Folliculin-interacting protein FNIP2 impacts on overweight and obesity through a polymorphism in a conserved 3′ untranslated region

Fernández, Lilia; Deleyto-Seldas, Nerea; Colmenarejo, Gonzalo; Sanz, Alejandro F.; Wagner, Sonia; Plata-Gómez, Ana Belén; Gómez-Patiño, Mónica; Molina, Susana; Espinosa‐Salinas, Isabel; Aguilar-Aguilar, Elena; Ortega, Sagrario; Graña‐Castro, Osvaldo; Loria-Kohen, Viviana; Fernández-Marcos, Pablo J.; Efeyan, Alejo; Molina, Ana Ramı́rez de

doi:10.1186/s13059-022-02798-5

Cited by 3 publications

(1 citation statement)

References 58 publications

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“…Similarly, the conserved mammalian region of ZNF804A gene has been associated with schizophrenia risk 36 . A conserved region in the 3'UTR of FNIP2, the protein interacting with folliculin, is considered to cause OB 37 . In addition, the non-coding regions (H3K4me1, H3K27ac) play a synergistic role in the development of both diseases.…”

Section: Discussionmentioning

confidence: 99%

Investigating the shared genetic architecture between schizophrenia and obesity

Yu²,

Fu³

et al. 2023

Preprint

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Evidence for reciprocal comorbidity of schizophrenia (SCZ) and obesity (OB) has grown in recent years. However, little is known regarding the shared genetic architecture or causality underlying the phenotypic association between SCZ and OB. Leveraging summary statistics from the hitherto largest genome-wide association study (GWAS) on each trait, we investigated the genetic overlap and causal associations of SCZ with OB. Our study demonstrated a genetic correlation between SCZ and OB, and the correlation was more evident in local genomic regions. The cross-trait meta-analysis identified 27 significant SNPs shared between SCZ and OB, most of which had the same direction of influence on both diseases. Mendelian randomization analysis showed a causal association of SCZ with OB, but not vice versa. Combining the gene expression information, we found that the genetic correlation between SCZ and OB is enriched in six regions of brain, led by the brain frontal cortex, and within these regions 34 functional genes were found to have an impact on both SCZ and OB. Taken together, our comprehensive genome-wide cross-trait analysis suggests a shared genetic basis including pleiotropic loci, tissue enrichment, and shared function genes between SCZ and OB. This work provides novel insights into the intrinsic genetic overlap of SCZ and OB, and highlights new opportunities and avenues for future investigation.

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Section: Discussionmentioning

confidence: 99%

Investigating the shared genetic architecture between schizophrenia and obesity

Yu²,

Fu³

et al. 2023

Preprint

View full text Add to dashboard Cite

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Skeletal muscle of young females under resistance exercise exhibits a unique innate immune cell infiltration profile compared to males and elderly individuals

Castrogiovanni,

Sanfilippo,

Imbesi

et al. 2024

J Muscle Res Cell Motil

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Folliculin-interacting protein FNIP2 impacts on overweight and obesity through a polymorphism in a conserved 3′ untranslated region

et al. 2022

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Background Overweight and obesity are defined by an anomalous or excessive fat accumulation that may compromise health. To find single-nucleotide polymorphisms (SNPs) influencing metabolic phenotypes associated with the obesity state, we analyze multiple anthropometric and clinical parameters in a cohort of 790 healthy volunteers and study potential associations with 48 manually curated SNPs, in metabolic genes functionally associated with the mechanistic target of rapamycin (mTOR) pathway. Results We identify and validate rs2291007 within a conserved region in the 3′UTR of folliculin-interacting protein FNIP2 that correlates with multiple leanness parameters. The T-to-C variant represents the major allele in Europeans and disrupts an ancestral target sequence of the miRNA miR-181b-5p, thus resulting in increased FNIP2 mRNA levels in cancer cell lines and in peripheral blood from carriers of the C allele. Because the miRNA binding site is conserved across vertebrates, we engineered the T-to-C substitution in the endogenous Fnip2 allele in mice. Primary cells derived from Fnip2 C/C mice show increased mRNA stability, and more importantly, Fnip2 C/C mice replicate the decreased adiposity and increased leanness observed in human volunteers. Finally, expression levels of FNIP2 in both human samples and mice negatively associate with leanness parameters, and moreover, are the most important contributor in a multifactorial model of body mass index prediction. Conclusions We propose that rs2291007 influences human leanness through an evolutionarily conserved modulation of FNIP2 mRNA levels. Graphical Abstract

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Folliculin-interacting protein FNIP2 impacts on overweight and obesity through a polymorphism in a conserved 3′ untranslated region

Cited by 3 publications

References 58 publications

Investigating the shared genetic architecture between schizophrenia and obesity

Investigating the shared genetic architecture between schizophrenia and obesity

Skeletal muscle of young females under resistance exercise exhibits a unique innate immune cell infiltration profile compared to males and elderly individuals

Folliculin-interacting protein FNIP2 impacts on overweight and obesity through a polymorphism in a conserved 3′ untranslated region

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