David Meyre

Publications (103)1343.48 Total impact

• Article: Common variants near BDNF and SH2B1 show nominal evidence of association with snacking behavior in European populations.

  Sébastien Robiou-du-Pont, Loïc Yengo, Emmanuel Vaillant, Stéphane Lobbens, Emmanuelle Durand, Fritz Horber, Olivier Lantieri, Michel Marre, Beverley Balkau, Philippe Froguel, David Meyre
  [show abstract] [hide abstract]
  ABSTRACT: We investigated the effect of 24 obesity-predisposing single nucleotide polymorphisms (SNPs), separately and in combination, on snacking behavior in three European populations. The 24 SNPs were genotyped in 7,502 subjects (1,868 snackers and 5,634 non-snackers). We tested the hypothesis that obesity risk variants or a genetic risk score increases snacking using a logistic regression adjusted for sex, age, and body mass index. The obesity genetic risk score was not associated with snacking (odds ratio (OR) = 1.00 [0.98-1.02], P value = 0.48). The obesity risk variants of two SNPs (rs925946 and rs7498665) close to the BDNF and SH2B1 genes showed nominal evidence of association with increased snacking (OR = 1.09 [1.01-1.17], P value = 0.0348 and OR = 1.11 [1.04-1.19], P value = 0.00703, respectively) but did not survive Bonferroni corrections for multiple testing. The associations of rs925946 and rs7498665 obesity risk variants with increased BMI (β = 0.180 [0.022-0.339], P value = 0.0258 and β = 0.166 [0.019-0.313], P value = 0.0271, respectively) were slightly attenuated after adjusting for snacking (β = 0.151 [-0.006 to 0.309], P value = 0.0591 and β = 0.152 [0.006-0.297], P value = 0.0413). Our data suggest that genetic predisposition to obesity does not significantly contribute to snacking behavior. The nominal associations of rs925946 and rs7498665 obesity risk variants near the BDNF and SH2B1 genes with increased snacking deserve further investigation.
  Journal of Molecular Medicine 05/2013; · 4.67 Impact Factor
• Article: Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture.

  Sonja I Berndt, Stefan Gustafsson, Reedik Mägi, Andrea Ganna, Eleanor Wheeler, Mary F Feitosa, Anne E Justice, Keri L Monda, Damien C Croteau-Chonka, Felix R Day, [......], Joel N Hirschhorn, Cecilia M Lindgren, Andrew P Morris, David Meyre, André Scherag, Mark I McCarthy, Elizabeth K Speliotes, Kari E North, Ruth J F Loos, Erik Ingelsson
  [show abstract] [hide abstract]
  ABSTRACT: Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
  Nature Genetics 04/2013; · 35.53 Impact Factor
• Article: Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture

  Sonja I Berndt, Stefan Gustafsson, Reedik Magi, Andrea Ganna, Eleanor Wheeler, Mary F Feitosa, Anne E Justice, Keri L Monda, Damien C Croteau-Chonka, Felix R Day, [......], Joel N Hirschhorn, Cecilia M Lindgren, Andrew P Morris, David Meyre, Andre Scherag, Mark I McCarthy, Elizabeth K Speliotes, Kari E North, Ruth J F Loos, Erik Ingelsson
  [show abstract] [hide abstract]
  ABSTRACT: Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
  Nature Genetics 04/2013; · 35.53 Impact Factor
• Source

  Available from: Miguel Klunder

  Article: Analysis of the contribution of FTO, NPC1, ENPP1, NEGR1, GNPDA2 and MC4R genes to obesity in Mexican children.

