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RaptorX-Property: a web server for protein structure property prediction.
Wang, S, Li, W, Liu, S, Xu, J
Nucleic acids research. 2016;(W1):W430-5
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Abstract
RaptorX Property (http://raptorx2.uchicago.edu/StructurePropertyPred/predict/) is a web server predicting structure property of a protein sequence without using any templates. It outperforms other servers, especially for proteins without close homologs in PDB or with very sparse sequence profile (i.e. carries little evolutionary information). This server employs a powerful in-house deep learning model DeepCNF (Deep Convolutional Neural Fields) to predict secondary structure (SS), solvent accessibility (ACC) and disorder regions (DISO). DeepCNF not only models complex sequence-structure relationship by a deep hierarchical architecture, but also interdependency between adjacent property labels. Our experimental results show that, tested on CASP10, CASP11 and the other benchmarks, this server can obtain ∼84% Q3 accuracy for 3-state SS, ∼72% Q8 accuracy for 8-state SS, ∼66% Q3 accuracy for 3-state solvent accessibility, and ∼0.89 area under the ROC curve (AUC) for disorder prediction.
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Rare coding variants and X-linked loci associated with age at menarche.
Lunetta, KL, Day, FR, Sulem, P, Ruth, KS, Tung, JY, Hinds, DA, Esko, T, Elks, CE, Altmaier, E, He, C, et al
Nature communications. 2015;:7756
Abstract
More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only ∼3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency protein-coding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08-4.6%; effect sizes 0.08-1.25 years per allele; P<5 × 10(-8)). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P=9.4 × 10(-13)) and FAAH2 (rs5914101, P=4.9 × 10(-10)). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty-acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-year-later menarche (P=2.8 × 10(-11)), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain ∼0.5% variance, indicating that these overlooked sources of variation do not substantially explain the 'missing heritability' of this complex trait.
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Genetic variant in fat mass and obesity-associated gene associated with type 2 diabetes risk in Han Chinese.
Qian, Y, Liu, S, Lu, F, Li, H, Dong, M, Lin, Y, Du, J, Lin, Y, Gong, J, Jin, G, et al
BMC genetics. 2013;:86
Abstract
BACKGROUND Genome-wide association study (GWAS) has identified that rs8050136 C/A polymorphism in fat mass and obesity-associated gene (FTO) was associated with the risk of type 2 diabetes (T2D) in Europeans. But this association was abolished after adjustment for body mass index (BMI), suggesting that the effect of rs8050136 on T2D risk might be mediated by BMI in Europeans. However, the findings in subsequent studies were inconsistent among Asian populations. To determine whether rs8050136 polymorphism in FTO is independently associated with the risk of T2D in Chinese, we conducted a case-control study with 2,925 T2D patients and 3,281 controls in Han Chinese. RESULTS Logistic regression revealed that the A allele of rs8050136 was significantly associated with an increased risk of T2D, independent of BMI (odds ratio (OR) = 1.17, 95% confidence interval (95% CI) = 1.03-1.32, p = 0.016). Meta-analysis containing 10 reported studies and our data with a total of 15,819 cases and 18,314 controls further confirmed the association between rs8050136 polymorphism and T2D risk in East Asians (OR = 1.13, 95% CI = 1.07-1.19). CONCLUSIONS Our findings indicate that the genetic variant in FTO may contribute to T2D risk in Han Chinese and rs8050136 polymorphism may be a genetic marker for T2D susceptibility.
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Association of genetic variation in FTO with risk of obesity and type 2 diabetes with data from 96,551 East and South Asians.
Li, H, Kilpeläinen, TO, Liu, C, Zhu, J, Liu, Y, Hu, C, Yang, Z, Zhang, W, Bao, W, Cha, S, et al
Diabetologia. 2012;(4):981-95
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Abstract
AIMS/HYPOTHESIS FTO harbours the strongest known obesity-susceptibility locus in Europeans. While there is growing evidence for a role for FTO in obesity risk in Asians, its association with type 2 diabetes, independently of BMI, remains inconsistent. To test whether there is an association of the FTO locus with obesity and type 2 diabetes, we conducted a meta-analysis of 32 populations including 96,551 East and South Asians. METHODS All studies published on the association between FTO-rs9939609 (or proxy [r (2) > 0.98]) and BMI, obesity or type 2 diabetes in East or South Asians were invited. Each study group analysed their data according to a standardised analysis plan. Association with type 2 diabetes was also adjusted for BMI. Random-effects meta-analyses were performed to pool all effect sizes. RESULTS The FTO-rs9939609 minor allele increased risk of obesity by 1.25-fold/allele (p = 9.0 × 10(-19)), overweight by 1.13-fold/allele (p = 1.0 × 10(-11)) and type 2 diabetes by 1.15-fold/allele (p = 5.5 × 10(-8)). The association with type 2 diabetes was attenuated after adjustment for BMI (OR 1.10-fold/allele, p = 6.6 × 10(-5)). The FTO-rs9939609 minor allele increased BMI by 0.26 kg/m(2) per allele (p = 2.8 × 10(-17)), WHR by 0.003/allele (p = 1.2 × 10(-6)), and body fat percentage by 0.31%/allele (p = 0.0005). Associations were similar using dominant models. While the minor allele is less common in East Asians (12-20%) than South Asians (30-33%), the effect of FTO variation on obesity-related traits and type 2 diabetes was similar in the two populations. CONCLUSIONS/INTERPRETATION FTO is associated with increased risk of obesity and type 2 diabetes, with effect sizes similar in East and South Asians and similar to those observed in Europeans. Furthermore, FTO is also associated with type 2 diabetes independently of BMI.
