Genome-wide association study for early-onset and morbid adult obesity identifies three new risk loci in European populations

Meyre, David; Delplanque, Jérôme; Chèvre, Jean-Claude; Lecœur, Cécile; Lobbens, Stéphane; Gallina, Sophie; Durand, Emmanuelle; Vatin, Vincent; Degraeve, Franck; Proença, Christine; Gaget, Stefan; Körner, Antje; Kovacs, Peter; Kieß, Wieland; Tichet, Jean; Marre, Michel; Hartikainen, Anna-Liisa; Horber, Fritz F.; Potoczna, Natascha; Herçberg, Serge; Lévy-Marchal, Claire; Pattou, François; Heude, Barbara; Tauber, Maïthé; McCarthy, Mark I.; Blakemore, Alexandra I. F.; Montpetit, Alexandre; Polychronakos, Constantin; Weill, Jacques; Coin, Lachlan; Asher, Julian E.; Elliott, Paul; Järvelin, Marjo‐Riitta; Visvikis‐Siest, Sophie; Balkau, Beverley; Sladek, Robert; Balding, David J.; Walley, Andrew J.; Dina, Christian; Froguel, Philippe

doi:10.1038/ng.301

Cited by 586 publications

(539 citation statements)

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“…These obesity susceptibility genes are associated with both common childhood and adult obesity, as shown in large population-based or case-control GWAS performed during the past several years (Meyre et al 2009;den Hoed et al 2010;Sandholt et al 2010;Wu et al 2010;) ( Table 1). It is interesting to note that among the obesity susceptibility genes that have been identified using GWAS, different variants of the same gene (FTO, MC4R, and BNDF) may also be responsible for rare non-syndromic forms of childhood obesity.…”

Section: Common Childhood Obesitymentioning

confidence: 92%

“…Five of these obesity susceptibility genes (FTO, MC4R, MAF, NPC1, and PTER) were identified in the first or second casecontrol GWAS for early-onset (less than 6 years of age) and morbid-adult obesity (BMI C 40 kg/m 2 ) (Hinney et al 2007;Meyre et al 2009). More recent meta-analysis of several case-control GWAS using *40,000 individuals has determined that three of these obesity susceptibility genes (FTO, MC4R, and NPC1) are also associated with body fat percentage which serves as an accurate measure for whole body adiposity (Kilpelainen et al 2011;den Hoed et al 2012).…”

Section: Gene-diet Interactions Predisposing To Common Childhood Obesitymentioning

confidence: 99%

“…More recent meta-analysis of several case-control GWAS using *40,000 individuals has determined that three of these obesity susceptibility genes (FTO, MC4R, and NPC1) are also associated with body fat percentage which serves as an accurate measure for whole body adiposity (Kilpelainen et al 2011;den Hoed et al 2012). It has been hypothesized that individuals possessing these obesity susceptibility genes associated with extreme (early-onset and morbid-adult) obesity and body fat percentage may either possess more than the average number and/or enhance phenotypic expression of other common obesity susceptibility genes (Meyre et al 2009). The following sections will provide information describing what is now understood about obesity susceptibility genes interacting with either a high-fat diet or sugar-sweetened beverages to promote weight gain.…”

Section: Gene-diet Interactions Predisposing To Common Childhood Obesitymentioning

confidence: 99%

“…Studies have demonstrated that the NPC1 protein has a central role in regulating the transport of lipoproteinderived lipids, such as cholesterol and fatty acids, from late endosomes/lysosomes to other cellular compartments (Garver et al 2002;Chen et al 2005). Although the NPC1 gene has been primarily investigated in relation to an autosomal-recessive lipid-storage disorder characterized by hepatosplenomegaly and neurological degeneration, four independent GWAS have now reported that a variant of the NPC1 gene (rs1805081 encoding H215R) is associated with measures of common childhood obesity (BMI and body fat percentage) among European and Chinese populations (Meyre et al 2009;Wu et al 2010;Kilpelainen et al 2011;den Hoed et al 2012). In addition, a study performed using an Npc1 mouse model indicated that Npc1 heterozygous (Npc1 ?/-) mice are predisposed to weight gain when fed a high-fat diet, but not when fed a low-fat diet, consistent with a gene-diet interaction responsible for promoting weight gain (Jelinek et al 2009).…”

Section: Obesity Susceptibility Genes That Interact With Dietary Fatsmentioning

confidence: 99%

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The genetics of childhood obesity and interaction with dietary macronutrients

et al. 2013

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The genes contributing to childhood obesity are categorized into three different types based on distinct genetic and phenotypic characteristics. These types of childhood obesity are represented by rare monogenic forms of syndromic or non-syndromic childhood obesity, and common polygenic childhood obesity. In some cases, genetic susceptibility to these forms of childhood obesity may result from different variations of the same gene. Although the prevalence for rare monogenic forms of childhood obesity has not increased in recent times, the prevalence of common childhood obesity has increased in the United States and developing countries throughout the world during the past few decades. A number of recent genome-wide association studies and mouse model studies have established the identification of susceptibility genes contributing to common childhood obesity. Accumulating evidence suggests that this type of childhood obesity represents a complex metabolic disease resulting from an interaction with environmental factors, including dietary macronutrients. The objective of this article is to provide a review on the origins, mechanisms, and health consequences of obesity susceptibility genes and interaction with dietary macronutrients that predispose to childhood obesity. It is proposed that increased knowledge of these obesity susceptibility genes and interaction with dietary macronutrients will provide valuable insight for individual, family, and community preventative lifestyle intervention, and eventually targeted nutritional and medicinal therapies.

