Brain and behavior · 2019
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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Saucedo-Uribe Erasmo, Genis-Mendoza Alma Delia, Díaz-Anzaldúa Adriana, Martínez-Magaña José Jaime, Tovilla-Zarate Carlos Alfonso, Juárez-Rojop Isela, Lanzagorta Nuria, Escamilla Michael, González-Castro Thelma Beatriz, López Narvaez María Lilia, Hernández-Díaz Yazmín, Nicolini Humberto
Аннотация
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 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.
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.
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 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.
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.