The prevalence of obesity in children and adults in the United States has increased dramatically over the past decade. Besides environmental factors, genetic factors are known to play an important role in the pathogenesis of obesity. A number of genetic determinants of adult BMI have already been established through genome wide association studies. In this study, we examined 25 single nucleotide polymorphisms (SNPs) corresponding to thirteen previously reported genomic loci in 6,078 children with measures of BMI. Fifteen of these SNPs yielded at least nominally significant association to BMI, representing nine different loci including INSIG2, FTO, MC4R, TMEM18, GNPDA2, NEGR1, BDNF, KCTD15 and 1q25. Other loci revealed no evidence for association, namely at MTCH2, SH2B1, 12q13 and 3q27. For the 15 associated variants, the genotype score explained 1.12% of the total variation for BMI z-score. We conclude that among thirteen loci that have been reported to associate with adult BMI, at least nine also contribute to the determination of BMI in childhood as demonstrated by their associations in our pediatric cohort.
Obesity and related complications are major health burdens. Almost 700 million adults are currently obese globally and the prevalence is predicted to rise towards 2030. The sudden change of lifestyle with physical inactivity and excessive calorie intake undoubtedly have a major part of the epidemic development; however, some individuals seem to be more prone to be affected by an unhealthy lifestyle than others. Hence, genetic predisposition also has an essential role in determining disease susceptibility and response to lifestyle factors. Since the introduction of genome-wide association studies (GWAS), the success of identifying obesity susceptibility variants have increased, and a total of 32 variants have been identified associating genome-wide significantly with body mass index (BMI) and 18 with measures of fat distribution during four overall obesity GWAS waves. However, the immediate success of the GWAS approach has eased off, but the proportion of explained variance for BMI by the identified obesity variants remains low. This review suggests and discusses new initiatives to take GWAS of obesity to the next level, including gene–environment interactions as modulating/masking factors, low-frequent or rare variants and ways to address such analyses, and finally reflections about the applicability of epigenetic modifications when elucidating the genetic background of obesity.
obesity; genome-wide association studies; future perspectives; gene–environment interaction; low-frequent and rare variants; epigenetic modifications
Meta-analyses of population-based genome-wide association studies (GWAS) in adults have recently led to the detection of new genetic loci for obesity. Here we aimed to discover additional obesity loci in extremely obese children and adolescents. We also investigated if these results generalize by estimating the effects of these obesity loci in adults and in population-based samples including both children and adults. We jointly analysed two GWAS of 2,258 individuals and followed-up the best, according to lowest p-values, 44 single nucleotide polymorphisms (SNP) from 21 genomic regions in 3,141 individuals. After this DISCOVERY step, we explored if the findings derived from the extremely obese children and adolescents (10 SNPs from 5 genomic regions) generalized to (i) the population level and (ii) to adults by genotyping another 31,182 individuals (GENERALIZATION step). Apart from previously identified FTO, MC4R, and TMEM18, we detected two new loci for obesity: one in SDCCAG8 (serologically defined colon cancer antigen 8 gene; p = 1.85×10−8 in the DISCOVERY step) and one between TNKS (tankyrase, TRF1-interacting ankyrin-related ADP-ribose polymerase gene) and MSRA (methionine sulfoxide reductase A gene; p = 4.84×10−7), the latter finding being limited to children and adolescents as demonstrated in the GENERALIZATION step. The odds ratios for early-onset obesity were estimated at ∼1.10 per risk allele for both loci. Interestingly, the TNKS/MSRA locus has recently been found to be associated with adult waist circumference. In summary, we have completed a meta-analysis of two GWAS which both focus on extremely obese children and adolescents and replicated our findings in a large followed-up data set. We observed that genetic variants in or near FTO, MC4R, TMEM18, SDCCAG8, and TNKS/MSRA were robustly associated with early-onset obesity. We conclude that the currently known major common variants related to obesity overlap to a substantial degree between children and adults.
Genome-wide association studies (GWAS) have successfully contributed to the detection of genetic variants involved in body-weight regulation. We jointly analysed two GWAS for early-onset extreme obesity in 2,258 individuals of European origin and followed-up the findings in 3,141 individuals. Evidence for association of markers in two new genetic loci was shown (SDCCAG8 on chromosome 1q43–q44 and between TNKS/MSRA on chromosome 8p23.1). We also re-identified variants in or near FTO, MC4R, and TMEM18 to be associated with extreme obesity. In addition, we assessed the effect of the markers in 31,182 obese, lean, normal weight, and unselected individuals from population-based samples and showed that the variants near FTO, MC4R, TMEM18, and SDCCAG8 were consistently associated with obesity. For variants of TNKS/MSRA, the obesity association was limited to children and adolescents. In summary, we detected two new obesity loci and confirmed that the currently known major common variants related to obesity overlap to a substantial degree between children and adults.
