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FTO genotype is associated with phenotypic variability of body mass index.

ABSTRACT: There is evidence across several species for genetic control of phenotypic variation of complex traits, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using ?170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype), is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of ?0.5?kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI, possibly mediated by DNA methylation. Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.

SUBMITTER: Yang J

PROVIDER: S-EPMC3564953 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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FTO genotype is associated with phenotypic variability of body mass index.

Yang Jian J Loos Ruth J F RJ Powell Joseph E JE Medland Sarah E SE Speliotes Elizabeth K EK Chasman Daniel I DI Rose Lynda M LM Thorleifsson Gudmar G Steinthorsdottir Valgerdur V Mägi Reedik R Waite Lindsay L Smith Albert Vernon AV Yerges-Armstrong Laura M LM Monda Keri L KL Hadley David D Mahajan Anubha A Li Guo G Kapur Karen K Vitart Veronique V Huffman Jennifer E JE Wang Sophie R SR Palmer Cameron C Esko Tõnu T Fischer Krista K Zhao Jing Hua JH Demirkan Ayşe A Isaacs Aaron A Feitosa Mary F MF Luan Jian'an J Heard-Costa Nancy L NL White Charles C Jackson Anne U AU Preuss Michael M Ziegler Andreas A Eriksson Joel J Kutalik Zoltán Z Frau Francesca F Nolte Ilja M IM Van Vliet-Ostaptchouk Jana V JV Hottenga Jouke-Jan JJ Jacobs Kevin B KB Verweij Niek N Goel Anuj A Medina-Gomez Carolina C Estrada Karol K Bragg-Gresham Jennifer Lynn JL Sanna Serena S Sidore Carlo C Tyrer Jonathan J Teumer Alexander A Prokopenko Inga I Mangino Massimo M Lindgren Cecilia M CM Assimes Themistocles L TL Shuldiner Alan R AR Hui Jennie J Beilby John P JP McArdle Wendy L WL Hall Per P Haritunians Talin T Zgaga Lina L Kolcic Ivana I Polasek Ozren O Zemunik Tatijana T Oostra Ben A BA Junttila M Juhani MJ Grönberg Henrik H Schreiber Stefan S Peters Annette A Hicks Andrew A AA Stephens Jonathan J Foad Nicola S NS Laitinen Jaana J Pouta Anneli A Kaakinen Marika M Willemsen Gonneke G Vink Jacqueline M JM Wild Sarah H SH Navis Gerjan G Asselbergs Folkert W FW Homuth Georg G John Ulrich U Iribarren Carlos C Harris Tamara T Launer Lenore L Gudnason Vilmundur V O'Connell Jeffrey R JR Boerwinkle Eric E Cadby Gemma G Palmer Lyle J LJ James Alan L AL Musk Arthur W AW Ingelsson Erik E Psaty Bruce M BM Beckmann Jacques S JS Waeber Gerard G Vollenweider Peter P Hayward Caroline C Wright Alan F AF Rudan Igor I Groop Leif C LC Metspalu Andres A Khaw Kay Tee KT van Duijn Cornelia M CM Borecki Ingrid B IB Province Michael A MA Wareham Nicholas J NJ Tardif Jean-Claude JC Huikuri Heikki V HV Cupples L Adrienne LA Atwood Larry D LD Fox Caroline S CS Boehnke Michael M Collins Francis S FS Mohlke Karen L KL Erdmann Jeanette J Schunkert Heribert H Hengstenberg Christian C Stark Klaus K Lorentzon Mattias M Ohlsson Claes C Cusi Daniele D Staessen Jan A JA Van der Klauw Melanie M MM Pramstaller Peter P PP Kathiresan Sekar S Jolley Jennifer D JD Ripatti Samuli S Jarvelin Marjo-Riitta MR de Geus Eco J C EJ Boomsma Dorret I DI Penninx Brenda B Wilson James F JF Campbell Harry H Chanock Stephen J SJ van der Harst Pim P Hamsten Anders A Watkins Hugh H Hofman Albert A Witteman Jacqueline C JC Zillikens M Carola MC Uitterlinden André G AG Rivadeneira Fernando F Zillikens M Carola MC Kiemeney Lambertus A LA Vermeulen Sita H SH Abecasis Goncalo R GR Schlessinger David D Schipf Sabine S Stumvoll Michael M Tönjes Anke A Spector Tim D TD North Kari E KE Lettre Guillaume G McCarthy Mark I MI Berndt Sonja I SI Heath Andrew C AC Madden Pamela A F PA Nyholt Dale R DR Montgomery Grant W GW Martin Nicholas G NG McKnight Barbara B Strachan David P DP Hill William G WG Snieder Harold H Ridker Paul M PM Thorsteinsdottir Unnur U Stefansson Kari K Frayling Timothy M TM Hirschhorn Joel N JN Goddard Michael E ME Visscher Peter M PM

Nature 20120916 7419

There is evidence across several species for genetic control of phenotypic variation of complex traits, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of ...[more]

