Open AccessDifferential effects on neurodevelopment of FTO variants in obesity and bipolar disorder suggested by in silico prediction of functional impact: An analysis in Mexican population
Author(s) -
SaucedoUribe Erasmo,
GenisMendoza Alma Delia,
DíazAnzaldúa Adriana,
MartínezMagaña José Jaime,
TovillaZarate Carlos Alfonso,
JuárezRojop Isela,
Lanzagorta Nuria,
Escamilla Michael,
GonzálezCastro Thelma Beatriz,
López Narvaez María Lilia,
HernándezDíaz Yazmín,
Nicolini Humberto
Publication year - 2019
Publication title -
brain and behavior
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.915
H-Index - 41
ISSN - 2162-3279
DOI - 10.1002/brb3.1249
Subject(s) - in silico , transcriptome , biology , genetics , transcription factor , genetic association , population , bipolar disorder , snp , single nucleotide polymorphism , computational biology , gene , bioinformatics , medicine , genotype , gene expression , neuroscience , cognition , environmental health
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.