  Aurora Mejía-Benítez, Miguel Klünder-Klünder, Loic Yengo, David Meyre, Celia Aradillas, Esperanza Cruz, Elva Pérez-Luque, Juan Manuel Malacara, Maria Eugenia Garay, Jesús Peralta-Romero, Samuel Flores-Huerta, Jaime García-Mena, Philippe Froguel, Miguel Cruz, Amélie Bonnefond
  [show abstract] [hide abstract]
  ABSTRACT: BACKGROUND: Recent genome wide association studies (GWAS) and previous positional linkage studies have identified more than 50 single nucleotide polymorphisms (SNPs) associated with obesity, mostly in Europeans. We aimed to assess the contribution of some of these SNPs to obesity risk and to the variation of related metabolic traits, in Mexican children. METHODS: The association of six European obesity-related SNPs in or near FTO, NPC1, ENPP1, NEGR1, GNPDA2 and MC4R genes with risk of obesity was tested in 1,463 school-aged Mexican children (Ncases = 514; Ncontrols = 949). We also assessed effects of these SNPs on the variation of body mass index (BMI), fasting serum insulin levels, fasting plasma glucose levels, total cholesterol and triglyceride levels, in a subset of 1,171 nonobese Mexican children. RESULTS: We found a significant effect of GNPDA2 rs10938397 on risk of obesity (odds ratio [OR] = 1.30; P = 1.34 x 10-3). Furthermore, we found nominal associations between obesity risk or BMI variation and the following SNPs: ENPP1 rs7754561, MC4R rs17782313 and NEGR1 rs2815752. Importantly, the at-risk alleles of both MC4R rs17782313 and NPC1 rs1805081 showed significant effect on increased fasting glucose levels (beta = 0.36 mmol/L; P = 1.47 x 10-3) and decreased fasting serum insulin levels (beta = -0.10 muU/mL; P = 1.21 x 10-3), respectively. CONCLUSION: Our present results suggest that some obesity-associated SNPs previously reported in Europeans also associate with risk of obesity, or metabolic quantitative traits, in Mexican children. Importantly, we found new associations between MC4R and fasting glucose levels, and between NPC1 and fasting insulin levels.
  BMC Medical Genetics 02/2013; 14(1):21. · 2.33 Impact Factor
• Article: Rare genomic structural variants in complex disease: lessons from the replication of associations with obesity.

  Robin G Walters, Lachlan J M Coin, Aimo Ruokonen, Adam J de Smith, Julia S El-Sayed Moustafa, Sebastien Jacquemont, Paul Elliott, Tõnu Esko, Anna-Liisa Hartikainen, Jaana Laitinen, [......], Beverley Balkau, François Pattou, Andres Metspalu, Henry Völzke, Peter Vollenweider, Kári Stefansson, Marjo-Riitta Järvelin, Jacques S Beckmann, Philippe Froguel, Alexandra I F Blakemore
  [show abstract] [hide abstract]
  ABSTRACT: The limited ability of common variants to account for the genetic contribution to complex disease has prompted searches for rare variants of large effect, to partly explain the 'missing heritability'. Analyses of genome-wide genotyping data have identified genomic structural variants (GSVs) as a source of such rare causal variants. Recent studies have reported multiple GSV loci associated with risk of obesity. We attempted to replicate these associations by similar analysis of two familial-obesity case-control cohorts and a population cohort, and detected GSVs at 11 out of 18 loci, at frequencies similar to those previously reported. Based on their reported frequencies and effect sizes (OR≥25), we had sufficient statistical power to detect the large majority (80%) of genuine associations at these loci. However, only one obesity association was replicated. Deletion of a 220 kb region on chromosome 16p11.2 has a carrier population frequency of 2×10(-4) (95% confidence interval [9.6×10(-5)-3.1×10(-4)]); accounts overall for 0.5% [0.19%-0.82%] of severe childhood obesity cases (P = 3.8×10(-10); odds ratio = 25.0 [9.9-60.6]); and results in a mean body mass index (BMI) increase of 5.8 kg.m(-2) [1.8-10.3] in adults from the general population. We also attempted replication using BMI as a quantitative trait in our population cohort; associations with BMI at or near nominal significance were detected at two further loci near KIF2B and within FOXP2, but these did not survive correction for multiple testing. These findings emphasise several issues of importance when conducting rare GSV association, including the need for careful cohort selection and replication strategy, accurate GSV identification, and appropriate correction for multiple testing and/or control of false discovery rate. Moreover, they highlight the potential difficulty in replicating rare CNV associations across different populations. Nevertheless, we show that such studies are potentially valuable for the identification of variants making an appreciable contribution to complex disease.
  PLoS ONE 01/2013; 8(3):e58048. · 4.09 Impact Factor
• Article: Novel association approach for variable number tandem repeats (VNTRs) identifies DOCK5 as a susceptibility gene for severe obesity.

