Liu Xuanshi, Hinney Anke, Scholz Markus, Scherag André, Tönjes Anke, Stumvoll Michael, Stadler Peter F, Hebebrand Johannes, Böttcher Yvonne
IFB Adiposity Diseases, University of Leipzig, Leipzig, Germany; Bioinformatics Group, Department of Computer Science, University of Leipzig, Leipzig, Germany.
Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy Universitätsklinikum Essen, University of Duisburg-Essen, Essen, Germany.
PLoS One. 2015 Mar 20;10(3):e0119206. doi: 10.1371/journal.pone.0119206. eCollection 2015.
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.
全基因组关联研究（GWAS）已成功应用于发现与肥胖相关的关联。然而，GWAS设计通常基于无亲缘关系的个体，等位基因亲本来源的遗传信息缺失。考虑亲本来源可能会为导致肥胖的遗传机制提供进一步的见解。我们假设，在经过充分复制的脂肪量和肥胖相关（FTO）基因内可能存在变异，这些变异可能根据来自母亲或父亲的传递而赋予不同的肥胖风险。使用了索布族人群的全基因组基因型和系谱信息。通过AlphaImpute生成了525名个体的分阶段基因型。随后，选择了FTO内含子1至3内的22个单核苷酸多态性（SNP），并使用PLINK进行了亲本来源特异性关联分析。有趣的是，我们鉴定出了几个根据亲本来源具有不同遗传效应（P≤0.05）的SNP——其中包括rs1861868、rs1121980和rs9939973（均在内含子1中）。为了证实我们的发现，我们在705个德国三人组中研究了选定的变异，这些三人组包括一名（极度）肥胖的儿童或青少年以及其父母双方。同样，如亲本不对称性测试所示，我们在第2和第3内含子中观察到了亲本来源效应的证据（P≤0.05）。我们的结果表明，几个FTO变异传递的肥胖风险可能取决于等位基因的亲本来源。有必要开展更大规模的基于家系的研究来重复我们的发现。
