Chen Jason A, Wang Qing, Davis-Turak Jeremy, Li Yun, Karydas Anna M, Hsu Sandy C, Sears Renee L, Chatzopoulou Doxa, Huang Alden Y, Wojta Kevin J, Klein Eric, Lee Jason, Beekly Duane L, Boxer Adam, Faber Kelley M, Haase Claudia M, Miller Josh, Poon Wayne W, Rosen Ami, Rosen Howard, Sapozhnikova Anna, Shapira Jill, Varpetian Arousiak, Foroud Tatiana M, Levenson Robert W, Levey Allan I, Kukull Walter A, Mendez Mario F, Ringman John, Chui Helena, Cotman Carl, DeCarli Charles, Miller Bruce L, Geschwind Daniel H, Coppola Giovanni
Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles.
Memory and Aging Center, University of California, San Francisco.
JAMA Neurol. 2015 Apr;72(4):414-22. doi: 10.1001/jamaneurol.2014.4040.
Previous studies have indicated a heritable component of the etiology of neurodegenerative diseases such as Alzheimer disease (AD), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP). However, few have examined the contribution of low-frequency coding variants on a genome-wide level.
To identify low-frequency coding variants that affect susceptibility to AD, FTD, and PSP.
DESIGN, SETTING, AND PARTICIPANTS: We used the Illumina HumanExome BeadChip array to genotype a large number of variants (most of which are low-frequency coding variants) in a cohort of patients with neurodegenerative disease (224 with AD, 168 with FTD, and 48 with PSP) and in 224 control individuals without dementia enrolled between 2005-2012 from multiple centers participating in the Genetic Investigation in Frontotemporal Dementia and Alzheimer's Disease (GIFT) Study. An additional multiancestral replication cohort of 240 patients with AD and 240 controls without dementia was used to validate suggestive findings. Variant-level association testing and gene-based testing were performed.
Statistical association of genetic variants with clinical diagnosis of AD, FTD, and PSP.
Genetic variants typed by the exome array explained 44%, 53%, and 57% of the total phenotypic variance of AD, FTD, and PSP, respectively. An association with the known AD gene ABCA7 was replicated in several ancestries (discovery P=.0049, European P=.041, African American P=.043, and Asian P=.027), suggesting that exonic variants within this gene modify AD susceptibility. In addition, 2 suggestive candidate genes, DYSF (P=5.53×10(-5)) and PAXIP1 (P=2.26×10(-4)), were highlighted in patients with AD and differentially expressed in AD brain. Corroborating evidence from other exome array studies and gene expression data points toward potential involvement of these genes in the pathogenesis of AD.
Low-frequency coding variants with intermediate effect size may account for a significant fraction of the genetic susceptibility to AD and FTD. Furthermore, we found evidence that coding variants in the known susceptibility gene ABCA7, as well as candidate genes DYSF and PAXIP1, confer risk for AD.
先前的研究表明神经退行性疾病如阿尔茨海默病（AD）、额颞叶痴呆（FTD）和进行性核上性麻痹（PSP）的病因存在遗传因素。然而，很少有研究在全基因组水平上考察低频编码变异的作用。
鉴定影响AD、FTD和PSP易感性的低频编码变异。
设计、背景和参与者：我们使用Illumina HumanExome BeadChip芯片对一组神经退行性疾病患者（224例AD患者、168例FTD患者和48例PSP患者）以及2005年至2012年间从多个参与额颞叶痴呆和阿尔茨海默病基因研究（GIFT研究）中心招募的224例无痴呆对照个体中的大量变异（其中大多数是低频编码变异）进行基因分型。另外一个包含240例AD患者和240例无痴呆对照的多祖先复制队列用于验证提示性发现。进行了变异水平关联测试和基于基因的测试。
基因变异与AD、FTD和PSP临床诊断的统计学关联。
外显子芯片分型的基因变异分别解释了AD、FTD和PSP总表型变异的44%、53%和57%。与已知AD基因ABCA7的关联在多个祖先群体中得到重复（发现P = 0.0049，欧洲人P = 0.041，非裔美国人P = 0.043，亚洲人P = 0.027），表明该基因内的外显子变异改变了AD易感性。此外，在AD患者中突出显示了2个提示性候选基因，即肌营养不良蛋白（DYSF，P = 5.53×10⁻⁵）和PAXIP1（P = 2.26×10⁻⁴），且在AD脑内差异表达。来自其他外显子芯片研究和基因表达数据的佐证证据表明这些基因可能参与AD的发病机制。
具有中等效应大小的低频编码变异可能在很大程度上解释了AD和FTD的遗传易感性。此外，我们发现证据表明已知易感基因ABCA7以及候选基因DYSF和PAXIP1中的编码变异会增加AD风险。