  Julia S El-Sayed Moustafa, Hariklia Eleftherohorinou, Adam J de Smith, Johanna C Andersson-Assarsson, Alexessander Couto Alves, Eleni Hadjigeorgiou, Robin G Walters, Julian E Asher, Leonardo Bottolo, Jessica L Buxton, [......], Christian Dina, Sophie Visvikis-Siest, Peter Jacobson, Lars Sjöström, Lena M S Carlsson, Andrew Walley, Mario Falchi, Philippe Froguel, Alexandra I F Blakemore, Lachlan J M Coin
  [show abstract] [hide abstract]
  ABSTRACT: Variable number tandem repeats (VNTRs) constitute a relatively under-examined class of genomic variants in the context of complex disease because of their sequence complexity and the challenges in assaying them. Recent large-scale genome-wide copy number variant mapping and association efforts have highlighted the need for improved methodology for association studies using these complex polymorphisms. Here we describe the in-depth investigation of a complex region on chromosome 8p21.2 encompassing the dedicator of cytokinesis 5 (DOCK5) gene. The region includes two VNTRs of complex sequence composition which flank a common 3975 bp deletion, all three of which were genotyped by polymerase chain reaction and fragment analysis in a total of 2744 subjects. We have developed a novel VNTR association method named VNTRtest, suitable for association analysis of multi-allelic loci with binary and quantitative outcomes, and have used this approach to show significant association of the DOCK5 VNTRs with childhood and adult severe obesity (P(empirical)= 8.9 × 10(-8) and P= 3.1 × 10(-3), respectively) which we estimate explains ~0.8% of the phenotypic variance. We also identified an independent association between the 3975 base pair (bp) deletion and obesity, explaining a further 0.46% of the variance (P(combined)= 1.6 × 10(-3)). Evidence for association between DOCK5 transcript levels and the 3975 bp deletion (P= 0.027) and both VNTRs (P(empirical)= 0.015) was also identified in adipose tissue from a Swedish family sample, providing support for a functional effect of the DOCK5 deletion and VNTRs. These findings highlight the potential role of DOCK5 in human obesity and illustrate a novel approach for analysis of the contribution of VNTRs to disease susceptibility through association studies.
  Human Molecular Genetics 05/2012; 21(16):3727-38. · 7.64 Impact Factor
• Source

  Available from: Aline Meirhaeghe

  Article: A genome-wide association meta-analysis identifies new childhood obesity loci.

  Jonathan P Bradfield, H Rob Taal, Nicholas J Timpson, André Scherag, Cecile Lecoeur, Nicole M Warrington, Elina Hypponen, Claus Holst, Beatriz Valcarcel, Elisabeth Thiering, [......], I Sadaf Farooqi, Mark I McCarthy, Philippe Froguel, David Meyre, Johannes Hebebrand, Marjo-Riitta Jarvelin, Vincent W V Jaddoe, George Davey Smith, Hakon Hakonarson, Struan F A Grant
  [show abstract] [hide abstract]
  ABSTRACT: Multiple genetic variants have been associated with adult obesity and a few with severe obesity in childhood; however, less progress has been made in establishing genetic influences on common early-onset obesity. We performed a North American, Australian and European collaborative meta-analysis of 14 studies consisting of 5,530 cases (≥95th percentile of body mass index (BMI)) and 8,318 controls (<50th percentile of BMI) of European ancestry. Taking forward the eight newly discovered signals yielding association with P < 5 × 10(-6) in nine independent data sets (2,818 cases and 4,083 controls), we observed two loci that yielded genome-wide significant combined P values near OLFM4 at 13q14 (rs9568856; P = 1.82 × 10(-9); odds ratio (OR) = 1.22) and within HOXB5 at 17q21 (rs9299; P = 3.54 × 10(-9); OR = 1.14). Both loci continued to show association when two extreme childhood obesity cohorts were included (2,214 cases and 2,674 controls). These two loci also yielded directionally consistent associations in a previous meta-analysis of adult BMI(1).
  Nature Genetics 04/2012; 44(5):526-31. · 35.53 Impact Factor
• Article: Loss-of-Function Mutations in MC4R Are Very Rare in the Greek Severely Obese Adult Population.

