Desrivières S, Lourdusamy A, Tao C, Toro R, Jia T, Loth E, Medina L M, Kepa A, Fernandes A, Ruggeri B, Carvalho F M, Cocks G, Banaschewski T, Barker G J, Bokde A L W, Büchel C, Conrod P J, Flor H, Heinz A, Gallinat J, Garavan H, Gowland P, Brühl R, Lawrence C, Mann K, Martinot M L P, Nees F, Lathrop M, Poline J-B, Rietschel M, Thompson P, Fauth-Bühler M, Smolka M N, Pausova Z, Paus T, Feng J, Schumann G
1] Institute of Psychiatry, King's College, London, UK [2] MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, UK.
Center for Computational Systems Biology, Fudan University, Shanghai, China.
Mol Psychiatry. 2015 Feb;20(2):263-74. doi: 10.1038/mp.2013.197. Epub 2014 Feb 11.
Despite the recognition that cortical thickness is heritable and correlates with intellectual ability in children and adolescents, the genes contributing to individual differences in these traits remain unknown. We conducted a large-scale association study in 1583 adolescents to identify genes affecting cortical thickness. Single-nucleotide polymorphisms (SNPs; n=54,837) within genes whose expression changed between stages of growth and differentiation of a human neural stem cell line were selected for association analyses with average cortical thickness. We identified a variant, rs7171755, associating with thinner cortex in the left hemisphere (P=1.12 × 10(-)(7)), particularly in the frontal and temporal lobes. Localized effects of this SNP on cortical thickness differently affected verbal and nonverbal intellectual abilities. The rs7171755 polymorphism acted in cis to affect expression in the human brain of the synaptic cell adhesion glycoprotein-encoding gene NPTN. We also found that cortical thickness and NPTN expression were on average higher in the right hemisphere, suggesting that asymmetric NPTN expression may render the left hemisphere more sensitive to the effects of NPTN mutations, accounting for the lateralized effect of rs7171755 found in our study. Altogether, our findings support a potential role for regional synaptic dysfunctions in forms of intellectual deficits.
尽管人们认识到皮质厚度具有遗传性，且与儿童和青少年的智力能力相关，但导致这些特征个体差异的基因仍不为人知。我们对1583名青少年进行了一项大规模关联研究，以确定影响皮质厚度的基因。选择在人类神经干细胞系生长和分化阶段之间表达发生变化的基因内的单核苷酸多态性（SNP；n = 54,837），用于与平均皮质厚度进行关联分析。我们鉴定出一个变体rs7171755，它与左半球较薄的皮质相关（P = 1.12 × 10(-)(7)），特别是在额叶和颞叶。该SNP对皮质厚度的局部影响对语言和非语言智力能力有不同影响。rs7171755多态性以顺式作用影响突触细胞粘附糖蛋白编码基因NPTN在人脑中的表达。我们还发现，右半球的皮质厚度和NPTN表达平均较高，这表明不对称的NPTN表达可能使左半球对NPTN突变的影响更敏感，这解释了我们研究中发现的rs7171755的侧化效应。总之，我们的研究结果支持区域突触功能障碍在智力缺陷形式中的潜在作用。