PMID: 22982992

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Project description:BackgroundFat-mass and obesity-associated (FTO) gene is a gene located in chromosome region 16q12.2. Genetic variants in FTO are associated with the obesity phenotype in European and Hispanic populations. However, this association still remains controversial in Asian population. We aimed to test the association of FTO genetic variants with obesity and obesity-related metabolic traits among children living in Beijing, China.MethodsWe genotyped FTO variants rs9939609 in 670 children (332 girls and 338 boys) aged 8-11 years living in Beijing, and analyzed its association with obesity and obesity-related metabolic traits. Overweight and obesity were defined by age- and sex-specific BMI reference for Chinese children. Obesity-related metabolic traits included fasting plasma glucose, lipid profiles, leptin, ghrelin, adiponectin and blood pressures.ResultsThe frequency of rs9939609 A allele was 12.2%, which was 21.9% for the heterozygote and 1.2% for the homozygote of the A allele. The obesity prevalence among the carriers of AA/AT genotypes was significantly higher than that among those with TT genotype (36.4% vs. 22.6%, P=0.004). Compared to the carrier of TT genotype, the likelihood of obesity was 1.79 (95% confidence interval (95% CI) 1.20-2.67, P=0.004) for the carrier of AA/AT genotype, after adjustment of sex, age and puberty stages. The BMI Z-score of children with AA/AT genotype were significantly higher than that of their counterparts with the TT genotype (1.1±0.1 vs. 0.8±0.1, P=0.02). The concentration of triglyceride was 1.03±0.52 mmol/L among TT carrier and 1.13±0.68 mmol/L among AA/AT carrier (P=0.045). While, the concentrations of adiponectin were 18.0±0.4 μg/ml among carriers of TT and 16.2±0.7 μg/ml among subjects with AA/AT genotype (P=0.03). The level of glucose marginally increased in the AA/AT genotype subjects (4.67±0.40 mmol/L vs. 4.60±0.35 mmol/L, P=0.08). The evidence of association was reduced after adjustment for BMI (P=0.38 for triglyceride, P=0.20 for adiponectin and glucose). There was weak evidence of association between rs9939609 and other obesity-related metabolic traits including total cholesterol (3.92±0.03 mmol/L vs. 4.02±0.05 mmol/L, P=0.10), insulin (2.69±1.77 ng/ml vs. 3.12±2.91 ng/ml, P=0.14), and insulin resistance (HOMA-IR 0.56±0.03 vs. 0.66±0.05, P=0.10).ConclusionsGenetic variation in the FTO gene associates with obesity in Chinese children.

Project description:BACKGROUND:The risk of obesity is determined by complex interactions between genetic and environmental factors. Little research to date has investigated the interaction between gene and food intake. The aim of the current study is to explore the potential effect of fat mass and obesity-associated protein gene (FTO) rs9939609 and rs9930506 single nucleotide polymorphism (SNP) on the pattern of food intake in the Emirati population. METHODS:Adult healthy Emirati subjects with Body mass index (BMI) of 16-40 kg/m2 were included in the study. Genotyping for FTO rs9939609(A>T) and rs9930506(A>G) was performed using DNA from saliva samples. Subjects were categorized according to the WHO classification by calculating the BMI to compare different classes. Dietary intake was assessed by a sixty-one-item FFQ that estimated food and beverage intakes over the past year. The daily energy, macronutrient, and micronutrient consumption were computed. RESULTS:We included 169 subjects in the final analysis (mean age 30.49± 9.1years, 57.4% females). The mean BMI of the study population was 26.19 kg/m2. Both SNPs were in Hardy Weinberg Equilibrium. The rs9939609 AA genotype was significantly associated with higher BMI (p = 0.004); the effect was significant in females (p = 0.028), but not in males (p = 0.184). Carbohydrate intake was significantly higher in AA subjects with a trend of lower fat intake compared to other genotypes. The odds ratio for the AA was 3.78 in the fourth quartile and 2.67 for the A/T in the second quartile of total carbohydrate intake, considering the first quartile as a reference (95% CI = 1.017-14.1 and 1.03-6.88, respectively). Fat intake was significantly lower in the FTO rs9930506 GG subjects. The presence of FTO rs9930506 GG genotype decreased the fat intake in subjects with FTO rs9939609 AA (p = 0.037). CONCLUSIONS:The results of this study highlight the interaction of the FTO risk alleles on the food intake in Emirati subjects. The FTO rs9939609 AA subjects had higher carbohydrate and lower fat intake. The latter was accentuated in presence of rs9930506 GG genotype.

Project description:To evaluate the associations between six single-nucleotide polymorphisms (SNPs) in intron 1 of FTO and body mass index (BMI), a case-control association study of 2314 unrelated Mexican-Mestizo adult subjects was performed. The association between each SNP and BMI was tested using logistic and linear regression adjusted for age, gender, and ancestry and assuming additive, recessive, and dominant effects of the minor allele. Association analysis after BMI stratification showed that all five FTO SNPs (rs1121980, rs17817449, rs3751812, rs9930506, and rs17817449), were significantly associated with obesity class II/III under an additive model (P<0.05). Interestingly, we also documented a genetic model-dependent influence of gender on the effect of FTO variants on increased BMI. Two SNPs were specifically associated in males under a dominant model, while the remainder were associated with females under additive and recessive models (P<0.05). The SNP rs9930506 showed the highest increased in obesity risk in females (odds ratio = 4.4). Linear regression using BMI as a continuous trait also revealed differential FTO SNP contributions. Homozygous individuals for the risk alleles of rs17817449, rs3751812, and rs9930506 were on average 2.18 kg/m(2) heavier than homozygous for the wild-type alleles; rs1121980 and rs8044769 showed significant but less-strong effects on BMI (1.54 kg/m(2) and 0.9 kg/m(2), respectively). Remarkably, rs9930506 also exhibited positive interactions with age and BMI in a gender-dependent manner. Women carrying the minor allele of this variant have a significant increase in BMI by year (0.42 kg/m(2), P = 1.17 x 10(-10)). Linear regression haplotype analysis under an additive model, confirmed that the TGTGC haplotype harboring all five minor alleles, increased the BMI of carriers by 2.36 kg/m(2) (P = 1.15 x 10(-5)). Our data suggest that FTO SNPs make differential contributions to obesity risk and support the hypothesis that gender differences in the mechanisms involving these variants may contribute to disease development.

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FTO genotype is associated with phenotypic variability of body mass index.

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FTO genotype is associated with phenotypic variability of body mass index.

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