Ferrari Raffaele, Grassi Mario, Graziano Francesca, Palluzzi Fernando, Archetti Silvana, Bonomi Elisa, Bruni Amalia C, Maletta Raffaele G, Bernardi Livia, Cupidi Chiara, Colao Rosanna, Rainero Innocenzo, Rubino Elisa, Pinessi Lorenzo, Galimberti Daniela, Scarpini Elio, Serpente Maria, Nacmias Benedetta, Piaceri Irene, Bagnoli Silvia, Rossi Giacomina, Giaccone Giorgio, Tagliavini Fabrizio, Benussi Luisa, Binetti Giuliano, Ghidoni Roberta, Singleton Andrew, Hardy John, Momeni Parastoo, Padovani Alessandro, Borroni Barbara
Department of Molecular Neuroscience, Institute of Neurology, UCL, London, UK.
Department of Brain and Behavioural Sciences, Medical and Genomic Statistics Unit, University of Pavia, Pavia, Italy.
J Alzheimers Dis. 2017;56(4):1271-1278. doi: 10.3233/JAD-160949.
In frontotemporal dementia (FTD), age at disease onset (AAO) is unpredictable in both early and late-onset cases; AAO variability is found even in autosomal dominant FTD. The present study was aimed at identifying genetic modifiers modulating AAO in a large cohort of Italian FTD patients. We conducted an association analysis on 411 FTD patients, belonging to 7 Italian Centers, and for whom AAO was available. Population structure was evaluated by principal component analysis to infer continuous axes of genetic variation, and single linear regression models were applied. A genetic score (GS) was calculated on the basis of suggestive single nucleotide polymorphisms (SNPs) found by association analyses. GS showed genome-wide significant slope decrease by -3.86 (95% CI: -4.64 to -3.07, p < 2×10-16) per standard deviation of the GS for 6 SNPs mapping to genes involved in neuronal development and signaling, axonal myelinization, and glutamatergic/GABA neurotransmission. An increase of the GS was associated with a decrease of the AAO. Our data indicate that there is indeed a genetic component that underpins and modulates up to 14.5% of variability of AAO in Italian FTD. Future studies on genetic modifiers in FTD are warranted.
在额颞叶痴呆（FTD）中，早发型和晚发型病例的发病年龄（AAO）均无法预测；即使在常染色体显性FTD中也存在AAO变异性。本研究旨在确定在一大群意大利FTD患者中调节AAO的遗传修饰因子。我们对来自7个意大利中心的411例FTD患者进行了关联分析，这些患者的AAO数据可用。通过主成分分析评估群体结构以推断遗传变异的连续轴，并应用单线性回归模型。根据关联分析发现的提示性单核苷酸多态性（SNP）计算遗传评分（GS）。对于映射到参与神经元发育和信号传导、轴突髓鞘形成以及谷氨酸能/γ-氨基丁酸神经传递的基因的6个SNP而言，每标准差的GS显示全基因组显著斜率下降-3.86（95%可信区间：-4.64至-3.07，p<2×10-16）。GS增加与AAO降低相关。我们的数据表明，确实存在一个遗传成分，它支撑并调节意大利FTD中高达14.5%的AAO变异性。有必要对FTD中的遗传修饰因子进行进一步研究。
