Debette Stéphanie, Ibrahim Verbaas Carla A, Bressler Jan, Schuur Maaike, Smith Albert, Bis Joshua C, Davies Gail, Wolf Christiane, Gudnason Vilmundur, Chibnik Lori B, Yang Qiong, deStefano Anita L, de Quervain Dominique J F, Srikanth Velandai, Lahti Jari, Grabe Hans J, Smith Jennifer A, Priebe Lutz, Yu Lei, Karbalai Nazanin, Hayward Caroline, Wilson James F, Campbell Harry, Petrovic Katja, Fornage Myriam, Chauhan Ganesh, Yeo Robin, Boxall Ruth, Becker James, Stegle Oliver, Mather Karen A, Chouraki Vincent, Sun Qi, Rose Lynda M, Resnick Susan, Oldmeadow Christopher, Kirin Mirna, Wright Alan F, Jonsdottir Maria K, Au Rhoda, Becker Albert, Amin Najaf, Nalls Mike A, Turner Stephen T, Kardia Sharon L R, Oostra Ben, Windham Gwen, Coker Laura H, Zhao Wei, Knopman David S, Heiss Gerardo, Griswold Michael E, Gottesman Rebecca F, Vitart Veronique, Hastie Nicholas D, Zgaga Lina, Rudan Igor, Polasek Ozren, Holliday Elizabeth G, Schofield Peter, Choi Seung Hoan, Tanaka Toshiko, An Yang, Perry Rodney T, Kennedy Richard E, Sale Michèle M, Wang Jing, Wadley Virginia G, Liewald David C, Ridker Paul M, Gow Alan J, Pattie Alison, Starr John M, Porteous David, Liu Xuan, Thomson Russell, Armstrong Nicola J, Eiriksdottir Gudny, Assareh Arezoo A, Kochan Nicole A, Widen Elisabeth, Palotie Aarno, Hsieh Yi-Chen, Eriksson Johan G, Vogler Christian, van Swieten John C, Shulman Joshua M, Beiser Alexa, Rotter Jerome, Schmidt Carsten O, Hoffmann Wolfgang, Nöthen Markus M, Ferrucci Luigi, Attia John, Uitterlinden Andre G, Amouyel Philippe, Dartigues Jean-François, Amieva Hélène, Räikkönen Katri, Garcia Melissa, Wolf Philip A, Hofman Albert, Longstreth W T, Psaty Bruce M, Boerwinkle Eric, DeJager Philip L, Sachdev Perminder S, Schmidt Reinhold, Breteler Monique M B, Teumer Alexander, Lopez Oscar L, Cichon Sven, Chasman Daniel I, Grodstein Francine, Müller-Myhsok Bertram, Tzourio Christophe, Papassotiropoulos Andreas, Bennett David A, Ikram M Arfan, Deary Ian J, van Duijn Cornelia M, Launer Lenore, Fitzpatrick Annette L, Seshadri Sudha, Mosley Thomas H
Department of Neurology, Boston University School of Medicine, Boston, Massachusetts; Institut National de la Santé et de la Recherche Médicale, Epidemiology, University of Bordeaux; Department of Neurology, University Hospital of Bordeaux, Bordeaux, France.
Genetic Epidemiology Unit, Department of Epidemiology, Erasmus Medical Center University Medical Center, Rotterdam, The Netherlands; Department of Neurology, Erasmus Medical Center University Medical Center, Rotterdam, The Netherlands.
Biol Psychiatry. 2015 Apr 15;77(8):749-63. doi: 10.1016/j.biopsych.2014.08.027. Epub 2014 Nov 25.
Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting.
We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged ≥45 years. Replication of suggestive associations (p < 5 × 10(-6)) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults.
rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10(-10)) and replication cohorts (p = 5.65 × 10(-8)). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10(-8), and rs6813517 [SPOCK3], p = 2.58 × 10(-8)) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism.
This largest study to date exploring the genetics of memory function in ~40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.
老年人的记忆表现能够反映基因对认知功能和痴呆进程的影响。我们旨在确定社区环境中基因对言语陈述性记忆的作用。
我们对基因组流行病学心脏与衰老研究队列联盟的19个队列中段落或单词列表延迟回忆进行了全基因组关联研究，这些队列包括29076名无痴呆和中风的欧洲裔个体，年龄≥45岁。在10617名欧洲裔参与者、3811名非裔美国人以及1561名年轻人中对提示性关联（p < 5×10⁻⁶）进行重复验证。
APOE附近的rs4420638与发现队列（p = 5.57×10⁻¹⁰）和重复验证队列（p = 5.65×10⁻⁸）中较差的延迟回忆表现相关。这种关联在段落延迟回忆中比单词列表延迟回忆更强，且在年龄最大的人群中更明显。在总样本的子集中，有两个与特定测试的关联在发现和重复验证的联合分析中达到全基因组显著性（rs11074779 [HS3ST4]，p = 3.11×10⁻⁸；rs6813517 [SPOCK3]，p = 2.58×10⁻⁸），位于参与免疫反应的基因附近。一个结合了58个独立提示性记忆风险变异的基因评分与725份尸检样本中阿尔茨海默病病理学的增加相关。记忆风险位点与138个人类海马体样本中基因表达的关联显示，与WDR48和CLDN5存在顺式关联，二者均与泛素代谢有关。
这项迄今为止对约40000名老年人记忆功能遗传学进行的最大规模研究揭示了全基因组关联，并提示免疫和泛素途径的参与。