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Physical activity attenuates the influence of FTO variants on obesity risk: a meta-analysis of 218,166 adults and 19,268 children.
Kilpeläinen, TO, Qi, L, Brage, S, Sharp, SJ, Sonestedt, E, Demerath, E, Ahmad, T, Mora, S, Kaakinen, M, Sandholt, CH, et al
PLoS medicine. 2011;(11):e1001116
Abstract
BACKGROUND The FTO gene harbors the strongest known susceptibility locus for obesity. While many individual studies have suggested that physical activity (PA) may attenuate the effect of FTO on obesity risk, other studies have not been able to confirm this interaction. To confirm or refute unambiguously whether PA attenuates the association of FTO with obesity risk, we meta-analyzed data from 45 studies of adults (n = 218,166) and nine studies of children and adolescents (n = 19,268). METHODS AND FINDINGS All studies identified to have data on the FTO rs9939609 variant (or any proxy [r(2)>0.8]) and PA were invited to participate, regardless of ethnicity or age of the participants. PA was standardized by categorizing it into a dichotomous variable (physically inactive versus active) in each study. Overall, 25% of adults and 13% of children were categorized as inactive. Interaction analyses were performed within each study by including the FTO×PA interaction term in an additive model, adjusting for age and sex. Subsequently, random effects meta-analysis was used to pool the interaction terms. In adults, the minor (A-) allele of rs9939609 increased the odds of obesity by 1.23-fold/allele (95% CI 1.20-1.26), but PA attenuated this effect (p(interaction) = 0.001). More specifically, the minor allele of rs9939609 increased the odds of obesity less in the physically active group (odds ratio = 1.22/allele, 95% CI 1.19-1.25) than in the inactive group (odds ratio = 1.30/allele, 95% CI 1.24-1.36). No such interaction was found in children and adolescents. CONCLUSIONS The association of the FTO risk allele with the odds of obesity is attenuated by 27% in physically active adults, highlighting the importance of PA in particular in those genetically predisposed to obesity.
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Meta-analysis added power to identify variants in FTO associated with type 2 diabetes and obesity in the Asian population.
Liu, Y, Liu, Z, Song, Y, Zhou, D, Zhang, D, Zhao, T, Chen, Z, Yu, L, Yang, Y, Feng, G, et al
Obesity (Silver Spring, Md.). 2010;(8):1619-24
Abstract
Several common variants in the intron 1 of FTO (fat mass and associated obesity) gene have been reliably associated with BMI and obesity in European populations. We analyzed two variants (rs9939609 and rs8050136) in 4,189 Chinese Han individuals and conducted a meta-analysis of published studies in Asian population to investigate whether these variants are associated with type 2 diabetes (T2D) and obesity in Asian population. In this study, both the minor allele A of rs9939609 and the minor allele A of rs805136 were associated with increased risk of T2D, independent of measures of BMI; the odds ratios (ORs) per copy of the risk allele were 1.19 for rs9939609 (95% confidence interval (CI), 1.04-1.37; P = 0.01) and 1.22 for rs8050136 (95% CI, 1.07-1.40; P = 0.004) after adjusting for age, sex, and BMI. Our results also showed association with risk of obesity (rs9939609: OR = 1.39 (95% CI 1.04-1.85), P = 0.02; rs8050136: OR = 1.45 (95% CI 1.09-1.93), P = 0.01) but no association with overweight. These results were consistent with the pooled results from our meta-analysis study (for diabetes, rs8050136, P = 1.3 x 10(-3); rs9939609, P = 9.8 x 10(-4); for obesity, rs8050136, P = 2.2 x 10(-7); rs9939609, P = 9.0 x 10(-9)). Our findings indicate that the two variants (rs9939609 and rs8050136) in the FTO gene contribute to obesity and T2D in the Asian populations.