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Brain Behav. 2019 Apr 29:e01249. doi: 10.1002/brb3.1249. [Epub ahead of print]

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.

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Center of Advanced Neurosciences, Department of Psychiatry, Autonomous University of Nuevo Leon, Hospital Universitario "Dr. José Eleuterio González", Monterrey, Mexico.
Laboratory of Genomics of Psychiatric and Neurodegenerative Diseases, National Institute of Genomic Medicine, Mexico City, Mexico.
Children's Psychiatric Hospital "Dr. Juan N. Navarro", Psychiatric Attention Services, Mexico City, Mexico.
Department of Psychiatric Genetics, Clinical Investigations, National Institute of Psychiatry Ramón de la Fuente Muñiz, Mexico City, Mexico.
Multidisciplinary Academic Division of Comalcalco, Universidad Juárez Autónoma de Tabasco, Comalcalco, Tabasco, Mexico.
Academic Division of Health Sciences, Autonomous University of Tabasco, Villahermosa, Tabasco, Mexico.
Department of Clinical Research, Carracci Medical Group, Mexico City, Mexico.
Center of Emphasis in Neurosciences, Health Sciences Center, Texas Tech University, El Paso, Texas, USA.
Multidisciplinary Academic Division of Jalpa de Mendez, Universidad Juárez Autónoma de Tabasco, Comalcalco, Tabasco, Mexico.
General Hospital of Yajalón "Manuel Velasco Siles", Ministry of Health of Chiapas, Yajalón, Chiapas, Mexico.



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.


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.


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 RPGRIP1L and FTO upstream regions were associated with BD. The prediction analysis showed that FTO BD-associated variants disturb binding sites of SP1 and SP2; obesity-associated variants, on the other hand, disturb binding sites of FOXP1, which are transcription factors highly expressed during prenatal development stages of the brain.


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.


FTO variants; bipolar disorder; in silico functional prediction; neurodevelopment

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