Indications for potential parent-of-origin effects within the FTO gene

PLoS One. 2015 Mar 20;10(3):e0119206. doi: 10.1371/journal.pone.0119206. eCollection 2015.

Abstract

Genome-Wide Association Studies (GWAS) were successfully applied to discover associations with obesity. However, the GWAS design is usually based on unrelated individuals and inheritance information on the parental origin of the alleles is missing. Taking into account parent-of-origin may provide further insights into the genetic mechanisms contributing to obesity. We hypothesized that there may be variants within the robustly replicated fat mass and obesity associated (FTO) gene that may confer different risk for obesity depending on transmission from mother or father. Genome-wide genotypes and pedigree information from the Sorbs population were used. Phased genotypes among 525 individuals were generated by AlphaImpute. Subsequently, 22 SNPs within FTO introns 1 to 3 were selected and parent-of-origin specific association analyses were performed using PLINK. Interestingly, we identified several SNPs conferring different genetic effects (P≤0.05) depending on parental origin--among them, rs1861868, rs1121980 and rs9939973 (all in intron 1). To confirm our findings, we investigated the selected variants in 705 German trios comprising an (extremely) obese child or adolescent and both parents. Again, we observed evidence for POE effects in intron 2 and 3 (P≤0.05) as indicated by the parental asymmetry test. Our results suggest that the obesity risk transmitted by several FTO variants may depend on the parental origin of the allele. Larger family-based studies are warranted to replicate our findings.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alleles
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO
  • Body Mass Index
  • Comorbidity
  • Family
  • Female
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study*
  • Genotype
  • Germany
  • Humans
  • Introns
  • Linkage Disequilibrium
  • Male
  • Middle Aged
  • Obesity / epidemiology
  • Obesity / genetics*
  • Polymorphism, Single Nucleotide
  • Proteins / genetics*

Substances

  • Proteins
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO
  • FTO protein, human

Grant support

This work was supported by the German Research Foundation (BO 3147/4-1 to Y.B and DFG - SFB 1052 C01, SPP 1629 TO 718/2-1 to A.T.). This work was further supported by grants from the German Diabetes Association (to Y.B.) and from the DDS Foundation to Y.B. Y.B was further supported by a research grant from the IFB AdiposityDiseases ADI-K50D; K7-45; and ADI-K7-39, ADI-K-7-38. IFB AdiposityDiseases is supported by the Federal Ministry of Education and Research (BMBF), Germany, FKZ: 01EO1001. This work was further supported by the Kompetenznetz Adipositas (Competence network for Obesity) funded by the Federal Ministry of Education and Research (German Obesity Biomaterial Bank; FKZ 01GI1128), a grant from Deutsche Forschungsgemeinschaft the SFB 1052/1: “Obesity mechanisms” (project A01) (to M.S.). This work is supported by LIFE - Leipzig Research Center for Civilization Diseases, University of Leipzig. LIFE is funded by means of the European Union, by the European Regional Development Fund (ERDF) and by means of the Free State of Saxony within the framework of the excellence initiative. The work of A.H. was supported by grants from the European Union (FP7 no262055 ESGI), the BMBF (NGFN-Plus; 01GS0820) and the Deutsche Forschungsgemeinschaft (HI1865/2-1). A.S. who performed the PAT analyses is supported by the Federal Ministry of Education and Research (BMBF), Germany, FKZ: 01EO1002, 01GI1120A, and 01GI1120B. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.