Yiyi Ma, Dolly Reyes-Dumeyer, Angel Piriz, Patricia Recio, Diones Rivera Mejia, Martin Medrano, Rafael A. Lantigua, Jean Paul G. Vonsattel, Giuseppe Tosto, Andrew F. Teich, Benjamin Ciener, Sandra Leskinen, Sharanya Sivakumar, Michael DeTure, Duara Ranjan, Dennis Dickson, Melissa Murray, Edward Lee, David A. Wolk, Lee-Way Jin, Brittany N. Dugger, Annie Hiniker, Robert A. Rissman, Richard Mayeux, Badri N. Vardarajan
{"title":"从两个种族群体的尸检大脑看阿尔茨海默病的表观遗传和遗传风险。","authors":"Yiyi Ma, Dolly Reyes-Dumeyer, Angel Piriz, Patricia Recio, Diones Rivera Mejia, Martin Medrano, Rafael A. Lantigua, Jean Paul G. Vonsattel, Giuseppe Tosto, Andrew F. Teich, Benjamin Ciener, Sandra Leskinen, Sharanya Sivakumar, Michael DeTure, Duara Ranjan, Dennis Dickson, Melissa Murray, Edward Lee, David A. Wolk, Lee-Way Jin, Brittany N. Dugger, Annie Hiniker, Robert A. Rissman, Richard Mayeux, Badri N. Vardarajan","doi":"10.1007/s00401-024-02778-y","DOIUrl":null,"url":null,"abstract":"<div><p> Genetic variants and epigenetic features both contribute to the risk of Alzheimer’s disease (AD). We studied the AD association of CpG-related single nucleotide polymorphisms (CGS), which act as a hub of both the genetic and epigenetic effects, in Caribbean Hispanics (CH) and generalized the findings to Non-Hispanic Whites (NHW). First, we conducted a genome-wide, sliding-window-based association with AD, in 7,155 CH and 1,283 NHW participants. Next, using data from the dorsolateral prefrontal cortex in 179 CH brains, we tested the cis- and trans-effects of AD-associated CGS on brain DNA methylation to mRNA expression. For the genes with significant cis- and trans-effects, we investigated their enriched pathways. We identified six genetic loci in CH with CGS dosage associated with AD at genome-wide significance levels: <i>ADAM20</i> (Score = 55.19, <i>P</i> = 4.06 × 10<sup>–8</sup>), the intergenic region between <i>VRTN</i> and <i>SYNDIG1L</i> (Score = − 37.67, <i>P</i> = 2.25 × 10<sup>–9</sup>), <i>SPG7</i> (16q24.3) (Score = 40.51, <i>P</i> = 2.23 × 10<sup>–8</sup>), <i>PVRL2</i> (Score = 125.86, <i>P</i> = 1.64 × 10<sup>–9</sup>), <i>TOMM40</i> (Score = − 18.58, <i>P</i> = 4.61 × 10<sup>–8</sup>), and <i>APOE</i> (Score = 75.12, <i>P</i> = 7.26 × 10<sup>–26</sup>). CGSes in <i>PVRL2</i> and <i>APOE</i> were also significant in NHW. Except for <i>ADAM20</i>, CGSes in the other five loci were associated with CH brain methylation levels (mQTLs) and CGSes in <i>SPG7, PVRL2,</i> and <i>APOE</i> were also mQTLs in NHW. Except for <i>SYNDIG1L</i> (<i>P</i> = 0.08), brain methylation levels in the other five loci affected downstream mRNA expression in CH (<i>P</i> < 0.05), and methylation at <i>VRTN</i> and <i>TOMM40</i> were also associated with mRNA expression in NHW. Gene expression in these six loci were also regulated by CpG sites in genes that were enriched in the neuron projection and glutamatergic synapse pathways (FDR < 0.05). DNA methylation at all six loci and mRNA expression of <i>SYNDIG1</i> and <i>TOMM40</i> were significantly associated with Braak Stage in CH. In summary, we identified six CpG-related genetic loci associated with AD in CH, harboring both genetic and epigenetic risks. However, their downstream effects on mRNA expression maybe ethnic specific and different from NHW.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":null,"pages":null},"PeriodicalIF":9.3000,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11343944/pdf/","citationCount":"0","resultStr":"{\"title\":\"Epigenetic and genetic risk of Alzheimer disease from autopsied brains in two ethnic groups\",\"authors\":\"Yiyi Ma, Dolly Reyes-Dumeyer, Angel Piriz, Patricia Recio, Diones Rivera Mejia, Martin Medrano, Rafael A. Lantigua, Jean Paul G. Vonsattel, Giuseppe Tosto, Andrew F. Teich, Benjamin Ciener, Sandra Leskinen, Sharanya Sivakumar, Michael DeTure, Duara Ranjan, Dennis Dickson, Melissa Murray, Edward Lee, David A. Wolk, Lee-Way Jin, Brittany N. Dugger, Annie Hiniker, Robert A. Rissman, Richard Mayeux, Badri N. Vardarajan\",\"doi\":\"10.1007/s00401-024-02778-y\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p> Genetic variants and epigenetic features both contribute to the risk of Alzheimer’s disease (AD). We studied the AD association of CpG-related single nucleotide polymorphisms (CGS), which act as a hub of both the genetic and epigenetic effects, in Caribbean Hispanics (CH) and generalized the findings to Non-Hispanic Whites (NHW). First, we conducted a genome-wide, sliding-window-based association with AD, in 7,155 CH and 1,283 NHW participants. Next, using data from the dorsolateral prefrontal cortex in 179 CH brains, we tested the cis- and trans-effects of AD-associated CGS on brain DNA methylation to mRNA expression. For the genes with significant cis- and trans-effects, we investigated their enriched pathways. We identified six genetic loci in CH with CGS dosage associated with AD at genome-wide significance levels: <i>ADAM20</i> (Score = 55.19, <i>P</i> = 4.06 × 