性别特异性阿尔茨海默病生物标志物的遗传预测因子。
Sex-specific genetic predictors of Alzheimer's disease biomarkers.
机构信息
Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA.
Vanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Vanderbilt University School of Medicine, 1207 17th Avenue S, Nashville, TN, 37212, USA.
出版信息
Acta Neuropathol. 2018 Dec;136(6):857-872. doi: 10.1007/s00401-018-1881-4. Epub 2018 Jul 2.
Cerebrospinal fluid (CSF) levels of amyloid-β 42 (Aβ42) and tau have been evaluated as endophenotypes in Alzheimer's disease (AD) genetic studies. Although there are sex differences in AD risk, sex differences have not been evaluated in genetic studies of AD endophenotypes. We performed sex-stratified and sex interaction genetic analyses of CSF biomarkers to identify sex-specific associations. Data came from a previous genome-wide association study (GWAS) of CSF Aβ42 and tau (1527 males, 1509 females). We evaluated sex interactions at previous loci, performed sex-stratified GWAS to identify sex-specific associations, and evaluated sex interactions at sex-specific GWAS loci. We then evaluated sex-specific associations between prefrontal cortex (PFC) gene expression at relevant loci and autopsy measures of plaques and tangles using data from the Religious Orders Study and Rush Memory and Aging Project. In Aβ42, we observed sex interactions at one previous and one novel locus: rs316341 within SERPINB1 (p = 0.04) and rs13115400 near LINC00290 (p = 0.002). These loci showed stronger associations among females (β = - 0.03, p = 4.25 × 10; β = 0.03, p = 3.97 × 10) than males (β = - 0.02, p = 0.009; β = 0.01, p = 0.20). Higher levels of expression of SERPINB1, SERPINB6, and SERPINB9 in PFC was associated with higher levels of amyloidosis among females (corrected p values < 0.02) but not males (p > 0.38). In total tau, we observed a sex interaction at a previous locus, rs1393060 proximal to GMNC (p = 0.004), driven by a stronger association among females (β = 0.05, p = 4.57 × 10) compared to males (β = 0.02, p = 0.03). There was also a sex-specific association between rs1393060 and tangle density at autopsy (p = 0.047; p = 0.96), and higher levels of expression of two genes within this locus were associated with lower tangle density among females (OSTN p = 0.006; CLDN16 p = 0.002) but not males (p ≥ 0.32). Results suggest a female-specific role for SERPINB1 in amyloidosis and for OSTN and CLDN16 in tau pathology. Sex-specific genetic analyses may improve understanding of AD's genetic architecture.
脑脊液（CSF）中淀粉样蛋白-β42（Aβ42）和 tau 的水平已被评估为阿尔茨海默病（AD）遗传研究中的表型。尽管 AD 风险存在性别差异，但 AD 表型的遗传研究并未评估性别差异。我们对 CSF 生物标志物进行了性别分层和性别相互作用的遗传分析，以确定性别特异性关联。数据来自先前的 CSF Aβ42 和 tau 的全基因组关联研究（GWAS）（1527 名男性，1509 名女性）。我们评估了先前基因座的性别相互作用，进行了性别分层 GWAS 以确定性别特异性关联，并评估了性别特异性 GWAS 基因座的性别相互作用。然后，我们使用宗教秩序研究和拉什记忆与衰老项目中的相关基因座的前额叶皮层（PFC）基因表达数据，评估了这些基因座与斑块和缠结的尸检测量值之间的性别特异性关联。在 Aβ42 中，我们在一个先前和一个新的基因座观察到了性别相互作用：SERPINB1 内的 rs316341（p=0.04）和 LINC00290 附近的 rs13115400（p=0.002）。这些基因座在女性中表现出更强的关联（β=−0.03，p=4.25×10；β=0.03，p=3.97×10），而在男性中则较弱（β=−0.02，p=0.009；β=0.01，p=0.20）。PFC 中 SERPINB1、SERPINB6 和 SERPINB9 的表达水平较高与女性的淀粉样蛋白水平较高有关（校正后的 p 值<0.02），但与男性无关（p>0.38）。在总 tau 中，我们在先前的基因座 rs1393060 附近观察到了性别相互作用（靠近 GMNC，p=0.004），这是由女性中更强的关联驱动的（β=0.05，p=4.57×10），而在男性中则较弱（β=0.02，p=0.03）。rs1393060 与尸检时的缠结密度之间也存在性别特异性关联（p=0.047；p=0.96），并且该基因座内的两个基因的表达水平较高与女性的缠结密度较低有关（OSTN p=0.006；CLDN16 p=0.002），但与男性无关（p≥0.32）。结果表明，SERPINB1 在淀粉样蛋白形成中具有女性特异性作用，OSTN 和 CLDN16 在 tau 病理学中具有女性特异性作用。性别特异性遗传分析可能会提高对 AD 遗传结构的理解。
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