  Konstantinos Rouskas, David Meyre, Fanny Stutzmann, Konstantinos Paletas, Dimitrios Papazoglou, Vincent Vatin, Marion Marchand, Anastasia Kouvatsi, Philippe Froguel
  [show abstract] [hide abstract]
  ABSTRACT: Melanocortin-4 receptor (MC4R) loss-of-function mutations are the commonest genetic cause of human monogenic obesity, so far. The contribution of MC4R coding mutations to severe obesity in the high-obesity prone Greek population has not been investigated to date. We determined the MC4R coding sequence of 510 obese and 469 lean control subjects of Greek origin, and we estimated the prevalence and the penetrance on obesity of MC4R loss-of-function mutations. The functional impact of novel nonsynonymous variants detected was investigated in vitro. We found two novel synonymous mutations (L23L and I102I), four nonsynonymous mutations (T112M, S127L, N274S, and S295L), and two polymorphisms (V103I and I251L) previously described in literature. We also detected a novel mutation (L207V) in a severely obese 69-year-old female patient, although the mutation did not cosegregate with obesity in the corresponding pedigree and had no functional consequences on MC4R protein function. Loss-of-function mutations represented 75% of all nonsynonymous rare mutations identified among lean carriers and only 25% among obese subjects (P = 0.0001). The prevalence of loss-of-function mutations was lower in the obese group than in lean control subjects (0.20 vs. 0.64%) but this difference was not significant. Therefore, the estimated penetrance of deleterious MC4R mutations was very low (6.3%) in heterozygous Greek carriers of MC4R loss-of-function mutations. Our data suggest that MC4R loss-of-function mutations are rare in the Greek population. MC4R genetic deficiency is unlikely to explain the high propensity to develop severe obesity in this specific population.
  Obesity 03/2012; · 4.28 Impact Factor
• Source

  Available from: Sarah G Buxbaum

  Article: Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.

  Zari Dastani, Marie-France Hivert, Nicholas Timpson, John R B Perry, Xin Yuan, Robert A Scott, Peter Henneman, Iris M Heid, Jorge R Kizer, Leo-Pekka Lyytikäinen, [......], Eric E Schadt, David P Strachan, Muredach P Reilly, Nilesh J Samani, Heribert Schunkert, L Adrienne Cupples, Manjinder S Sandhu, Paul M Ridker, Daniel J Rader, Sekar Kathiresan
  [show abstract] [hide abstract]
  ABSTRACT: Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10(-3), n = 22,044), increased triglycerides (p = 2.6×10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8×10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10(-13), n = 96,748) and decreased BMI (p = 1.4×10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.
  PLoS Genetics 03/2012; 8(3):e1002607. · 8.69 Impact Factor
• Source

  Available from: Atsuhiko Ichimura

  Article: Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human.

  Atsuhiko Ichimura, Akira Hirasawa, Odile Poulain-Godefroy, Amélie Bonnefond, Takafumi Hara, Loïc Yengo, Ikuo Kimura, Audrey Leloire, Ning Liu, Keiko Iida, [......], Anastasia Kouvatsi, Johannes Hebebrand, Anke Hinney, Andre Scherag, François Pattou, David Meyre, Taka-aki Koshimizu, Isabelle Wolowczuk, Gozoh Tsujimoto, Philippe Froguel
  [show abstract] [hide abstract]
  ABSTRACT: Free fatty acids provide an important energy source as nutrients, and act as signalling molecules in various cellular processes. Several G-protein-coupled receptors have been identified as free-fatty-acid receptors important in physiology as well as in several diseases. GPR120 (also known as O3FAR1) functions as a receptor for unsaturated long-chain free fatty acids and has a critical role in various physiological homeostasis mechanisms such as adipogenesis, regulation of appetite and food preference. Here we show that GPR120-deficient mice fed a high-fat diet develop obesity, glucose intolerance and fatty liver with decreased adipocyte differentiation and lipogenesis and enhanced hepatic lipogenesis. Insulin resistance in such mice is associated with reduced insulin signalling and enhanced inflammation in adipose tissue. In human, we show that GPR120 expression in adipose tissue is significantly higher in obese individuals than in lean controls. GPR120 exon sequencing in obese subjects reveals a deleterious non-synonymous mutation (p.R270H) that inhibits GPR120 signalling activity. Furthermore, the p.R270H variant increases the risk of obesity in European populations. Overall, this study demonstrates that the lipid sensor GPR120 has a key role in sensing dietary fat and, therefore, in the control of energy balance in both humans and rodents.
  Nature 02/2012; 483(7389):350-4. · 36.28 Impact Factor
• Article: A genome-wide association search for type 2 diabetes genes in African Americans.

