²,

Díaz³

et al. 2010

Horm Res Paediatr

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Background/Aims: The common polymorphism rs17782313 lying 188 kb downstream of the MC4R gene has recently been found to be unequivocally associated with body mass index (BMI) and obesity risk in adults and children. Our objective was to test the association between rs17782313 and neonatal weight gain in a contemporary population. Methods: This was a cross-sectional, hospital-based study using 278 healthy Caucasian newborns [142 girls; gestational age (mean ± SD) 39.3 ± 1.4 weeks, birth weight 3.1 ± 0.6 kg]. Body composition was assessed by dual-energy X-ray absorptiometry (DXA) at ∼13 days (range 9–20) and rs17782313 was genotyped by restriction fragment length polymorphism analysis. Results: rs17782313 was not associated with weight, length or ponderal index at birth. However, it was associated with changes in BMI (p = 0.0004) over the first 2 weeks of life and with body weight (p = 0.02) and BMI (p = 0.007) at age 2 weeks. Despite this, DXA measures of fat and lean mass failed to show any simple associations. Conclusion: Similar to other genetic variants associated with childhood and adult obesity, the association between rs17782313 genotype and body weight develops rapidly during the first 2 weeks of life, once caloric intake is regulated by the infant’s appetite.

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“…No associations were observed with body size at birth or during the first 3 years of life [32]. Association between the near-MC4R locus and childhood obesity (OR~1.4) was confirmed in European American children and adolescents, which is more than twice the effect size for adult obesity risk, whereas no such associations were observed in African-American children [69]. Of the more recently identified loci, significant associations with BMI were observed for the TMEM18, GNPDA2 and KCTD15 loci in a population-based sample of 11-yearold children [34].…”

Section: Figurementioning

confidence: 99%

Recent progress in the genetics of common obesity

Loos

2009

Brit J Clinical Pharma

125

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The genetic contribution to interindividual variation in common obesity has been estimated at 40–70%. Yet, despite a relatively high heritability, the search for obesity susceptibility genes has been an arduous task. This paper reviews recent progress made in the obesity genetics field with an emphasis on established obesity susceptibility loci identified through candidate gene as well as genome‐wide studies. For the last 15 years, candidate gene and genome‐wide linkage studies have been the two main genetic epidemiological approaches to identify genetic loci for common traits, yet progress has been slow and success limited. Only recently have candidate gene studies started to succeed; by means of large‐scale studies and meta‐analyses at least five variants in four candidate genes have been found to be robustly associated with obesity‐related traits. Genome‐wide linkage studies, however, have so far not been able to pinpoint genetic loci for common obesity. The genome‐wide association approach, which has become available in recent years, has dramatically changed the pace of gene discoveries for common disease, including obesity. Three waves of large‐scale high‐density genome‐wide association studies have already discovered at least 15 previously unanticipated genetic loci incontrovertibly associated with body mass index and extreme obesity risk. Although the combined contribution of these loci to the variation in obesity risk at the population level is small and their predictive value is typically low, these recently discovered loci are set to improve fundamentally our insights into the pathophysiology of obesity.

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Investigation of the Locus Near MC4R With Childhood Obesity in Americans of European and African Ancestry

Cited by 72 publications

References 19 publications

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

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

Association between a Common Variant near MC4R and Change in Body Mass Index Develops by Two Weeks of Age

Recent progress in the genetics of common obesity

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