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

Xuanshi Liu; Anke Hinney; Markus Scholz; André Scherag; Anke Tönjes; Michael Stumvoll; Peter F Stadler; Johannes Hebebrand; Yvonne Böttcher

doi:10.1371/journal.pone.0119206

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.

Authors

Xuanshi Liu¹, Anke Hinney², Markus Scholz³, André Scherag⁴, Anke Tönjes⁵, Michael Stumvoll⁶, Peter F Stadler⁷, Johannes Hebebrand², Yvonne Böttcher⁸

Affiliations

¹ IFB Adiposity Diseases, University of Leipzig, Leipzig, Germany; Bioinformatics Group, Department of Computer Science, University of Leipzig, Leipzig, Germany.
² Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy Universitätsklinikum Essen, University of Duisburg-Essen, Essen, Germany.
³ Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
⁴ Clinical Epidemiology, Integrated Research and Treatment Center (IFB) Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany.
⁵ Department of Medicine, University of Leipzig, Leipzig, Germany.
⁶ IFB Adiposity Diseases, University of Leipzig, Leipzig, Germany; Department of Medicine, University of Leipzig, Leipzig, Germany.
⁷ Fraunhofer Institute for Cell Therapy and Immunology, AG RNomics, Leipzig, Germany; Interdisciplinary Center of Bioinformatics, University of Leipzig, Leipzig, Germany; Institute for Theoretical Chemistry, University of Vienna, Vienna, Austria; Sante Fe Institute, Santa Fe, New Mexico, United States of America.
⁸ IFB Adiposity Diseases, University of Leipzig, Leipzig, Germany.

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

Grants and funding

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 n^o262055 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.