  Nicholette D Palmer, Caitrin W McDonough, Pamela J Hicks, Bong H Roh, Maria R Wing, S Sandy An, Jessica M Hester, Jessica N Cooke, Meredith A Bostrom, Megan E Rudock, [......], Angelo Scuteri, David Schlessinger, Manuela Uda, Aimo Ruokonen, Marjo-Riitta Jarvelin, Dawn M Waterworth, Peter Vollenweider, Leena Peltonen, Vincent Mooser, Robert Sladek
  [show abstract] [hide abstract]
  ABSTRACT: African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.
  PLoS ONE 01/2012; 7(1):e29202. · 4.09 Impact Factor
• Article: Estimation of newborn risk for child or adolescent obesity: lessons from longitudinal birth cohorts.

  Anita Morandi, David Meyre, Stéphane Lobbens, Ken Kleinman, Marika Kaakinen, Sheryl L Rifas-Shiman, Vincent Vatin, Stefan Gaget, Anneli Pouta, Anna-Liisa Hartikainen, Jaana Laitinen, Aimo Ruokonen, Shikta Das, Anokhi Ali Khan, Paul Elliott, Claudio Maffeis, Matthew W Gillman, Marjo-Riitta Järvelin, Philippe Froguel
  [show abstract] [hide abstract]
  ABSTRACT: Prevention of obesity should start as early as possible after birth. We aimed to build clinically useful equations estimating the risk of later obesity in newborns, as a first step towards focused early prevention against the global obesity epidemic. We analyzed the lifetime Northern Finland Birth Cohort 1986 (NFBC1986) (N = 4,032) to draw predictive equations for childhood and adolescent obesity from traditional risk factors (parental BMI, birth weight, maternal gestational weight gain, behaviour and social indicators), and a genetic score built from 39 BMI/obesity-associated polymorphisms. We performed validation analyses in a retrospective cohort of 1,503 Italian children and in a prospective cohort of 1,032 U.S. children. In the NFBC1986, the cumulative accuracy of traditional risk factors predicting childhood obesity, adolescent obesity, and childhood obesity persistent into adolescence was good: AUROC = 0·78[0·74-0.82], 0·75[0·71-0·79] and 0·85[0·80-0·90] respectively (all p<0·001). Adding the genetic score produced discrimination improvements ≤1%. The NFBC1986 equation for childhood obesity remained acceptably accurate when applied to the Italian and the U.S. cohort (AUROC = 0·70[0·63-0·77] and 0·73[0·67-0·80] respectively) and the two additional equations for childhood obesity newly drawn from the Italian and the U.S. datasets showed good accuracy in respective cohorts (AUROC = 0·74[0·69-0·79] and 0·79[0·73-0·84]) (all p<0·001). The three equations for childhood obesity were converted into simple Excel risk calculators for potential clinical use. This study provides the first example of handy tools for predicting childhood obesity in newborns by means of easily recorded information, while it shows that currently known genetic variants have very little usefulness for such prediction.
  PLoS ONE 01/2012; 7(11):e49919. · 4.09 Impact Factor
• Source

  Available from: Rosa-Maria Guéant-Rodriguez

  Article: A genome-wide association study identifies rs2000999 as a strong genetic determinant of circulating Haptoglobin levels

