FTO genotype and aging: pleiotropic longitudinal effects on adiposity, brain function, impulsivity and diet

Chuang, Yi‐Fang; Tanaka, Toshiko; Beason‐Held, Lori L.; An, Yang; Terracciano, Antonio; Sutin, Angelina R.; Kraut, Michael A.; Singleton, Andrew B.; Resnick, Susan M.; Thambisetty, Madhav

doi:10.1038/mp.2014.49

Cited by 62 publications

(43 citation statements)

References 38 publications

(37 reference statements)

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“…In this line of evidence, we found that FTO variants associated with reduced longitudinal functioning in the medial prefrontal cortex and this reduction correlated with higher rates of impulsivity, behavioral disinhibition, and risky decision-making, which are common symptoms in BD (Chuang et al, 2015). These FTO-associated changes in brain-behavior relationship lead us to hypothesize that the link between BD symptomatology and eating behavior (particularly the way in which eating is controlled) could be a process modulated by FTO genetic variants.…”

Section: Discussionsupporting

confidence: 53%

“…In this line of evidence, we found that FTO variants associated with BMI only remained in BD patients, even when the BDC group had higher rates of obesity, which suggests that the effect of these variants modulating BMI could be higher in BD patients than in non‐BD obese individuals. Supporting this result, a neuro‐image study recently reported that carriers of FTO ‐obesity risk variants have a reduced longitudinal functioning in the medial prefrontal cortex and this reduction correlated with higher rates of impulsivity, behavioral disinhibition, and risky decision‐making, which are common symptoms in BD (Chuang et al., ). These FTO ‐associated changes in brain‐behavior relationship lead us to hypothesize that the link between BD symptomatology and eating behavior (particularly the way in which eating is controlled) could be a process modulated by FTO genetic variants.…”

Section: Discussionmentioning

confidence: 79%

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Differential effects on neurodevelopment of FTO variants in obesity and bipolar disorder suggested by in silico prediction of functional impact: An analysis in Mexican population

et al. 2019

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Introduction Several studies indicate that polygenic obesity is linked to fat‐mass and obesity‐associated ( FTO ) genetic variants. Nevertheless, the link between variants in FTO and mental disorders has been barely explored. The present work aims to determine whether FTO genetic variants are associated with bipolar disorder and obesity, and to perform an in silico prediction of variant‐dependent functional impact on the developing brain transcriptome. Methods Four hundred and forty‐six Mexican mestizos were included in a genetic association analysis. SNP ‐sequence kernel association test and linear mixed models were implemented for genetic association assessment. For functional impact prediction, we analyzed the mapping of regulatory elements, the modification of binding sites of transcription factors and the expression of transcription factors in the brain developing transcriptome, searching on different databases. Results In the set‐based analysis, we found different associated regions to BD (bipolar disorder) and obesity. The promoter flanking region of FTO intron 1 was associated with differential effects on BMI , while intron 2 of RPGRIP 1L and FTO upstream regions were associated with BD . The prediction analysis showed that FTO BD ‐associated variants disturb binding sites of SP 1 and SP 2; obesity‐associated variants, on the other hand, disturb binding sites of FOXP 1, which are transcription factors highly expressed during prenatal development stages of the brain. Conclusion Our results suggest a possible effect of FTO variants on neurodevelopment in obesity and bipolar disorder, which gives new insights into the molecular mechanism underlying this association.

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Section: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 79%

Differential effects on neurodevelopment of FTO variants in obesity and bipolar disorder suggested by in silico prediction of functional impact: An analysis in Mexican population

et al. 2019

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“…Subjects with one or more risk alleles of the FTO have also been proposed to develop poorer eating behaviors and a higher intake of high-fat foods or refined starches, which may be associated with BMI; whereas subjects with the nonrisk TT genotype rs1421085 may benefit from improving their attitude in terms of their self-regulation score (subscale score of dietary restraint) when attempting weight reduction (Harbron et al, 2014). SNP rs1421085 showed dosedependent incremental increase in BMI during aging, consistent with reduced brain function in regions intrinsic to impulse control and taste responsiveness (Chuang et al, 2015).…”

Section: Discussionmentioning

confidence: 91%

Genetic variation of FTO: rs1421085 T>C, rs8057044 G>A, rs9939609 T>A, and copy number (CNV) in Mexican Mayan school‐aged children with obesity/overweight and with normal weight

