Admixture mapping reveals the association between Native American ancestry at 3q13.11 and reduced risk of Alzheimer's disease in Caribbean Hispanics.
Admixture mapping reveals the association between Native American ancestry at 3q13.11 and reduced risk of Alzheimer's disease in Caribbean Hispanics.
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DOI：
10.1186/s13195-021-00866-9
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发表时间：
2021-07-03
期刊：
影响因子：
--
通讯作者：
Blue EE
中科院分区：
文献类型：
--
作者：
Horimoto ARVR;Xue D;Thornton TA;Blue EE
遗传学研究主要在欧洲血统人群中进行，确定了数十个与晚发性阿尔茨海默病（AD）相关的基因座。然而，AD的大部分遗传性仍然无法解释;由于AD的患病率在不同人群中存在差异，该疾病的遗传结构也可能因人群而异，存在新的变异或基因座。我们在2565名加勒比海西班牙裔样本中进行了AD的全基因组分析，以更好地了解该人群中AD的遗传贡献。统计分析包括混合物分布和关联检验。从独立的转录组学研究中收集了感兴趣区域内差异基因表达的证据，这些研究比较了主要具有欧洲血统的AD病例和对照样本。我们的AD全基因组关联研究没有发现达到全基因组意义的位点。然而，一项全基因组混合作图分析检测了单倍型的祖先起源与AD状态之间的关联，检测到与染色体3q13.11（103.7-107.7Mb，P = 8.76E−07）的全基因组显著关联，这是由美洲原住民祖先赋予的保护作用驱动的（OR = 0.58，95%CI = 0.47−0.73）。在该区域内，在考虑独立测试的数量后，两个变异与AD显著相关（rs 12494162，P = 2.33E-06; rs 1731642，P = 6.36E-05）。显著混合物映射信号由跨越5个蛋白质编码基因（ALCAM、BBX、CBLB、CCDC 54、CD 47）和4个脑源性拓扑相关结构域的15个单倍型块组成，并且包括与脑中ALCAM、BBX、CBLB和CD 47的表达显著相关的标记物。ALCAM和BBX也显着差异表达在AD病例和欧洲血统的对照组之间的大脑。这些结果为AD和3q13.11多个基因之间的关系提供了多种族证据，并说明了通过混合物映射利用遗传祖先多样性对AD的新见解的效用。在线版本包含补充材料，可通过10.1186/s13195-021-00866-9获得。
Genetic studies have primarily been conducted in European ancestry populations, identifying dozens of loci associated with late-onset Alzheimer’s disease (AD). However, much of AD’s heritability remains unexplained; as the prevalence of AD varies across populations, the genetic architecture of the disease may also vary by population with the presence of novel variants or loci. We conducted genome-wide analyses of AD in a sample of 2565 Caribbean Hispanics to better understand the genetic contribution to AD in this population. Statistical analysis included both admixture mapping and association testing. Evidence for differential gene expression within regions of interest was collected from independent transcriptomic studies comparing AD cases and controls in samples with primarily European ancestry. Our genome-wide association study of AD identified no loci reaching genome-wide significance. However, a genome-wide admixture mapping analysis that tests for association between a haplotype’s ancestral origin and AD status detected a genome-wide significant association with chromosome 3q13.11 (103.7–107.7Mb, P = 8.76E−07), driven by a protective effect conferred by the Native American ancestry (OR = 0.58, 95%CI = 0.47−0.73). Within this region, two variants were significantly associated with AD after accounting for the number of independent tests (rs12494162, P = 2.33E−06; rs1731642, P = 6.36E−05). The significant admixture mapping signal is composed of 15 haplotype blocks spanning 5 protein-coding genes (ALCAM, BBX, CBLB, CCDC54, CD47) and four brain-derived topologically associated domains, and includes markers significantly associated with the expression of ALCAM, BBX, CBLB, and CD47 in the brain. ALCAM and BBX were also significantly differentially expressed in the brain between AD cases and controls with European ancestry. These results provide multiethnic evidence for a relationship between AD and multiple genes at 3q13.11 and illustrate the utility of leveraging genetic ancestry diversity via admixture mapping for new insights into AD. The online version contains supplementary material available at 10.1186/s13195-021-00866-9.
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影响因子：
11
作者：
Chouraki, V.;De Bruijn, R. F. A. G.;Chapuis, J.;Bis, J. C.;Reitz, C.;Schraen, S.;Ibrahim-Verbaas, C. A.;Grenier-Boley, B.;Delay, C.;Rogers, R.;Demiautte, F.;Mounier, A.;Fitzpatrick, A. L.;Berr, C.;Dartigues, J-F;Uitterlinden, A. G.;Hofman, A.;Breteler, M.;Becker, J. T.;Lathrop, M.;Schupf, N.;Alperovitch, A.;Mayeux, R.;van Duijn, C. M.;Buee, L.;Amouyel, P.;Lopez, O. L.;Ikram, M. A.;Tzourio, C.;Lambert, J-C
通讯作者：
Lambert, J-C
影响因子：
5.8
作者：
Gogarten, Stephanie M.;Sofer, Tamar;Conomos, Matthew P.
通讯作者：
Conomos, Matthew P.
影响因子：
3.7
作者：
Aubry, Soline;Shin, William;Shelanski, Michael L.
通讯作者：
Shelanski, Michael L.
影响因子：
2.1
作者：
Conomos MP;Miller MB;Thornton TA
通讯作者：
Thornton TA
影响因子：
12.3
作者：
Gay, Nicole R.;Gloudemans, Michael;Montgomery, Stephen B.
通讯作者：
Montgomery, Stephen B.