  Philippe Froguel, Ndeye Coumba Ndiaye, Amélie Bonnefond, Nabila Bouatia-Naji, Aurélie Dechaume, Gérard Siest, Bernard Herbeth, Mario Falchi, Leonardo Bottolo, Rosa-Maria Guéant-Rodriguez, [......], David Meyre, Joris R Delanghe, Peter Jacobson, Lars Sjöström, Lena MS Carlsson, Andrew Walley, Paul Elliott, Marjo-Riita Jarvelin, George V Dedoussis, Sophie Visvikis-Siest
  [show abstract] [hide abstract]
  ABSTRACT: Haptoglobin is an acute phase inflammatory marker. Its main function is to bind hemoglobin released from erythrocytes to aid its elimination, and thereby haptoglobin prevents the generation of reactive oxygen species in the blood. Haptoglobin levels have been repeatedly associated with a variety of inflammation-linked infectious and non-infectious diseases, including malaria, tuberculosis, human immunodeficiency virus, hepatitis C, diabetes, carotid atherosclerosis, and acute myocardial infarction. However, a comprehensive genetic assessment of the inter-individual variability of circulating haptoglobin levels has not been conducted so far. We used a genome-wide association study initially conducted in 631 French children followed by a replication in three additional European sample sets and we identified a common single nucleotide polymorphism (SNP), rs2000999 located in the Haptoglobin gene (HP) as a strong genetic predictor of circulating Haptoglobin levels (Poverall = 8.1×10-59), explaining 45.4 % of its genetic variability (11.8% of Hp global variance). The functional relevance of rs2000999 was further demonstrated by its specific association with HP mRNA levels ( = 0.23±0.08, P = 0.007). Finally, SNP rs2000999 was associated with decreased total and low-density lipoprotein cholesterol in 8,789 European children (Ptotal cholesterol = 0.002 and PLDL = 0.0008). Given the central position of haptoglobin in many inflammation-related metabolic pathways, the relevance of rs2000999 genotyping when evaluating haptoglobin concentration should be further investigated in order to improve its diagnostic/therapeutic and/or prevention impact.
  PLoS ONE 01/2012; · 4.09 Impact Factor
• Article: Heterozygous mutations causing partial prohormone convertase 1 deficiency contribute to human obesity.

  John W M Creemers, Hélène Choquet, Pieter Stijnen, Vincent Vatin, Marie Pigeyre, Sigri Beckers, Sandra Meulemans, Manuel E Than, Loïc Yengo, Maithé Tauber, Beverley Balkau, Paul Elliott, Marjo-Riitta Jarvelin, Wim Van Hul, Luc Van Gaal, Fritz Horber, François Pattou, Philippe Froguel, David Meyre
  [show abstract] [hide abstract]
  ABSTRACT: Null mutations in the PCSK1 gene, encoding the proprotein convertase 1/3 (PC1/3), cause recessive monogenic early onset obesity. Frequent coding variants that modestly impair PC1/3 function mildly increase the risk for common obesity. The aim of this study was to determine the contribution of rare functional PCSK1 mutations to obesity. PCSK1 exons were sequenced in 845 nonconsanguineous extremely obese Europeans. Eight novel nonsynonymous PCSK1 mutations were identified, all heterozygous. Seven mutations had a deleterious effect on either the maturation or the enzymatic activity of PC1/3 in cell lines. Of interest, five of these novel mutations, one of the previously described frequent variants (N221D), and the mutation found in an obese mouse model (N222D), affect residues at or near the structural calcium binding site Ca-1. The prevalence of the newly identified mutations was assessed in 6,233 obese and 6,274 lean European adults and children, which showed that carriers of any of these mutations causing partial PCSK1 deficiency had an 8.7-fold higher risk to be obese than wild-type carriers. These results provide the first evidence of an increased risk of obesity in heterozygous carriers of mutations in the PCSK1 gene. Furthermore, mutations causing partial PCSK1 deficiency are present in 0.83% of extreme obesity phenotypes.
  Diabetes 12/2011; 61(2):383-90. · 8.29 Impact Factor
• Article: Common variants in FTO, MC4R, TMEM18, PRL, AIF1, and PCSK1 show evidence of association with adult obesity in the Greek population.

  Konstantinos Rouskas, Anastasia Kouvatsi, Konstantinos Paletas, Dimitrios Papazoglou, Apostolos Tsapas, Stéphane Lobbens, Vincent Vatin, Emmanuelle Durand, Yann Labrune, Jérôme Delplanque, David Meyre, Philippe Froguel
  [show abstract] [hide abstract]
  ABSTRACT: Twenty-four single-nucleotide polymorphisms (SNPs) have been reproducibly associated with obesity. We performed a follow-up study for obesity in the Greek adult population. A total of 510 obese and 469 lean adults were genotyped for 24 SNPs. We tested the association with obesity status using logistic regression and we evaluated the combined genetic risk of 24 SNPs by calculating the area under the receiver-operating characteristic (ROC) curves. We nominally replicated the association with obesity (BMI ≥30 kg/m(2)) of six SNPs in or near the FTO, MC4R, TMEM18, PRL, AIF1, and PCSK1 loci (1.28 ≤ odds ratio (OR) ≤ 1.35; 0.004 ≤ P ≤ 0.043). The discrimination ability for obesity was slightly stronger (P = 9.59 × 10(-6)) when the genetic information of the 24 SNPs was added to nongenetic risk factors (area under the curve (AUC) = 0.722) in comparison with nongenetic factors analyzed alone (AUC = 0.685). Our data suggest that SNPs in or near the FTO, MC4R, TMEM18, PRL, AIF1, and PCSK1 loci contribute to obesity risk in the Greek population.
  Obesity 06/2011; 20(2):389-95. · 4.28 Impact Factor
• Source

