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Early-Onset Alzheimer Disease and Candidate Risk Genes Involved in Endolysosomal Transport
JAMA Neurology ( IF 20.4 ) Pub Date : 2017-09-01 , DOI: 10.1001/jamaneurol.2017.1518
Brian W Kunkle 1 , Badri N Vardarajan 2, 3, 4 , Adam C Naj 5 , Patrice L Whitehead 1 , Sophie Rolati 1 , Susan Slifer 1 , Regina M Carney 1 , Michael L Cuccaro 1 , Jeffery M Vance 1 , John R Gilbert 1 , Li-San Wang 6 , Lindsay A Farrer 7, 8, 9, 10, 11 , Christiane Reitz 2, 3, 4 , Jonathan L Haines 12 , Gary W Beecham 1 , Eden R Martin 1 , Gerard D Schellenberg 6 , Richard P Mayeux 2, 3, 4, 13, 14 , Margaret A Pericak-Vance 1
Affiliation  

Importance  Mutations in APP, PSEN1, and PSEN2 lead to early-onset Alzheimer disease (EOAD) but account for only approximately 11% of EOAD overall, leaving most of the genetic risk for the most severe form of Alzheimer disease unexplained. This extreme phenotype likely harbors highly penetrant risk variants, making it primed for discovery of novel risk genes and pathways for AD.

Objective  To search for rare variants contributing to the risk for EOAD.

Design, Setting, and Participants  In this case-control study, whole-exome sequencing (WES) was performed in 51 non-Hispanic white (NHW) patients with EOAD (age at onset <65 years) and 19 Caribbean Hispanic families previously screened as negative for established APP, PSEN1, and PSEN2 causal variants. Participants were recruited from John P. Hussman Institute for Human Genomics, Case Western Reserve University, and Columbia University. Rare, deleterious, nonsynonymous, or loss-of-function variants were filtered to identify variants in known and suspected AD genes, variants in multiple unrelated NHW patients, variants present in 19 Hispanic EOAD WES families, and genes with variants in multiple unrelated NHW patients. These variants/genes were tested for association in an independent cohort of 1524 patients with EOAD, 7046 patients with late-onset AD (LOAD), and 7001 cognitively intact controls (age at examination, >65 years) from the Alzheimer’s Disease Genetics Consortium. The study was conducted from January 21, 2013, to October 13, 2016.

Main Outcomes and Measures  Alzheimer disease diagnosed according to standard National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer Disease and Related Disorders Association criteria. Association between Alzheimer disease and genetic variants and genes was measured using logistic regression and sequence kernel association test–optimal gene tests, respectively.

Results  Of the 1524 NHW patients with EOAD, 765 (50.2%) were women and mean (SD) age was 60.0 (4.9) years; of the 7046 NHW patients with LOAD, 4171 (59.2%) were women and mean (SD) age was 77.4 (8.6) years; and of the 7001 NHW controls, 4215 (60.2%) were women and mean (SD) age was 77.4 (8.6) years. The gene PSD2, for which multiple unrelated NHW cases had rare missense variants, was significantly associated with EOAD (P = 2.05 × 10−6; Bonferroni-corrected P value [BP] = 1.3 × 10−3) and LOAD (P = 6.22 × 10−6; BP = 4.1 × 10−3). A missense variant in TCIRG1, present in a NHW patient and segregating in 3 cases of a Hispanic family, was more frequent in EOAD cases (odds ratio [OR], 2.13; 95% CI, 0.99-4.55; P = .06; BP = 0.413), and significantly associated with LOAD (OR, 2.23; 95% CI, 1.37-3.62; P = 7.2 × 10−4; BP = 5.0 × 10−3). A missense variant in the LOAD risk gene RIN3 showed suggestive evidence of association with EOAD after Bonferroni correction (OR, 4.56; 95% CI, 1.26-16.48; P = .02, BP = 0.091). In addition, a missense variant in RUFY1 identified in 2 NHW EOAD cases showed suggestive evidence of an association with EOAD as well (OR, 18.63; 95% CI, 1.62-213.45; P = .003; BP = 0.129).

