Sex-Specific Association of the X Chromosome With Cognitive Change and Tau Pathology in Aging and Alzheimer Disease.
Sex-Specific Association of the X Chromosome With Cognitive Change and Tau Pathology in Aging and Alzheimer Disease.
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DOI：
10.1001/jamaneurol.2021.2806
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发表时间：
2021-10-01
期刊：
影响因子：
29
通讯作者：
Dubal DB
中科院分区：
文献类型：
--
作者：
Davis EJ;Solsberg CW;White CC;Miñones-Moyano E;Sirota M;Chibnik L;Bennett DA;De Jager PL;Yokoyama JS;Dubal DB
这项队列研究确定了X染色体是否与衰老和阿尔茨海默病中的性别特异性认知变化和tau病理学相关。大脑中X染色体基因的表达是否与男性和女性的认知变化或衰老和阿尔茨海默病中的tau病理学相关？在这项对508名个体的队列研究中，通过RNA测序评估的X染色体基因表达与女性的认知变化相关，但与男性无关，与阿尔茨海默病病理学无关。与认知相反，X染色体基因表达与男性而非女性的神经病理性tau蛋白负荷相关。X染色体转录组，代表了女性和男性基因组的重要组成部分，与认知轨迹和衰老和阿尔茨海默病中的神经病理学tau负荷以性别特异性方式相关。X染色体占男性和女性人类基因组的5%，其对认知衰老和阿尔茨海默病（AD）的影响在很大程度上是未知的。确定X染色体是否与衰老和AD中的性别特异性认知变化和tau病理学相关。本研究从宗教秩序研究和拉什记忆和衰老项目联合队列中的尸检老年人的背外侧前额叶皮层的RNA测序数据集，研究了X染色体的差异基因表达谱。从1994年至2017年入组的队列研究中收集样本。最后一次分析数据是在2021年5月。主要分析检查了通过背外侧前额叶皮质RNA测序测量的X染色体基因表达是否与衰老和AD期间的认知变化相关，独立于AD病理学以及女性和男性的转录组水平。X染色体基因表达是否与神经系统缠结负担相关，这是一种影响认知的tau病理学指标，也在女性和男性中进行了探索。背外侧前额叶皮层的RNA测序样本来自508名个体（平均[SD]死亡年龄为88.4 [6.6]岁; 315 [62.0%]例为女性; 197 [38.8%]例在死亡时有AD临床诊断; 293例[58.2%]在死亡时病理诊断为AD）入组宗教秩序研究和拉什记忆和衰老项目联合队列，并每年随访一次，平均（SD）为6.3（3.9）年。X染色体基因表达（29个基因），调整死亡年龄，教育和AD病理学，在女性而不是男性的全基因组水平上与认知变化显着相关。在大多数确定的X基因（19个基因）中，表达增加与女性认知能力下降较慢有关。与认知相反，X染色体基因表达（3个基因），经死亡年龄和教育调整，与男性而非女性全基因组水平的神经病理性tau负荷相关。在这项研究中，X染色体以性别特异性方式与衰老和AD中的认知轨迹和神经病理学tau负荷相关。这一点很重要，因为特定的X染色体因子可能会对女性、男性或两者的衰老和AD的生物学途径产生风险或弹性。
This cohort study determines whether the X chromosome is associated with sex-specific cognitive change and tau pathology in aging and Alzheimer disease. Is X chromosome gene expression in the brain associated with cognitive change or tau pathology in aging and Alzheimer disease in women and men? In this cohort study of 508 individuals, X chromosome gene expression assessed by RNA sequencing was associated with cognitive change in women but not men in a manner independent of Alzheimer disease pathology. In contrast with cognition, X chromosome gene expression was associated with neuropathologic tau burden in men but not women. The X chromosome transcriptome, representing a significant portion of the genome of women and men, is associated with cognitive trajectories and neuropathological tau burden in aging and Alzheimer disease in a sex-specific manner. The X chromosome represents 5% of the human genome in women and men, and its influence on cognitive aging and Alzheimer disease (AD) is largely unknown. To determine whether the X chromosome is associated with sex-specific cognitive change and tau pathology in aging and AD. This study examined differential gene expression profiling of the X chromosome from an RNA sequencing data set of the dorsolateral prefrontal cortex obtained from autopsied, elderly individuals enrolled in the Religious Orders Study and Rush Memory and Aging Project joint cohorts. Samples were collected from the cohort study with enrollment from 1994 to 2017. Data were last analyzed in May 2021. The main analysis examined whether X chromosome gene expression measured by RNA sequencing of the dorsolateral prefrontal cortex was associated with cognitive change during aging