Dyslipidemia, mainly characterized by high triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) levels, is an important etiological factor in the development of cardiovascular disease (CVD). Considering the relationship between childhood obesity and CVD risk, it would be worthwhile to evaluate whether previously identified lipid-related variants in adult subjects are associated with lipid variations in a childhood obesity study (n = 482). In an association analysis for 16 genome-wide association study (GWAS)-based candidate loci, we confirmed significant associations of a genetic predisposition to lipoprotein concentrations in a childhood obesity study. Having two loci (rs10503669 at LPL and rs16940212 at LIPC) that showed the strongest association with blood levels of TG and HDL-C, we calculated a genetic risk score (GRS), representing the sum of the risk alleles. It has been observed that increasing GRS is significantly associated with decreased HDL-C (effect size, -1.13 ± 0.07) compared to single nucleotide polymorphism combinations without two risk variants. In addition, a positive correlation was observed between allelic dosage score and risk allele (rs10503669 at LPL) on high TG levels (effect size, 10.89 ± 0.84). These two loci yielded consistent associations in our previous meta-analysis. Taken together, our findings demonstrate that the genetic architecture of circulating lipid levels (TG and HDL-C) overlap to a large extent in childhood as well as in adulthood. Post-GWAS functional characterization of these variants is further required to elucidate their pathophysiological roles and biological mechanisms.
childhood obesity; dyslipidemias; genetic risk score; genome-wide association study
Large-scale genome-wide association studies (GWAS) have identified many loci associated with body mass index (BMI), but few studies focused on obesity as a binary trait. Here we report the results of a GWAS and candidate SNP genotyping study of obesity, including extremely obese cases and never overweight controls as well as families segregating extreme obesity and thinness. We first performed a GWAS on 520 cases (BMI>35 kg/m2) and 540 control subjects (BMI<25 kg/m2), on measures of obesity and obesity-related traits. We subsequently followed up obesity-associated signals by genotyping the top ∼500 SNPs from GWAS in the combined sample of cases, controls and family members totaling 2,256 individuals. For the binary trait of obesity, we found 16 genome-wide significant signals within the FTO gene (strongest signal at rs17817449, P = 2.5×10−12). We next examined obesity-related quantitative traits (such as total body weight, waist circumference and waist to hip ratio), and detected genome-wide significant signals between waist to hip ratio and NRXN3 (rs11624704, P = 2.67×10−9), previously associated with body weight and fat distribution. Our study demonstrated how a relatively small sample ascertained through extreme phenotypes can detect genuine associations in a GWAS.
Epidemiological studies consistently show associations between asthma and obesity. Shared genetics may account for this association.
To identify genetic variants associated with both asthma and obesity.
Based on a literature search, we identified genes from: 1) Genome-wide association studies (GWAS) of Body Mass Index (BMI) (n=17 genes), 2) GWAS of asthma (n=14) and 3) candidate gene studies of BMI and asthma (n=7). We used GWAS data from the Childhood Asthma Management Program (CAMP) to analyze associations between single nucleotide polymorphisms (SNPs) in these genes and asthma (n=359 subjects) and BMI (n=537).
One top BMI GWAS SNP from the literature, rs10938397 near GNPDA2, was associated with both BMI (p=4 × 10−4) and asthma (p=0.03). Of the top asthma GWAS SNPs and the candidate gene SNPs, none was found to be associated with both BMI and asthma. Gene-based analyses that included all available SNPs in each gene found associations (p<0.05) with both phenotypes for several genes: NEGR1, ROBO1, DGKG, FAIM2, FTO and CHST8 among the BMI GWAS genes; ILRL1/IL18R1, DPP10, PDE4D, MYB, PDE10A, IL33 and especially PTPRD among the asthma GWAS genes; and PRKCA among the BMI and asthma candidate genes.
SNPs within several genes showed associations to BMI and asthma at a gene level, but none of these associations were significant after correction for multiple testing. Our analysis of known candidate genes reveals some evidence for shared genetics between asthma and obesity, but other shared genetic determinants are likely to be identified in novel loci.