  Available from: PubMed Central

  Article: Molecular basis of obesity: current status and future prospects.

  Hélène Choquet, David Meyre
  [show abstract] [hide abstract]
  ABSTRACT: Obesity is a global health problem that is gradually affecting each continent of the world. Obesity is a heterogeneous disorder, and the biological causes of obesity are complex. The rapid increase in obesity prevalence during the past few decades is due to major societal changes (sedentary lifestyle, over-nutrition) but who becomes obese at the individual level is determined to a great extent by genetic susceptibility. In this review, we evidence that obesity is a strongly heritable disorder, and provide an update on the molecular basis of obesity. To date, nine loci have been involved in Mendelian forms of obesity and 58 loci contribute to polygenic obesity, and rare and common structural variants have been reliably associated with obesity. Most of the obesity genes remain to be discovered, but promising technologies, methodologies and the use of "deep phenotyping" lead to optimism to chip away at the 'missing heritability' of obesity in the near future. In the longer term, the genetic dissection of obesity will help to characterize disease mechanisms, provide new targets for drug design, and lead to an early diagnosis, treatment, and prevention of obesity.
  Current Genomics 05/2011; 12(3):154-68. · 2.41 Impact Factor
• Source

  Available from: PubMed Central

  Article: Genetics of Obesity: What have we Learned?

  Hélène Choquet, David Meyre
  [show abstract] [hide abstract]
  ABSTRACT: Candidate gene and genome-wide association studies have led to the discovery of nine loci involved in Mendelian forms of obesity and 58 loci contributing to polygenic obesity. These loci explain a small fraction of the heritability for obesity and many genes remain to be discovered. However, efforts in obesity gene identification greatly modified our understanding of this disorder. In this review, we propose an overlook of major lessons learned from 15 years of research in the field of genetics and obesity. We comment on the existence of the genetic continuum between monogenic and polygenic forms of obesity that pinpoints the role of genes involved in the central regulation of food intake and genetic predisposition to obesity. We explain how the identification of novel obesity predisposing genes has clarified unsuspected biological pathways involved in the control of energy balance that have helped to understand past human history and to explore causality in epidemiology. We provide evidence that obesity predisposing genes interact with the environment and influence the response to treatment relevant to disease prediction.
  Current Genomics 05/2011; 12(3):169-79. · 2.41 Impact Factor
• Article: Childhood obesity is associated with shorter leukocyte telomere length.

  Jessica L Buxton, Robin G Walters, Sophie Visvikis-Siest, David Meyre, Philippe Froguel, Alexandra I F Blakemore
  [show abstract] [hide abstract]
  ABSTRACT: Obesity in adults is associated with shorter mean leukocyte telomere length (LTL), a marker of biological age that is also associated with age-related conditions including cardiovascular disease and type 2 diabetes. However, studies of childhood obesity and LTL have proved inconclusive. The objective of the study was to clarify the relationship between telomere length and childhood obesity by measuring the average LTL in a large case-control cohort. LTL was measured in 793 French children aged 2-17 yr (471 with early onset obesity and 322 nonobese controls) using multiplex quantitative real-time PCR. The average LTL in the two groups was compared, and the relationships between telomere length and selected anthropometric and biochemical measurements were examined. Obese children had a mean LTL that was 23.9% shorter than that of nonobese children (P < 0.0001). Telomere length was inversely associated with age (R = -0.17, P = 0.002 in controls; R = -0.15, P = 0.001 in cases), log weight (R= -0.13, P = 0.017 in controls; R = -0.16, P = 0.0004 in cases), and height (R = -0.15, P = 0.008 in controls; R = -0.17, P = 0.0002 in cases). The mean LTL of girls and boys was not significantly different in either the cases or controls or in the group overall. Obese girls and boys have significantly shorter leukocyte telomeres than their nonobese counterparts, a finding that highlights a potentially deleterious impact of early onset obesity on future health.
  The Journal of clinical endocrinology and metabolism 02/2011; 96(5):1500-5. · 6.50 Impact Factor
• Source

  Available from: Antje Körner

  Article: Evaluation of A2BP1 as an obesity gene.