10<sup>–8</sup>), the intergenic region between <i>VRTN</i> and <i>SYNDIG1L</i> (Score = − 37.67, <i>P</i> = 2.25 × 10<sup>–9</sup>), <i>SPG7</i> (16q24.3) (Score = 40.51, <i>P</i> = 2.23 × 10<sup>–8</sup>), <i>PVRL2</i> (Score = 125.86, <i>P</i> = 1.64 × 10<sup>–9</sup>), <i>TOMM40</i> (Score = − 18.58, <i>P</i> = 4.61 × 10<sup>–8</sup>), and <i>APOE</i> (Score = 75.12, <i>P</i> = 7.26 × 10<sup>–26</sup>). CGSes in <i>PVRL2</i> and <i>APOE</i> were also significant in NHW. Except for <i>ADAM20</i>, CGSes in the other five loci were associated with CH brain methylation levels (mQTLs) and CGSes in <i>SPG7, PVRL2,</i> and <i>APOE</i> were also mQTLs in NHW. Except for <i>SYNDIG1L</i> (<i>P</i> = 0.08), brain methylation levels in the other five loci affected downstream mRNA expression in CH (<i>P</i> < 0.05), and methylation at <i>VRTN</i> and <i>TOMM40</i> were also associated with mRNA expression in NHW. Gene expression in these six loci were also regulated by CpG sites in genes that were enriched in the neuron projection and glutamatergic synapse pathways (FDR < 0.05). DNA methylation at all six loci and mRNA expression of <i>SYNDIG1</i> and <i>TOMM40</i> were significantly associated with Braak Stage in CH. In summary, we identified six CpG-related genetic loci associated with AD in CH, harboring both genetic and epigenetic risks. However, their downstream effects on mRNA expression maybe ethnic specific and different from NHW.</p></div>\",\"PeriodicalId\":7012,\"journal\":{\"name\":\"Acta Neuropathologica\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":9.3000,\"publicationDate\":\"2024-08-23\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11343944/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Acta Neuropathologica\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://link.springer.com/article/10.1007/s00401-024-02778-y\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Acta Neuropathologica","FirstCategoryId":"3","ListUrlMain":"https://link.springer.com/article/10.1007/s00401-024-02778-y","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
Epigenetic and genetic risk of Alzheimer disease from autopsied brains in two ethnic groups
Genetic variants and epigenetic features both contribute to the risk of Alzheimer’s disease (AD). We studied the AD association of CpG-related single nucleotide polymorphisms (CGS), which act as a hub of both the genetic and epigenetic effects, in Caribbean Hispanics (CH) and generalized the findings to Non-Hispanic Whites (NHW). First, we conducted a genome-wide, sliding-window-based association with AD, in 7,155 CH and 1,283 NHW participants. Next, using data from the dorsolateral prefrontal cortex in 179 CH brains, we tested the cis- and trans-effects of AD-associated CGS on brain DNA methylation to mRNA expression. For the genes with significant cis- and trans-effects, we investigated their enriched pathways. We identified six genetic loci in CH with CGS dosage associated with AD at genome-wide significance levels: ADAM20 (Score = 55.19, P = 4.06 × 10–8), the intergenic region between VRTN and SYNDIG1L (Score = − 37.67, P = 2.25 × 10–9), SPG7 (16q24.3) (Score = 40.51, P = 2.23 × 10–8), PVRL2 (Score = 125.86, P = 1.64 × 10–9), TOMM40 (Score = − 18.58, P = 4.61 × 10–8), and APOE (Score = 75.12, P = 7.26 × 10–26). CGSes in PVRL2 and APOE were also significant in NHW. Except for ADAM20, CGSes in the other five loci were associated with CH brain methylation levels (mQTLs) and CGSes in SPG7, PVRL2, and APOE were also mQTLs in NHW. Except for SYNDIG1L (P = 0.08), brain methylation levels in the other five loci affected downstream mRNA expression in CH (P < 0.05), and methylation at VRTN and TOMM40 were also associated with mRNA expression in NHW. Gene expression in these six loci were also regulated by CpG sites in genes that were enriched in the neuron projection and glutamatergic synapse pathways (FDR < 0.05). DNA methylation at all six loci and mRNA expression of SYNDIG1 and TOMM40 were significantly associated with Braak Stage in CH. In summary, we identified six CpG-related genetic loci associated with AD in CH, harboring both genetic and epigenetic risks. However, their downstream effects on mRNA expression maybe ethnic specific and different from NHW.
期刊介绍：
Acta Neuropathologica publishes top-quality papers on the pathology of neurological diseases and experimental studies on molecular and cellular mechanisms using in vitro and in vivo models, ideally validated by analysis of human tissues. The journal accepts Original Papers, Review Articles, Case Reports, and Scientific Correspondence (Letters). Manuscripts must adhere to ethical standards, including review by appropriate ethics committees for human studies and compliance with principles of laboratory animal care for animal experiments. Failure to comply may result in rejection of the manuscript, and authors are responsible for ensuring accuracy and adherence to these requirements.
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