Association; Asthma; BMI; Children; Genetics; GWAS; Obesity; Polymorphism; SNP
Recently an association was demonstrated between the single nucleotide polymorphism (SNP), rs9939609, within the FTO locus and obesity as a consequence of a genome wide association (GWA) study of type 2 diabetes in adults. We examined the effects of two perfect surrogates for this SNP plus 11 other SNPs at this locus with respect to our childhood obesity cohort, consisting of both Caucasians and African Americans (AA). Utilizing data from our ongoing GWA study in our cohort of 418 Caucasian obese children (BMI≥95th percentile), 2,270 Caucasian controls (BMI<95th percentile), 578 AA obese children and 1,424 AA controls, we investigated the association of the previously reported variation at the FTO locus with the childhood form of this disease in both ethnicities. The minor allele frequencies (MAF) of rs8050136 and rs3751812 (perfect surrogates for rs9939609 i.e. both r2 = 1) in the Caucasian cases were 0.448 and 0.443 respectively while they were 0.391 and 0.386 in Caucasian controls respectively, yielding for both an odds ratio (OR) of 1.27 (95% CI 1.08–1.47; P = 0.0022). Furthermore, the MAFs of rs8050136 and rs3751812 in the AA cases were 0.449 and 0.115 respectively while they were 0.436 and 0.090 in AA controls respectively, yielding an OR of 1.05 (95% CI 0.91–1.21; P = 0.49) and of 1.31 (95% CI 1.050–1.643; P = 0.017) respectively. Investigating all 13 SNPs present on the Illumina HumanHap550 BeadChip in this region of linkage disequilibrium, rs3751812 was the only SNP conferring significant risk in AA. We have therefore replicated and refined the association in an AA cohort and distilled a tag-SNP, rs3751812, which captures the ancestral origin of the actual mutation. As such, variants in the FTO gene confer a similar magnitude of risk of obesity to children as to their adult counterparts and appear to have a global impact.
Obesity is a well-established risk factor for endometrial cancer, the most common gynecologic malignancy. Recent genome-wide association studies (GWAS) have identified multiple genetic markers for obesity. The authors evaluated the association of obesity-related single nucleotide polymorphisms (SNPs) with endometrial cancer using GWAS data from their recently completed study, the Shanghai Endometrial Cancer Genetics Study, which comprised 832 endometrial cancer cases and 2,049 controls (1996–2005). Thirty-five SNPs previously associated with obesity or body mass index (BMI; weight (kg)/height (m)2) at a minimum significance level of ≤5 × 10−7 in the US National Human Genome Research Institute's GWAS catalog (http://genome.gov/gwastudies) and representing 26 unique loci were evaluated by either direct genotyping or imputation. The authors found that for 22 of the 26 unique loci tested (84.6%), the BMI-associated risk variants were present at a higher frequency in cases than in population controls (P = 0.0003). Multiple regression analysis showed that 9 of 35 BMI-associated variants, representing 7 loci, were significantly associated (P ≤ 0.05) with the risk of endometrial cancer; for all but 1 SNP, the direction of association was consistent with that found for BMI. For consistent SNPs, the allelic odds ratios ranged from 1.15 to 1.29. These 7 loci are in the SEC16B/RASAL, TMEM18, MSRA, SOX6, MTCH2, FTO, and MC4R genes. The associations persisted after adjustment for BMI, suggesting that genetic markers of obesity provide value in addition to BMI in predicting endometrial cancer risk.
body mass index; endometrial neoplasms; genetics; genome-wide association study; obesity; risk factors
Childhood obesity strongly predisposes to some adult diseases. Recently, genome-wide association (GWA) studies in Caucasians identified multiple single nucleotide polymorphisms (SNPs) associated with BMI and obesity. The associations of those SNPs with BMI and obesity among other ethnicities are not fully described, especially in children. Among those previously identified SNPs, we selected six (rs7138803, rs1805081, rs6499640, rs17782313, rs6265, and rs10938397, in or near obesity-related genes FAIM2, NPC1, FTO, MC4R, BDNF, and GNPDA2, respectively) because of the relatively high minor allele frequencies in Chinese individuals and tested the associations of the SNPs with BMI and obesity in Chinese children.
RESEARCH DESIGN AND METHODS
We investigated the associations of these SNPs with BMI and obesity in school-aged children. A total of 3,503 children participated in the study, including 1,229 obese, 655 overweight, and 1,619 normal-weight children (diagnosed by the Chinese age- and sex-specific BMI cutoffs).