and AD, independent of AD pathology and at the transcriptome-wide level in women and men. Whether X chromosome gene expression was associated with neurofibrillary tangle burden, a measure of tau pathology that influences cognition, in women and men was also explored. Samples for RNA sequencing of the dorsolateral prefrontal cortex were obtained from 508 individuals (mean [SD] age at death, 88.4 [6.6] years; 315 [62.0%] were female; 197 [38.8%] had clinical diagnosis of AD at death; 293 [58.2%] had pathological diagnosis of AD at death) enrolled in the Religious Orders Study and Rush Memory and Aging Project joint cohorts and were followed up annually for a mean (SD) of 6.3 (3.9) years. X chromosome gene expression (29 genes), adjusted for age at death, education, and AD pathology, was significantly associated with cognitive change at the genome-wide level in women but not men. In the majority of identified X genes (19 genes), increased expression was associated with slower cognitive decline in women. In contrast with cognition, X chromosome gene expression (3 genes), adjusted for age at death and education, was associated with neuropathological tau burden at the genome-wide level in men but not women. In this study, the X chromosome was associated with cognitive trajectories and neuropathological tau burden in aging and AD in a sex-specific manner. This is important because specific X chromosome factors could contribute risk or resilience to biological pathways of aging and AD in women, men, or both.
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影响因子：
16.6
作者：
Natarajan P;Pampana A;Graham SE;Ruotsalainen SE;Perry JA;de Vries PS;Broome JG;Pirruccello JP;Honigberg MC;Aragam K;Wolford B;Brody JA;Antonacci-Fulton L;Arden M;Aslibekyan S;Assimes TL;Ballantyne CM;Bielak LF;Bis JC;Cade BE;Do R;Doddapaneni H;Emery LS;Hung YJ;Irvin MR;Khan AT;Lange L;Lee J;Lemaitre RN;Martin LW;Metcalf G;Montasser ME;Moon JY;Muzny D;O'Connell JR;Palmer ND;Peralta JM;Peyser PA;Stilp AM;Tsai M;Wang FF;Weeks DE;Yanek LR;Wilson JG;Abecasis G;Arnett DK;Becker LC;Blangero J;Boerwinkle E;Bowden DW;Chang YC;Chen YI;Choi WJ;Correa A;Curran JE;Daly MJ;Dutcher SK;Ellinor PT;Fornage M;Freedman BI;Gabriel S;Germer S;Gibbs RA;He J;Hveem K;Jarvik GP;Kaplan RC;Kardia SLR;Kenny E;Kim RW;Kooperberg C;Laurie CC;Lee S;Lloyd-Jones DM;Loos RJF;Lubitz SA;Mathias RA;Martinez KAV;McGarvey ST;Mitchell BD;Nickerson DA;North KE;Palotie A;Park CJ;Psaty BM;Rao DC;Redline S;Reiner AP;Seo D;Seo JS;Smith AV;Tracy RP;Vasan RS;Kathiresan S;Cupples LA;Rotter JI;Morrison AC;Rich SS;Ripatti S;Willer C;NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium;FinnGen;Peloso GM
通讯作者：
Peloso GM
影响因子：
25
作者：
Mostafavi S;Gaiteri C;Sullivan SE;White CC;Tasaki S;Xu J;Taga M;Klein HU;Patrick E;Komashko V;McCabe C;Smith R;Bradshaw EM;Root DE;Regev A;Yu L;Chibnik LB;Schneider JA;Young-Pearse TL;Bennett DA;De Jager PL
通讯作者：
De Jager PL
DOI：
10.3233/jad-179939
发表时间：
2018
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
--
作者：
Bennett DA;Buchman AS;Boyle PA;Barnes LL;Wilson RS;Schneider JA
通讯作者：
Schneider JA
影响因子：
9.8
作者：
Wise, Anastasia L.;Gyi, Lin;Manolio, Teri A.
通讯作者：
Manolio, Teri A.
影响因子：
25
作者：
Grubman, Alexandra;Chew, Gabriel;Polo, Jose M.
通讯作者：
Polo, Jose M.