The Hospital for Sick Children, University of Toronto, Toronto, Canada.
Hum Mol Genet. 2013 Mar 1;22(5):1050-8. doi: 10.1093/hmg/dds504. Epub 2012 Nov 30.
Genetic variations in fat mass- and obesity (FTO)-associated gene, a well-replicated gene locus of obesity, appear to be associated also with reduced regional brain volumes in elderly. Here, we examined whether FTO is associated with total brain volume in adolescence, thus exploring possible developmental effects of FTO. We studied a population-based sample of 598 adolescents recruited from the French Canadian founder population in whom we measured brain volume by magnetic resonance imaging. Total fat mass was assessed with bioimpedance and body mass index was determined with anthropometry. Genotype-phenotype associations were tested with Merlin under an additive model. We found that the G allele of FTO (rs9930333) was associated with higher total body fat [TBF (P = 0.002) and lower brain volume (P = 0.005)]. The same allele was also associated with higher lean body mass (P = 0.03) and no difference in height (P = 0.99). Principal component analysis identified a shared inverse variance between the brain volume and TBF, which was associated with FTO at P = 5.5 × 10(-6). These results were replicated in two independent samples of 413 and 718 adolescents, and in a meta-analysis of all three samples (n = 1729 adolescents), FTO was associated with this shared inverse variance at P = 1.3 × 10(-9). Co-expression networks analysis supported the possibility that the underlying FTO effects may occur during embryogenesis. In conclusion, FTO is associated with shared inverse variance between body adiposity and brain volume, suggesting that this gene may exert inverse effects on adipose and brain tissues. Given the completion of the overall brain growth in early childhood, these effects may have their origins during early development.
肥胖相关基因（FTO）的遗传变异与肥胖相关的基因座具有很好的重复性，似乎也与老年人的局部脑容量减少有关。在这里，我们研究了 FTO 是否与青春期的总脑容量有关，从而探索 FTO 可能的发育效应。我们研究了一个基于人群的样本，该样本由从法国加拿大创始人群中招募的 598 名青少年组成，我们通过磁共振成像测量了他们的脑容量。总脂肪量通过生物阻抗法评估，体重指数通过人体测量法确定。基因型-表型关联通过 Merlin 在加性模型下进行测试。我们发现 FTO 的 G 等位基因（rs9930333）与更高的总体脂肪量有关[总体脂肪（P=0.002）和更低的脑容量（P=0.005）]。该等位基因也与更高的瘦体重有关（P=0.03），而身高没有差异（P=0.99）。主成分分析确定了脑容量和 TBF 之间存在共同的反向方差，这种相关性在 P=5.5×10(-6)时与 FTO 有关。在两个独立的 413 名和 718 名青少年样本中以及在所有三个样本（n=1729 名青少年）的荟萃分析中，都复制了这些结果，FTO 与该共同反向方差在 P=1.3×10(-9)时有相关性。共表达网络分析支持了 FTO 可能在胚胎发生过程中产生潜在影响的可能性。总之，FTO 与身体肥胖和脑容量之间的共同反向方差有关，这表明该基因可能对脂肪组织和脑组织产生相反的影响。鉴于幼儿期整体大脑生长完成，这些影响可能起源于早期发育。
