利用非洲基因组资源小组对非裔美国人中新型阿尔茨海默病风险基因座和通路的荟萃分析。

Novel Alzheimer Disease Risk Loci and Pathways in African American Individuals Using the African Genome Resources Panel: A Meta-analysis.

作者信息

Kunkle Brian W, Schmidt Michael, Klein Hans-Ulrich, Naj Adam C, Hamilton-Nelson Kara L, Larson Eric B, Evans Denis A, De Jager Phil L, Crane Paul K, Buxbaum Joe D, Ertekin-Taner Nilufer, Barnes Lisa L, Fallin M Daniele, Manly Jennifer J, Go Rodney C P, Obisesan Thomas O, Kamboh M Ilyas, Bennett David A, Hall Kathleen S, Goate Alison M, Foroud Tatiana M, Martin Eden R, Wang Li-Sao, Byrd Goldie S, Farrer Lindsay A, Haines Jonathan L, Schellenberg Gerard D, Mayeux Richard, Pericak-Vance Margaret A, Reitz Christiane, Graff-Radford Neill R, Martinez Izri, Ayodele Temitope, Logue Mark W, Cantwell Laura B, Jean-Francois Melissa, Kuzma Amanda B, Adams L D, Vance Jeffery M, Cuccaro Michael L, Chung Jaeyoon, Mez Jesse, Lunetta Kathryn L, Jun Gyungah R, Lopez Oscar L, Hendrie Hugh C, Reiman Eric M, Kowall Neil W, Leverenz James B, Small Scott A, Levey Allan I, Golde Todd E, Saykin Andrew J, Starks Takiyah D, Albert Marilyn S, Hyman Bradley T, Petersen Ronald C, Sano Mary, Wisniewski Thomas, Vassar Robert, Kaye Jeffrey A, Henderson Victor W, DeCarli Charles, LaFerla Frank M, Brewer James B, Miller Bruce L, Swerdlow Russell H, Van Eldik Linda J, Paulson Henry L, Trojanowski John Q, Chui Helena C, Rosenberg Roger N, Craft Suzanne, Grabowski Thomas J, Asthana Sanjay, Morris John C, Strittmatter Stephen M, Kukull Walter A

机构信息

The John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida.

Dr. John T. MacDonald Foundation, Department of Human Genetics, University of Miami, Miami, Florida.

出版信息

JAMA Neurol. 2021 Jan 1;78(1):102-113. doi: 10.1001/jamaneurol.2020.3536.

DOI:10.1001/jamaneurol.2020.3536

PMID:33074286

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7573798/

Abstract

IMPORTANCE

Compared with non-Hispanic White individuals, African American individuals from the same community are approximately twice as likely to develop Alzheimer disease. Despite this disparity, the largest Alzheimer disease genome-wide association studies to date have been conducted in non-Hispanic White individuals. In the largest association analyses of Alzheimer disease in African American individuals, ABCA7, TREM2, and an intergenic locus at 5q35 were previously implicated.

OBJECTIVE

To identify additional risk loci in African American individuals by increasing the sample size and using the African Genome Resource panel.

DESIGN, SETTING, AND PARTICIPANTS: This genome-wide association meta-analysis used case-control and family-based data sets from the Alzheimer Disease Genetics Consortium. There were multiple recruitment sites throughout the United States that included individuals with Alzheimer disease and controls of African American ancestry. Analysis began October 2018 and ended September 2019.

MAIN OUTCOMES AND MEASURES

Diagnosis of Alzheimer disease.