After age and sex adjustment and correction for multiple testing, the SNPs rs17782313, rs6265, and rs10938397 were associated with BMI (P = 1.0 × 10−5, 0.038, and 0.00093, respectively) and also obesity (P = 5.0 × 10−6, 0.043, and 0.00085, respectively) in the Chinese children. The SNPs rs17782313 and rs10938397 were also significantly associated with waist circumference, waist-to-height ratio, and fat mass percentage.
Results of this study support obesity-related genes in adults as important genes for BMI variation in children and suggest that some SNPs identified by GWA studies in Caucasians also confer risk for obesity in Chinese children.
Childhood obesity has important consequences for health and wellbeing both during childhood and also in later adult life. The rising prevalence of childhood obesity poses a major public health challenge in both developed and developing countries by increasing the burden of chronic non-communicable diseases. Despite the urgent need for effective preventative strategies, there remains disagreement over its definition due to a lack of evidence on the optimal cut-offs linking childhood BMI to disease risks, and limited evidence on the most effective components of interventions to prevent childhood obesity. This article reviews the trends in childhood obesity, its genetic, nutritional and other risk factors, and preventative and treatment strategies. Particular emphasis is given to early-onset obesity in pre-school children, which, as a precursor to later childhood and adult obesity, provides insights into the developmental and genetic origins of obesity and also offers the potential for early preventative approaches with long-lasting benefits.
Obesity is a major risk factor for type 2 diabetes. Recent genome-wide association (GWA) studies have identified multiple loci robustly associated with BMI and risk of obesity. However, information on their associations with type 2 diabetes is limited. Such information could help increase our understanding of the link between obesity and type 2 diabetes. We examined the associations of 12 obesity susceptibility loci, individually and in combination, with risk of type 2 diabetes in the population-based European Prospective Investigation of Cancer (EPIC) Norfolk cohort.
We genotyped 12 SNPs, identified by GWA studies of BMI, in 20,428 individuals (aged 39–79 years at baseline) with an average follow-up of 12.9 years, during which 729 individuals developed type 2 diabetes. A genetic predisposition score was calculated by adding the BMI-increasing alleles across the 12 SNPs. Associations with incidence of type 2 diabetes were examined by logistic regression models.
Of the 12 SNPs, eight showed a trend with increased risk of type 2 diabetes, consistent with their BMI-increasing effects. Each additional BMI-increasing allele in the genetic predisposition score was associated with a 4% increased odds of developing type 2 diabetes (OR 1.041, 95% CI 1.005–1.078; p = 0.02). Adjustment for BMI completely abolished the association with incident type 2 diabetes (OR 1.003, 95% CI 0.967–1.039; p = 0.89).
The genetic predisposition to obesity leads to increased risk of developing type 2 diabetes, which is completely mediated by its obesity-predisposing effect.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-011-2044-5) contains supplementary material, which is available to authorized users.
Genetic predisposition; Genome-wide association studies; Obesity; Type 2 diabetes
Recent genome-wide association (GWA) analyses have identified common single nucleotide polymorphisms (SNPs) that are associated with obesity. However, the reported genetic variation in obesity explains only a minor fraction of the total genetic variation expected to be present in the population. Thus many genetic variants controlling obesity remain to be identified. The aim of this study was to use GWA followed by multiple stepwise validations to identify additional genes associated with obesity.
We performed a GWA analysis in 164 morbidly obese subjects (BMI:body mass index > 40 kg/m2) and 163 Swedish subjects (> 45 years) who had always been lean. The 700 SNPs displaying the strongest association with obesity in the GWA were analyzed in a second cohort comprising 460 morbidly obese subjects and 247 consistently lean Swedish adults. 23 SNPs remained significantly associated with obesity (nominal P< 0.05) and were in a step-wise manner followed up in five additional cohorts from Sweden, France, and Germany together comprising 4214 obese and 5417 lean or population-based control individuals. Three samples, n = 4133, were used to investigate the population-based associations with BMI. Gene expression in abdominal subcutaneous adipose tissue in relation to obesity was investigated for14 adults.