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Section: Common Childhood Obesitymentioning

confidence: 92%

Section: Gene-diet Interactions Predisposing To Common Childhood Obesitymentioning

confidence: 99%

Section: Gene-diet Interactions Predisposing To Common Childhood Obesitymentioning

confidence: 99%

Section: Obesity Susceptibility Genes That Interact With Dietary Fatsmentioning

confidence: 99%

See 2 more Smart Citations

The genetics of childhood obesity and interaction with dietary macronutrients

et al. 2013

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“…For example, of 19 loci identified, five were associated with BMI / obesity (FTO, MC4R, TFAP2B, NRXN3, MSRA) [20,58,59]. Additional likely causative genes for extreme obesity include TMEM18, NPC1, PTER, PRL and SDCCAG8 [20,60,61]. The biological role of several candidate genes for obesity (e.g., FTO, MC4R, POMC, SH2B1, BDNF, NPC1, NRX3 and NEGR1) [20,21] involve adipose tissue development and function or are known to act at the brain level indicating a role in regulation of eating behavior, hyperphagia and food intake.…”

Section: Yrbm Znf483mentioning

confidence: 99%

Clinically relevant known and candidate genes for obesity and their overlap with human infertility and reproduction

Butler

McGuire

Manzardo

2015

J Assist Reprod Genet

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Purpose Obesity is a growing public health concern now reaching epidemic status worldwide for children and adults due to multiple problems impacting on energy intake and expenditure with influences on human reproduction and infertility. A positive family history and genetic factors are known to play a role in obesity by influencing eating behavior, weight and level of physical activity and also contributing to human reproduction and infertility. Recent advances in genetic technology have led to discoveries of new susceptibility genes for obesity and causation of infertility. The goal of our study was to provide an update of clinically relevant candidate and known genes for obesity and infertility using high resolution chromosome ideograms with gene symbols and tabular form. Methods We used computer-based internet websites including PubMed to search for combinations of key words such as obesity, body mass index, infertility, reproduction, azoospermia, endometriosis, diminished ovarian reserve, estrogen along with genetics, gene mutations or variants to identify evidence for development of a master list of recognized obesity genes in humans and those involved with infertility and reproduction. Gene symbols for known and candidate genes for obesity were plotted on high resolution chromosome ideograms at the 850 band level. Both infertility and obesity genes were listed separately in alphabetical order in tabular form and those highlighted when involved with both conditions. Results By searching the medical literature and computer generated websites for key words, we found documented evidence for 370 genes playing a role in obesity and 153 genes for human reproduction or infertility. The obesity genes primarily affected common pathways in lipid metabolism, deposition or transport, eating behavior and food selection, physical activity or energy expenditure. Twenty-one of the obesity genes were also associated with human infertility and reproduction. Gene symbols were plotted on high resolution ideograms and their name, precise chromosome band location and description were summarized in tabular form. Conclusions Meaningful correlations in the obesity phenotype and associated human infertility and reproduction are represented with the location of genes on chromosome ideograms along with description of the gene and position in tabular form. These high resolution chromosome ideograms and tables will be useful in genetic awareness and counseling, diagnosis and treatment to improve clinical outcomes.

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Association Between Common Variants Near the Melanocortin 4 Receptor Gene and Severe Antipsychotic Drug–Induced Weight Gain

Malhotra

Correll

Chowdhury

et al. 2012

Arch Gen Psychiatry

164

113

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Context Second-generation antipsychotics (SGAs) are increasingly used in the treatment of many psychotic and non-psychotic disorders. Unfortunately, SGAs are often associated with substantial weight gain, with no means to predict which patients are at greatest risk. Objective To detect alleles of single nucleotide polymorphisms (SNPs) associated with antipsychotic drug-induced weight gain. Design Pharmacogenetic association study Setting Discovery cohort was collected at a U.S. general psychiatric hospital. Three additional cohorts were collected from psychiatric hospitals in the U.S. and Germany, and from a European antipsychotic drug trial. Participants The discovery cohort was comprised of 139 pediatric patients undergoing first exposure to SGA treatment. An additional three cohorts were comprised of 73, 40 and 92 subjects. Intervention Patients in the discovery cohort were treated with SGAs for twelve weeks. Additional cohorts were treated for six and twelve weeks. Main outcome measure We conducted a genome-wide association study (GWAS) assessing weight gain associated with twelve weeks of SGA treatment in patients undergoing first exposure to antipsychotic treatment. We next genotyped three independent cohorts of subjects assessed for antipsychotic drug-induced weight gain. Results GWAS yielded twenty SNPs at a single locus exceeding a statistical threshold of p < 10−5. This locus, near the melanocortin 4 receptor (MC4R) gene, overlaps a region previously identified by large-scale GWAS of obesity in the general population. Effects were recessive, with minor allele homozygotes gaining extreme amounts of weight over the 12-week trial. These results were replicated in three additional cohorts with SNP rs489693 demonstrating consistent recessive effects; meta analysis revealed a genome-wide significant effect (p=5.59×10−12). Moreover, we observed consistent effects on related metabolic indices, including triglycerides, leptin, insulin, and HOMA-IR in our discovery cohort. Conclusion These data implicate the MC4R locus in extreme SGA-induced weight gain and related metabolic disturbances. A priori identification of high-risk subjects could lead to alternative treatment strategies in this population.

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Genome-wide association study for early-onset and morbid adult obesity identifies three new risk loci in European populations

Cited by 586 publications

References 13 publications

The genetics of childhood obesity and interaction with dietary macronutrients

The genetics of childhood obesity and interaction with dietary macronutrients

Clinically relevant known and candidate genes for obesity and their overlap with human infertility and reproduction

Association Between Common Variants Near the Melanocortin 4 Receptor Gene and Severe Antipsychotic Drug–Induced Weight Gain

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