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
Date
2019
Journal Title
Journal ISSN
Volume Title
Publisher
John Wileyi & Sons
Abstract
Description
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 deter‐ mine 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 predic‐ tion, 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 (bipo‐ lar disorder) and obesity. The promoter flanking region of FTO intron 1 was associ‐ ated 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‐asso‐
ciated 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.
Conclusion: Our results suggest a possible effect of FTO variants on neurodevelop‐
ment in obesity and bipolar disorder, which gives new insights into the molecular
mechanism underlying this association.