Potassium channel, calcium activated, large conductance, subfamily M, alpha member (KCNMA1) rs2116830*G and BDNF rs988712*G were associated with obesity in five of six investigated case-control cohorts. In meta-analysis of 4838 obese and 5827 control subjects we obtained genome-wide significant allelic association with obesity for KCNMA1 rs2116830*G with P = 2.82 × 10-10 and an odds ratio (OR) based on cases vs controls of 1.26 [95% C.I. 1.12-1.41] and for BDNF rs988712*G with P = 5.2 × 10-17and an OR of 1.36 [95% C.I. 1.20-1.55]. KCNMA1 rs2116830*G was not associated with BMI in the population-based samples. Adipose tissue (P = 0.0001) and fat cell (P = 0.04) expression of KCNMA1 was increased in obesity.
We have identified KCNMA1 as a new susceptibility locus for obesity, and confirmed the association of the BDNF locus at the genome-wide significant level.
Genome-wide association studies (GWAS) analyze the genetic component of a phenotype or the etiology of a disease. Despite the success of many GWAS, little progress has been made in uncovering the underlying mechanisms for many diseases. The use of metabolomics as a readout of molecular phenotypes has enabled the discovery of previously undetected associations between diseases and signaling and metabolic pathways. In addition, combining GWAS and metabolomic information allows the simultaneous analysis of the genetic and environmental impacts on homeostasis. Most success has been seen in metabolic diseases such as diabetes, obesity and dyslipidemia. Recently, associations between loci such as FADS1, ELOVL2 or SLC16A9 and lipid concentrations have been explained by GWAS with metabolomics. Combining GWAS with metabolomics (mGWAS) provides the robust and quantitative information required for the development of specific diagnostics and targeted drugs. This review discusses the limitations of GWAS and presents examples of how metabolomics can overcome these limitations with the focus on metabolic diseases.
complex disease; genetics; metabolomics; metabolic traits; pathway inference
Obesity constitutes a major health problem in the United States. Hypertension, atherosclerosis, coronary artery disease, diabetes and gout are often associated with obesity and may be a direct result of persistent obesity in adult life.
Obesity frequently has its beginnings in childhood and adolescence. Unfortunately, obesity which develops in early life is a progressive problem. Eighty per cent of overweight children and adolescents will continue to be overweight as adults.12 Furthermore, adults with a history of obesity in childhood are the most resistant to treatment.
Recent studies have shown there is more than one body constitutional type among obese adolescents. Obese adolescents tend to eat less than non-obese controls. While obesity may be found to have many different causative factors, efforts to control this disease may be most successful in the area of primary prevention.
The prevalence of childhood obesity has increased dramatically during the past decades all over the world. The majority of obesity in adulthood has its origins in childhood which makes obesity a pediatric concern and the period when interventions should be done. Obesity is associated with increased morbidity and mortality in adult life and several adverse consequences in childhood like insulin resistance, type 2 diabetes, dyslipidemia, polycystic ovarian syndrome, pulmonary and orthopedic disorders and psychological problems. Both genetic and environmental factors play a role in the development of obesity. Prevention of obesity is critical, since effective treatment of this disease is limited. Food management and increased physical activity must be encouraged, promoted, and prioritized to protect children.
Conflict of interest:None declared.
childhood; obesity; incidence; prevention; treatment; complications
Childhood overweight and obesity have reached epidemic proportions worldwide, and the increase in weight-associated co-morbidities including premature type 2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular disease will soon become major healthcare and economic problems. A number of studies now indicate that the childhood obesity epidemic which has emerged during the past 30 years is a complex multi-factorial disease resulting from interaction of susceptibility genes with an obesogenic environment. This review will focus on gene-diet interactions suspected of having a prominent role in promoting childhood obesity. In particular, the specific genes that will be presented (FTO, MC4R, and NPC1) have recently been associated with childhood obesity through a genome-wide association study (GWAS) and were shown to interact with nutritional components to increase weight gain. Although a fourth gene (APOA2) has not yet been associated with childhood obesity, this review will also present information on what now represents the best characterized gene-diet interaction in promoting weight gain.
Adolescent; childhood; gene-diet; high-fat; nutrition; obesity; overweight.