Conclusions and Relevance  The genes PSD2, TCIRG1, RIN3, and RUFY1 all may be involved in endolysosomal transport—a process known to be important to development of AD. Furthermore, this study identified shared risk genes between EOAD and LOAD similar to previously reported genes, such as SORL1, PSEN2, and TREM2.



中文翻译:


早发性阿尔茨海默病和参与内溶酶体转运的候选风险基因



APP 、 PSEN1 和 PSEN2 的重要突变导致早发性阿尔茨海默病 (EOAD),但仅占 EOAD 总体的 11% 左右,导致最严重形式的阿尔茨海默病的大部分遗传风险无法解释。这种极端表型可能含有高度渗透性的风险变异,使其为发现 AD 的新风险基因和途径做好了准备。


目的寻找导致 EOAD 风险的罕见变异。


设计、背景和参与者在这项病例对照研究中,对 51 名患有 EOAD 的非西班牙裔白人 (NHW) 患者(发病年龄 <65 岁)和 19 名加勒比西班牙裔家庭进行了全外显子测序 (WES),这些患者之前被筛查为对于已确定的 APP、PSEN1 和 PSEN2 因果变异呈阴性。参与者是从约翰·P·赫斯曼人类基因组学研究所、凯斯西储大学和哥伦比亚大学招募的。过滤罕见、有害、非同义或功能丧失变异,以识别已知和可疑 AD 基因中的变异、多个不相关 NHW 患者中的变异、19 个西班牙裔 EOAD WES 家族中存在的变异以及多个不相关 NHW 患者中存在变异的基因。这些变异/基因在一个独立队列中进行了关联性测试,该队列由来自阿尔茨海默病遗传学联盟的 1524 名 EOAD 患者、7046 名晚发性 AD (LOAD) 患者和 7001 名认知完整的对照者(检查时年龄,>65 岁)组成。该研究于2013年1月21日至2016年10月13日进行。


主要结果和措施根据国家神经和交流障碍和中风研究所以及阿尔茨海默病和相关疾病协会的标准诊断阿尔茨海默病。分别使用逻辑回归和序列核关联测试-最佳基因测试来测量阿尔茨海默病与遗传变异和基因之间的关联。


结果1524 名患有 EOAD 的 NHW 患者中,765 名 (50.2%) 为女性,平均 (SD) 年龄为 60.0 (4.9) 岁;在 7046 名 LOAD NHW 患者中,4171 名 (59.2%) 为女性,平均 (SD) 年龄为 77.4 (8.6) 岁;在 7001 名 NHW 对照中,4215 名 (60.2%) 是女性,平均 (SD) 年龄为 77.4 (8.6) 岁。多个不相关的 NHW 病例具有罕见错义变异的基因 PSD2 与 EOAD(P = 2.05 × 10−6;Bonferroni 校正 P 值 [BP] = 1.3 × 10−3)和 LOAD(P = 6.22)显着相关。 × 10−6;BP = 4.1 × 10−3)。 TCIRG1 中的错义变异存在于 NHW 患者中,并在西班牙裔家庭的 3 例病例中分离,在 EOAD 病例中更为常见(比值比 [OR],2.13;95% CI,0.99-4.55;P = 0.06;BP = 0.413),并且与 LOAD 显着相关(OR,2.23;95% CI,1.37-3.62;P = 7.2 × 10−4;BP = 5.0 × 10−3)。 Bonferroni 校正后,LOAD 风险基因 RIN3 中的错义变异显示出与 EOAD 相关的暗示证据(OR,4.56;95% CI,1.26-16.48;P = 0.02,BP = 0.091)。此外,在 2 例 NHW EOAD 病例中发现的 RUFY1 错义变异也显示出与 EOAD 相关的暗示证据(OR,18.63;95% CI,1.62-213.45;P = 0.003;BP = 0.129)。


结论和相关性基因PSD2TCIRG1RIN3RUFY1都可能参与内溶酶体转运——已知这一过程对 AD 的发展很重要。此外,这项研究还发现了 EOAD 和 LOAD 之间的共享风险基因,类似于之前报道的基因,例如SORL1PSEN2TREM2

更新日期:2017-10-06
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