RESULTS

A total of 2784 individuals with Alzheimer disease (1944 female [69.8%]) and 5222 controls (3743 female [71.7%]) were analyzed (mean [SD] age at last evaluation, 74.2 [13.6] years). Associations with 4 novel common loci centered near the intracellular glycoprotein trafficking gene EDEM1 (3p26; P = 8.9 × 10-7), near the immune response gene ALCAM (3q13; P = 9.3 × 10-7), within GPC6 (13q31; P = 4.1 × 10-7), a gene critical for recruitment of glutamatergic receptors to the neuronal membrane, and within VRK3 (19q13.33; P = 3.5 × 10-7), a gene involved in glutamate neurotoxicity, were identified. In addition, several loci associated with rare variants, including a genome-wide significant intergenic locus near IGF1R at 15q26 (P = 1.7 × 10-9) and 6 additional loci with suggestive significance (P ≤ 5 × 10-7) such as API5 at 11p12 (P = 8.8 × 10-8) and RBFOX1 at 16p13 (P = 5.4 × 10-7) were identified. Gene expression data from brain tissue demonstrate association of ALCAM, ARAP1, GPC6, and RBFOX1 with brain β-amyloid load. Of 25 known loci associated with Alzheimer disease in non-Hispanic White individuals, only APOE, ABCA7, TREM2, BIN1, CD2AP, FERMT2, and WWOX were implicated at a nominal significance level or stronger in African American individuals. Pathway analyses strongly support the notion that immunity, lipid processing, and intracellular trafficking pathways underlying Alzheimer disease in African American individuals overlap with those observed in non-Hispanic White individuals. A new pathway emerging from these analyses is the kidney system, suggesting a novel mechanism for Alzheimer disease that needs further exploration.

CONCLUSIONS AND RELEVANCE

While the major pathways involved in Alzheimer disease etiology in African American individuals are similar to those in non-Hispanic White individuals, the disease-associated loci within these pathways differ.

摘要

重要性

与非西班牙裔白人个体相比，来自同一社区的非裔美国个体患阿尔茨海默病的可能性大约是前者的两倍。尽管存在这种差异，但迄今为止最大规模的阿尔茨海默病全基因组关联研究是在非西班牙裔白人个体中进行的。在对非裔美国个体进行的最大规模阿尔茨海默病关联分析中，ABCA7、TREM2和5q35处的一个基因间位点此前被认为与该病有关。

目的

通过增加样本量并使用非洲基因组资源面板来识别非裔美国个体中的其他风险基因座。

设计、背景和参与者：这项全基因组关联荟萃分析使用了来自阿尔茨海默病遗传学联盟的病例对照和基于家系的数据集。在美国各地有多个招募地点，纳入了患有阿尔茨海默病的个体和非裔美国血统的对照。分析于2018年10月开始，2019年9月结束。

主要结局和指标

阿尔茨海默病的诊断。

结果

共分析了2784例阿尔茨海默病患者（1944例女性[69.8%]）和5222例对照（3743例女性[71.7%]）（最后一次评估时的平均[标准差]年龄为74.2[13.6]岁）。发现与4个新的常见基因座相关，这些基因座分别位于细胞内糖蛋白运输基因EDEM1附近（3p26；P = 8.9×10−7）、免疫反应基因ALCAM附近（3q13；P = 9.3×10−7）、GPC6内（13q31；P = 4.1×10−7），GPC6是一个对将谷氨酸能受体招募到神经元膜至关重要的基因，以及VRK3内（19q13.33；P = 3.5×10−7），VRK3是一个参与谷氨酸神经毒性的基因。此外，还发现了几个与罕见变异相关的基因座，包括15q26处IGF1R附近一个全基因组显著的基因间位点（P = 1.7×10−9）以及另外6个具有提示性意义的位点（P≤5×10−7），如11p12处的API5（P = 8.8×10−8）和16p13处的RBFOX1（P = 5.4×10−7）。来自脑组织的基因表达数据表明ALCAM、ARAP1、GPC6和RBFOX1与脑β淀粉样蛋白负荷相关。在非西班牙裔白人个体中与阿尔茨海默病相关的25个已知基因座中，在非裔美国个体中只有APOE、ABCA7、TREM2、BIN1、CD2AP、FERMT2和WWOX在名义显著性水平或更高水平上有牵连。通路分析有力地支持了这样一种观点，即非裔美国个体中阿尔茨海默病潜在的免疫、脂质加工和细胞内运输通路与在非西班牙裔白人个体中观察到的通路重叠。这些分析中出现的一个新通路是肾脏系统，这提示了一种需要进一步探索的阿尔茨海默病新机制。