Recent genome-wide association (GWA) studies have identified 18 genetic loci for obesity. Using directly observed and imputed GWA genotyping data on approximately 5,000 Chinese women (1996–2007), the authors evaluated 17 single nucleotide polymorphisms (SNPs) that represent 17 distinct obesity loci. Two SNPs near the BAT2 and MC4R genes and 3 SNPs within the FTO, SEC16B, and SH2B1 genes were significantly associated with body mass index (weight (kg)/height (m)2), body weight, and the prevalence of obesity. The per-allele increase in body mass index ranged from 0.16 units (BAT2) to 0.38 units (SH2B1). Odds ratios for obesity ranged from 1.46 (95% confidence interval (CI): 1.12, 1.92) for BAT2 to 2.16 (95% CI: 1.39, 3.37) for MC4R. A genetic risk score calculated by summing the number of risk-increasing alleles that each woman carried at these 5 loci was significantly associated with the prevalence of obesity. Women carrying 5 or more risk alleles had a 3.13-fold (95% CI: 2.06, 4.77) higher prevalence of obesity than women carrying 1 or no risk alleles. Results from this study extend some previous GWA findings to Chinese women and show the need for additional studies to identify susceptibility loci in Chinese and other Asian populations.
body mass index; genome-wide association study; linkage disequilibrium; obesity; polymorphism, genetic; women
Large-scale genome-wide association (GWA) studies have thus far identified 16 loci incontrovertibly associated with obesity-related traits in adults. We examined associations of variants in these loci with anthropometric traits in children and adolescents.
RESEARCH DESIGN AND METHODS
Seventeen variants representing 16 obesity susceptibility loci were genotyped in 1,252 children (mean ± SD age 9.7 ± 0.4 years) and 790 adolescents (15.5 ± 0.5 years) from the European Youth Heart Study (EYHS). We tested for association of individual variants and a genetic predisposition score (GPS-17), calculated by summing the number of effect alleles, with anthropometric traits. For 13 variants, summary statistics for associations with BMI were meta-analyzed with previously reported data (Ntotal = 13,071 children and adolescents).
In EYHS, 15 variants showed associations or trends with anthropometric traits that were directionally consistent with earlier reports in adults. The meta-analysis showed directionally consistent associations with BMI for all 13 variants, of which 9 were significant (0.033–0.098 SD/allele; P < 0.05). The near-TMEM18 variant had the strongest effect (0.098 SD/allele P = 8.5 × 10−11). Effect sizes for BMI tended to be more pronounced in children and adolescents than reported earlier in adults for variants in or near SEC16B, TMEM18, and KCTD15, (0.028–0.035 SD/allele higher) and less pronounced for rs925946 in BDNF (0.028 SD/allele lower). Each additional effect allele in the GPS-17 was associated with an increase of 0.034 SD in BMI (P = 3.6 × 10−5), 0.039 SD, in sum of skinfolds (P = 1.7 × 10−7), and 0.022 SD in waist circumference (P = 1.7 × 10−4), which is comparable with reported results in adults (0.039 SD/allele for BMI and 0.033 SD/allele for waist circumference).
Most obesity susceptibility loci identified by GWA studies in adults are already associated with anthropometric traits in children/adolescents. Whereas the association of some variants may differ with age, the cumulative effect size is similar.
Obesity is characterized as an excess accumulation of body fat resulting from a positive energy balance. It is the major risk factor for type 2 diabetes (T2D). The evidence for familial aggregation of obesity and its associated metabolic diseases is substantial. To date, about 150 genetic loci identified in genome-wide association studies (GWAS) are linked with obesity and T2D, each accounting for only a small proportion of the predicted heritability. However, the percentage of overall trait variance explained by these associated loci is modest (~5–10% for T2D, ~2% for BMI). The lack of powerful genetic associations suggests that heritability is not entirely attributable to gene variations. Some of the familial aggregation as well as many of the effects of environmental exposures, may reflect epigenetic processes. This review summarizes our current knowledge on the genetic basis to individual risk of obesity and T2D, and explores the potential role of epigenetic contribution.
