Xin Wang, Iris Broce, Kacie D Deters, Chun Chieh Fan, Sarah Jane Banks
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We focused on the genetic variants within 10 genes previously shown to have sex-dependent effects on AD to reduce the burden of multiple comparisons: <i>BIN1</i>, <i>MS4A6A</i>, <i>DNAJA2</i>, <i>FERMT2</i>, <i>APOC1</i>, <i>APOC1P1</i>, <i>FAM193B</i>, <i>C2orf47</i>, <i>TYW5</i>, and <i>CR1.</i> Multivariate analysis of variance was applied to identify genetic variants associated with tau PET data in 3 regions of interests (composite regions of Braak I, Braak III/IV, and Braak V/VI stages) in women and men separately. We controlled for age, scanner manufacture, amyloid status, <i>APOE</i> ε4 carriership, diagnosis (CN vs MCI vs AD), and the first 10 genetic principal components to adjust for population stratification.</p><p><strong>Results: </strong>We identified 3 genetic loci within 3 different genes associated with tau deposits specifically in women: rs79711283 within <i>DNAJA2</i>, rs113357081 within <i>FERMT2</i>, and rs74614106 within <i>TYW5</i>. In men, we also identified 3 loci within <i>CR1</i> associated with tau deposits: rs115096248, rs113698814, and rs78150633.</p><p><strong>Discussion: </strong>Our findings revealed sex-specific genetic variants associated with tau deposition independent of <i>APOE</i> ε4, amyloid status, and clinical diagnosis. These results provide potential molecular targets for understanding the mechanism of sex-specific tau aggregation and developing sex-specific gene-guided precision prevention or therapeutic interventions for AD.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"8 6","pages":"e200043"},"PeriodicalIF":3.0000,"publicationDate":"2022-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/8c/9d/NXG-2022-200046.PMC9756308.pdf","citationCount":"0","resultStr":"{\"title\":\"Identification of Sex-Specific Genetic Variants Associated With Tau PET.\",\"authors\":\"Xin Wang, Iris Broce, Kacie D Deters, Chun Chieh Fan, Sarah Jane Banks\",\"doi\":\"10.1212/NXG.0000000000200043\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background and objectives: </strong>Important sex differences exist in tau pathology along the Alzheimer disease (AD) continuum, with women showing enhanced tau deposition compared with men, especially during the mild cognitive impairment (MCI) phase. This study aims to identify specific genetic variants associated with sex differences in regional tau aggregation, as measured with PET.</p><p><strong>Methods: </strong>Four hundred ninety-three participants (women, n = 246; men, n = 247) who self-identified as White from the AD Neuroimaging Initiative study, with genotyping data and <sup>18</sup>F-Flortaucipir tau PET data, were included irrespective of clinical diagnosis (cognitively normal [CN], MCI, and AD). We focused on the genetic variants within 10 genes previously shown to have sex-dependent effects on AD to reduce the burden of multiple comparisons: <i>BIN1</i>, <i>MS4A6A</i>, <i>DNAJA2</i>, <i>FERMT2</i>, <i>APOC1</i>, <i>APOC1P1</i>, <i>FAM193B</i>, <i>C2orf47</i>, <i>TYW5</i>, and <i>CR1.</i> Multivariate analysis of variance was applied to identify genetic variants associated with tau PET data in 3 regions of interests (composite regions of Braak I, Braak III/IV, and Braak V/VI stages) in women and men separately. We controlled for age, scanner manufacture, amyloid status, <i>APOE</i> ε4 carriership, diagnosis (CN vs MCI vs AD), and the first 10 genetic principal components to adjust for population stratification.</p><p><strong>Results: </strong>We identified 3 genetic loci within 3 different genes associated with tau deposits specifically in women: rs79711283 within <i>DNAJA2</i>, rs113357081 within <i>FERMT2</i>, and rs74614106 within <i>TYW5</i>. In men, we also identified 3 loci within <i>CR1</i> associated with tau deposits: rs115096248, rs113698814, and rs78150633.</p><p><strong>Discussion: </strong>Our findings revealed sex-specific genetic variants associated with tau deposition independent of <i>APOE</i> ε4, amyloid status, and clinical diagnosis. 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引用次数: 0
