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

Abstract

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.

Evidence that genes involved in hedgehog signaling are associated with both bipolar disorder and high BMI

“…RPGRIP1L represents a particularly interesting target, as its expression and activity are regulated by intronic variants located in the FTO gene (which is strongly associated with obesity and T2D) through long-range regulation 58 . RPGRIP1L was recently associated with BD in a sample including 276 patients and 170 controls of Mexican origin 59 . Taken together, our findings suggest that complementary analytical approaches may provide converging evidence and should be used together to be able to identify genes in which multiple SNPs with small effect sizes might play an additive effect, as well as genes in which single SNPs might play a more relevant role.…”

Invited Review: Epigenetics in neurodevelopment

“…Although FTO is named for its association with obesity [195], genetic associations have also noted that mutations in FTO are related to risk for bipolar disorder. In silico analysis indicated that these mutations disturb binding sites of SP1 and SP2, which are distinct from the obesity-associating binding site perturbation of FOXP1 [196]. Direct mutation of the enzymatic dioxygenese-encoding portion FTO was identified in a single family, leading to an autosomal recessive lethal syndrome associated with postnatal growth retardation, microcephaly, severe psychomotor delay, functional brain deficits and characteristic facial dysmorphism [197].…”

Genetic association analysis of 5‐HTR2A gene variants in eating disorders in a Mexican population

“…The second sample ( n = 69) has been recruited from 2016 to date. However, adult patients ( n = 5) were included from a different case–control study (Saucedo‐Uribe et al, ). The patients were evaluated and diagnosed by a medical specialist in psychiatry in the Children's Psychiatric Hospital “Dr.…”

“…The polymorphisms (rs6311 and rs6313) studied are available from the TaqMan SNP Genotyping Assay made to order by Applied Biosystems. However, for the second sample of patients (included the adult patients) genotypes of polymorphism rs6311 and rs6313 were extracted from a genetic database constructed with information from the Human Psych Array (Saucedo‐Uribe et al, ).…”