ADCY3, adenylate cyclase 3; AQP9, aquaporin 9; BDNF, brain-derived neurotrophic factor; CDKAL1, CDK5 regulatory subunit associated protein 1-like 1; CPEB4, cytoplasmic polyadenylation element binding protein 4; DUSP8, dual specificity phosphatase 8; DUSP22, dual specificity phosphatase 22; GALNT10, UDP-N-acetyl-alpha-d-galactosamine:polypeptide N-acetylgalactosaminyltransferase 10 (GalNAc-T10); GIPR, gastric inhibitory polypeptide receptor; GNPDA2, glucosamine-6-phosphate deaminase 2; GP2, glycoprotein 2 (zymogen granule membrane); HIPK3, homeodomain interacting protein kinase 3; IFI16, interferon, gamma-inducible protein 16; KCNQ1, potassium voltage-gated channel, KQT-like subfamily, member 1; KLHL32, kelch-like family member 32; LEPR, leptin receptor; MAP2K4, mitogen-activated protein kinase kinase 4; MAP2K5, mitogen-activated protein kinase kinase 5; MIR148A, microRNA 148a; MMP9, matrix metallopeptidase 9 (gelatinase B, 92 kDa gelatinase, 92 kDa type IV collagenase); MNDA, myeloid cell nuclear differentiation antigen; NFE2L3, nuclear factor, erythroid 2-like 3; PACS1, phosphofurin acidic cluster sorting protein 1; PAX6, paired box gene 6; PCSK1, proprotein convertase subtilisin/kexin type 1; PGC1α, peroxisome proliferative activated receptor, gamma, coactivator 1 alpha, PM2OD1; PRKCH, protein kinase C, eta; PRKD1, protein kinase D1; PRKG1, protein kinase, cGMP-dependent, type I; QPCTL, glutaminyl-peptide cyclotransferase-like; RBJ, DnaJ (Hsp40) homolog, subfamily C, member 27; RFC5, replication factor C (activator 1) 5; RMST, rhabdomyosarcoma 2 associated transcript (non-protein coding); SEC16B, SEC16 homolog B; TFAP2B, transcription factor AP-2 beta (activating enhancer binding protein 2 beta); TNNI3, troponin I type 3 (cardiac); TNNT1, troponin T type 1 (skeletal, slow); Obesity; Type 2 diabetes; GWAS; Positional cloning; Epigenetics
To investigate the genetic architecture of severe obesity, we performed a genome-wide association study of 775 cases and 3197 unascertained controls at ∼550 000 markers across the autosomal genome. We found convincing association to the previously described locus including the FTO gene. We also found evidence of association at a further six of 12 other loci previously reported to influence body mass index (BMI) in the general population and one of three associations to severe childhood and adult obesity and that cases have a higher proportion of risk-conferring alleles than controls. We found no evidence of homozygosity at any locus due to identity-by-descent associating with phenotype which would be indicative of rare, penetrant alleles, nor was there excess genome-wide homozygosity in cases relative to controls. Our results suggest that variants influencing BMI also contribute to severe obesity, a condition at the extreme of the phenotypic spectrum rather than a distinct condition.
West Virginia is a state at the forefront of the obesity epidemic and one that is experiencing immense health and economic costs as a result. The childhood obesity research discussed in this article was conducted over the past 10 years through 4 projects that range from a school-based cardiovascular risk screening program to an evaluation of state legislation targeting childhood obesity via modifications in the school environment. In the course of these projects, we have collected BMI and other health indices on students, provided feedback to students and their parents, and assessed the obesity and health-related beliefs of West Virginians through individual and focus-group interviews and questionnaires. Our work has been accomplished by using an active-consent process, and BMI has typically been only 1 component of the comprehensive health data we collect and feedback we provide. Collaboration with state and local partners and regular dissemination of our findings have been key elements of the approach taken. The research and policy implications of our findings and approach are discussed.
childhood obesity; body mass index; school-based screenings; perceptions
Obesity is a major health problem. Although heritability is substantial, genetic mechanisms predisposing to obesity are not very well understood. We have performed a genome wide association study (GWA) for early onset (extreme) obesity.
a) GWA (Genome-Wide Human SNP Array 5.0 comprising 440,794 single nucleotide polymorphisms) for early onset extreme obesity based on 487 extremely obese young German individuals and 442 healthy lean German controls; b) confirmatory analyses on 644 independent families with at least one obese offspring and both parents. We aimed to identify and subsequently confirm the 15 SNPs (minor allele frequency ≥10%) with the lowest p-values of the GWA by four genetic models: additive, recessive, dominant and allelic. Six single nucleotide polymorphisms (SNPs) in FTO (fat mass and obesity associated gene) within one linkage disequilibrium (LD) block including the GWA SNP rendering the lowest p-value (rs1121980; log-additive model: nominal p = 1.13×10−7, corrected p = 0.0494; odds ratio (OR)CT 1.67, 95% confidence interval (CI) 1.22–2.27; ORTT 2.76, 95% CI 1.88–4.03) belonged to the 15 SNPs showing the strongest evidence for association with obesity. For confirmation we genotyped 11 of these in the 644 independent families (of the six FTO SNPs we chose only two representing the LD bock). For both FTO SNPs the initial association was confirmed (both Bonferroni corrected p<0.01). However, none of the nine non-FTO SNPs revealed significant transmission disequilibrium.