  Lijun Ma, Robert L Hanson, Michael T Traurig, Yunhua L Muller, Bakhshish P Kaur, Jessica M Perez, David Meyre, Mao Fu, Antje Körner, Paul W Franks, Wieland Kiess, Sayuko Kobes, William C Knowler, Peter Kovacs, Philippe Froguel, Alan R Shuldiner, Clifton Bogardus, Leslie J Baier
  [show abstract] [hide abstract]
  ABSTRACT: A genome-wide association study (GWAS) in Pima Indians (n = 413) identified variation in the ataxin-2 binding protein 1 gene (A2BP1) that was associated with percent body fat. On the basis of this association and the obese phenotype of ataxin-2 knockout mice, A2BP1 was genetically and functionally analyzed to assess its potential role in human obesity. Variants spanning A2BP1 were genotyped in a population-based sample of 3,234 full-heritage Pima Indians, 2,843 of whom were not part of the initial GWAS study and therefore could serve as a sample to assess replication. Published GWAS data across A2BP1 were additionally analyzed in French adult (n = 1,426) and children case/control subjects (n = 1,392) (Meyre et al. Nat Genet 2009;41:157-159). Selected variants were genotyped in two additional samples of Caucasians (Amish, n = 1,149, and German children case/control subjects, n = 998) and one additional Native American (n = 2,531) sample. Small interfering RNA was used to knockdown A2bp1 message levels in mouse embryonic hypothalamus cells. No single variant in A2BP1 was reproducibly associated with obesity across the different populations. However, different variants within intron 1 of A2BP1 were associated with BMI in full-heritage Pima Indians (rs10500331, P = 1.9 × 10(-7)) and obesity in French Caucasian adult (rs4786847, P = 1.9 × 10(-10)) and children (rs8054147, P = 9.2 × 10(-6)) case/control subjects. Reduction of A2bp1 in mouse embryonic hypothalamus cells decreased expression of Atxn2, Insr, and Mc4r. Association analysis suggests that variation in A2BP1 influences obesity, and functional studies suggest that A2BP1 could potentially affect adiposity via the hypothalamic MC4R pathway.
  Diabetes 11/2010; 59(11):2837-45. · 8.29 Impact Factor
• Article: Lack of association of CD36 SNPs with early onset obesity: a meta-analysis in 9,973 European subjects.

  Hélène Choquet, Yann Labrune, Franck De Graeve, Anke Hinney, Johannes Hebebrand, André Scherag, Cécile Lecoeur, Maithé Tauber, Beverley Balkau, Paul Elliot, Marjo-Riita Jarvelin, Andrew J Walley, Philippe Besnard, Philippe Froguel, David Meyre
  [show abstract] [hide abstract]
  ABSTRACT: A recent study suggested that four CD36 polymorphisms (namely rs3211867, rs3211883, rs3211908, and rs1527483) were associated with an increased risk of obesity, an increased BMI and percentage of body fat in European adolescents. We first attempted to confirm these results in three independent case-control genome-wide association studies (GWAS) data totaling 3,509 subjects of French and German origin, but we were unable to find any association of these variants with early onset obesity risk. We then genotyped the four CD36 single-nucleotide polymorphisms (SNPs) in a large population-based study of 4,667 Finnish subjects and we did not replicate any of the recently reported associations with BMI. By combining all available data in a meta-analysis (N = 9,973), we found no evidence for an association of the reported four variants in CD36 with increased obesity risk or increased BMI (0.07 ≤ P values ≤ 0.93). Finally, we assessed the contribution of the full CD36 locus gene variation to obesity risk in 3,509 subjects and we did not detect any significant association with obesity after correction for multiple testing. In summary, we were unable to confirm the recently reported association of variants in CD36 with early onset obesity in populations of European ancestry.
  Obesity 10/2010; 19(4):833-9. · 4.28 Impact Factor