摘要
背景和目的：在阿尔茨海默病（AD）的连续过程中，tau病理学存在重要的性别差异，与男性相比，女性的tau沉积增强，尤其是在轻度认知障碍（MCI）阶段。本研究旨在确定与 PET 测量的区域性 tau 聚集的性别差异相关的特定基因变异：这项研究共纳入了 493 名自称为白人的 AD 神经影像学倡议研究参与者（女性，n = 246；男性，n = 247），这些参与者拥有基因分型数据和 18F-Flortaucipir tau PET 数据，与临床诊断（认知功能正常 [CN]、MCI 和 AD）无关。我们重点研究了 10 个基因中的遗传变异，这些基因以前曾被证明对 AD 有性别依赖性影响，以减少多重比较的负担：这些基因包括：BIN1、MS4A6A、DNAJA2、FERMT2、APOC1、APOC1P1、FAM193B、C2orf47、TYW5 和 CR1。应用多变量方差分析分别鉴定了女性和男性3个感兴趣区域（Braak I期、Braak III/IV期和Braak V/VI期的复合区域）中与tau PET数据相关的遗传变异。我们控制了年龄、扫描仪制造、淀粉样蛋白状态、APOE ε4携带者、诊断（CN vs MCI vs AD）以及前10个遗传主成分，以调整人群分层：我们在3个不同基因中发现了3个与女性tau沉积相关的基因位点：DNAJA2中的rs79711283、FERMT2中的rs113357081和TYW5中的rs74614106。在男性中，我们还发现了 CR1 中与 tau 沉积相关的 3 个位点：rs115096248、rs113698814 和 rs78150633：我们的发现揭示了与tau沉积相关的性别特异性遗传变异，它们与APOE ε4、淀粉样蛋白状态和临床诊断无关。这些结果为了解性别特异性tau聚集机制、开发以性别特异性基因为指导的AD精准预防或治疗干预措施提供了潜在的分子靶点。
Identification of Sex-Specific Genetic Variants Associated With Tau PET.
Background and objectives: Important sex differences exist in tau pathology along the Alzheimer disease (AD) continuum, with women showing enhanced tau deposition compared with men, especially during the mild cognitive impairment (MCI) phase. This study aims to identify specific genetic variants associated with sex differences in regional tau aggregation, as measured with PET.
Methods: Four hundred ninety-three participants (women, n = 246; men, n = 247) who self-identified as White from the AD Neuroimaging Initiative study, with genotyping data and 18F-Flortaucipir tau PET data, were included irrespective of clinical diagnosis (cognitively normal [CN], MCI, and AD). We focused on the genetic variants within 10 genes previously shown to have sex-dependent effects on AD to reduce the burden of multiple comparisons: BIN1, MS4A6A, DNAJA2, FERMT2, APOC1, APOC1P1, FAM193B, C2orf47, TYW5, and CR1. Multivariate analysis of variance was applied to identify genetic variants associated with tau PET data in 3 regions of interests (composite regions of Braak I, Braak III/IV, and Braak V/VI stages) in women and men separately. We controlled for age, scanner manufacture, amyloid status, APOE ε4 carriership, diagnosis (CN vs MCI vs AD), and the first 10 genetic principal components to adjust for population stratification.
Results: We identified 3 genetic loci within 3 different genes associated with tau deposits specifically in women: rs79711283 within DNAJA2, rs113357081 within FERMT2, and rs74614106 within TYW5. In men, we also identified 3 loci within CR1 associated with tau deposits: rs115096248, rs113698814, and rs78150633.
Discussion: Our findings revealed sex-specific genetic variants associated with tau deposition independent of APOE ε4, amyloid status, and clinical diagnosis. These results provide potential molecular targets for understanding the mechanism of sex-specific tau aggregation and developing sex-specific gene-guided precision prevention or therapeutic interventions for AD.
期刊介绍：
Neurology: Genetics is an online open access journal publishing peer-reviewed reports in the field of neurogenetics. Original articles in all areas of neurogenetics will be published including rare and common genetic variation, genotype-phenotype correlations, outlier phenotypes as a result of mutations in known disease-genes, and genetic variations with a putative link to diseases. This will include studies reporting on genetic disease risk and pharmacogenomics. In addition, Neurology: Genetics will publish results of gene-based clinical trials (viral, ASO, etc.). Genetically engineered model systems are not a primary focus of Neurology: Genetics, but studies using model systems for treatment trials are welcome, including well-powered studies reporting negative results.
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