Our GWA for extreme early onset obesity substantiates that variation in FTO strongly contributes to early onset obesity. This is a further proof of concept for GWA to detect genes relevant for highly complex phenotypes. We concurrently show that nine additional SNPs with initially low p-values in the GWA were not confirmed in our family study, thus suggesting that of the best 15 SNPs in the GWA only the FTO SNPs represent true positive findings.
Genetic variants responsible for susceptibility to obesity and its comorbidities among Hispanic children have not been identified. The VIVA LA FAMILIA Study was designed to genetically map childhood obesity and associated biological processes in the Hispanic population. A genome-wide association study (GWAS) entailed genotyping 1.1 million single nucleotide polymorphisms (SNPs) using the Illumina Infinium technology in 815 children. Measured genotype analysis was performed between genetic markers and obesity-related traits i.e., anthropometry, body composition, growth, metabolites, hormones, inflammation, diet, energy expenditure, substrate utilization and physical activity. Identified genome-wide significant loci: 1) corroborated genes implicated in other studies (MTNR1B, ZNF259/APOA5, XPA/FOXE1 (TTF-2), DARC, CCR3, ABO); 2) localized novel genes in plausible biological pathways (PCSK2, ARHGAP11A, CHRNA3); and 3) revealed novel genes with unknown function in obesity pathogenesis (MATK, COL4A1). Salient findings include a nonsynonymous SNP (rs1056513) in INADL (p = 1.2E-07) for weight; an intronic variant in MTNR1B associated with fasting glucose (p = 3.7E-08); variants in the APOA5-ZNF259 region associated with triglycerides (p = 2.5-4.8E-08); an intronic variant in PCSK2 associated with total antioxidants (p = 7.6E-08); a block of 23 SNPs in XPA/FOXE1 (TTF-2) associated with serum TSH (p = 5.5E-08 to 1.0E-09); a nonsynonymous SNP (p = 1.3E-21), an intronic SNP (p = 3.6E-13) in DARC identified for MCP-1; an intronic variant in ARHGAP11A associated with sleep duration (p = 5.0E-08); and, after adjusting for body weight, variants in MATK for total energy expenditure (p = 2.7E-08) and in CHRNA3 for sleeping energy expenditure (p = 6.0E-08). Unprecedented phenotyping and high-density SNP genotyping enabled localization of novel genetic loci associated with the pathophysiology of childhood obesity.
Obesity is increasing at an alarming rate throughout the world. Today it is estimated that there are more than 300 million obese people world-wide. Obesity is a condition of excess body fat often associated with a large number of debilitating and life-threatening disorders. It is still a matter of debate as to how to define obesity in young people. Overweight children have an increased risk of being overweight as adults. Genetics, behavior, and family environment play a role in childhood overweight. Childhood overweight increases the risk for certain medical and psychological conditions. Encourage overweight children to expand high energy activity, minimize low energy activity (screen watching), and develop healthful eating habits. Breast feeding is protective against obesity. Diet restriction is not recommended in very young children. Children are to be watched for gain in height rather than reduction in weight. Weight reduction of less than 10% is a normal variation, not significant in obesity.
Obesity; overweight; skins fold thickness; body mass index; WHO
Obesity causes severe healthcare problem worldwide leading to numerous diseases, such as cardiovascular diseases and diabetes mellitus. Previous Genome-Wide Association Study (GWAS) identified an association between a single nucleotide polymorphism (SNP) rs7138803, on chromosome 12q13 and obesity in European Caucasians. Since the genetic architecture governing the obesity may vary among different populations, we investigate the variant rs7138803 in Chinese population to find out whether it is associated with obesity.
A population-based cohort association study was carried out using the High Resolution Melt (HRM) method with 1851 participants. The association between rs7138803 genotypes and body mass index (BMI) was modeled with a general linear model, and a case–control study for the association between rs7138803 genotypes and obesity was performed using Pearson’s χ2 test. There was no indication of a deviation from Hardy-Weinberg equilibrium (HWE p value = 0.51) in our sample.
No association was detected between SNP rs7138803 and BMI in our Chinese Han population with a P value of 0.51. SNP rs7138803 was found to be not associated with common forms of obesity after adjusting for age and sex in the Chinese population. SNP rs7138803 was not associated with other obesity related traits, including T2DM, hypertension, lipid profiles, and ischemic stroke.
Our data suggest that the rs7138803 exerts no significant effect on obesity in Chinese Han population. Larger cohorts may be more appropriate to detect an effect of this SNP on common obesity.
FAIM2; Single nucleotide polymorphism; Obesity susceptibility