González-Herrera

Zavala-Castro

Ayala-Cáceres

et al. 2018

American J Hum Biol

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Objectives Genetic variation of the fat mass and obesity associated gene (FTO) has been identified as a risk factor for obesity and obesity traits. Distribution of FTO single nutleotide polymorphisms (SNPs) rs1421085T>C, rs9939609T>A, rs8057044G>A and copy number variation (CNV) was evaluated in association with childhood obesity or overweight status in children with Mayan ethnicity. Methods We included 318 school‐aged children with obesity or overweight status (body mass index [BMI]: >85th percentile) and 303 children with normal weight (BMI: 15th‐85th percentile). Genotyping was performed using real‐time polymerase chain reaction (RT‐PCR) with TaqMan probes. The cross‐sectional study was carried out using univariate and multivariate logistic regression models adjusted for gender. Results FTO‐SNP rs1421085 showed significant differences between children with obesity and children with normal weight for the heterozygous genotype (P = 0.003) and for allele frequencies (P = 0.023). Adjusting by gender, significant differences were found in frequencies of the hetezygous genotype of SNPs rs9939609 (P = 0.023) and rs1421085 (P = 0.003) as well as in allele frequencies (P = 0.042 and P = 0.013, respectively) between girls with obesity and girls without obesity. In contrast, SNP rs8057044 was significantly different only between heterozygous overweight versus normal weight boys (P = 0.035) and for the allele frequency of rs8057044 (P = 0.021). The mean relative CNV was significantly higher in male overweight children than in boys with normal weight (P = 0.000). Conclusions The FTO SNP rs1421085 is a genetic factor associated with obesity in Mayan school‐aged children. FTO SNPs rs1421085 and rs9939609 affect genetic susceptibility for obesity only in girls, whereas, SNP rs8057044 and CNV are associated with overweight status only in boys.

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“…Firstly, many genes are known to be pleiotropic, i.e. a single gene can affect many traits [18]. Transcription factors are a good example of this [19] but there are many other examples [20].…”

Section: Resultsmentioning

confidence: 99%

An additional k-means clustering step improves the biological features of WGCNA gene co-expression networks

et al. 2017

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BackgroundWeighted Gene Co-expression Network Analysis (WGCNA) is a widely used R software package for the generation of gene co-expression networks (GCN). WGCNA generates both a GCN and a derived partitioning of clusters of genes (modules). We propose k-means clustering as an additional processing step to conventional WGCNA, which we have implemented in the R package km2gcn (k-means to gene co-expression network, https://github.com/juanbot/km2gcn).ResultsWe assessed our method on networks created from UKBEC data (10 different human brain tissues), on networks created from GTEx data (42 human tissues, including 13 brain tissues), and on simulated networks derived from GTEx data. We observed substantially improved module properties, including: (1) few or zero misplaced genes; (2) increased counts of replicable clusters in alternate tissues (x3.1 on average); (3) improved enrichment of Gene Ontology terms (seen in 48/52 GCNs) (4) improved cell type enrichment signals (seen in 21/23 brain GCNs); and (5) more accurate partitions in simulated data according to a range of similarity indices.ConclusionsThe results obtained from our investigations indicate that our k-means method, applied as an adjunct to standard WGCNA, results in better network partitions. These improved partitions enable more fruitful downstream analyses, as gene modules are more biologically meaningful.Electronic supplementary materialThe online version of this article (doi:10.1186/s12918-017-0420-6) contains supplementary material, which is available to authorized users.

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FTO genotype and aging: pleiotropic longitudinal effects on adiposity, brain function, impulsivity and diet

Cited by 62 publications

References 38 publications

Differential effects on neurodevelopment of FTO variants in obesity and bipolar disorder suggested by in silico prediction of functional impact: An analysis in Mexican population

Differential effects on neurodevelopment of FTO variants in obesity and bipolar disorder suggested by in silico prediction of functional impact: An analysis in Mexican population

Genetic variation of FTO: rs1421085 T>C, rs8057044 G>A, rs9939609 T>A, and copy number (CNV) in Mexican Mayan school‐aged children with obesity/overweight and with normal weight

An additional k-means clustering step improves the biological features of WGCNA gene co-expression networks

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