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Genome-wide association study of occupational attainment as a proxy for cognitive reserve
Brain ( IF 14.5 ) Pub Date : 2021-09-16 , DOI: 10.1093/brain/awab351
Hyunwoong Ko 1, 2, 3 , Soyeon Kim 4, 5, 6 , Kiwon Kim 7 , Sang-Hyuk Jung 4 , Injeong Shim 4 , Soojin Cha 4 , Hyewon Lee 8 , Beomsu Kim 4 , Joohyun Yoon 9 , Tae Hyon Ha 9 , Seyul Kwak 2, 10 , Jae Myeong Kang 11 , Jun-Young Lee 2 , Jinho Kim 12 , Woong-Yang Park 13 , Kwangsik Nho 14 , Doh Kwan Kim 15 , Woojae Myung 9, 16 , Hong-Hee Won 4, 13
Affiliation  

Occupational attainment, which represents middle-age cognitive activities, is a known proxy marker of cognitive reserve for Alzheimer's disease. Previous genome-wide association studies (GWAS) have identified numerous genetic variants and revealed the genetic architecture of educational attainment, another marker of cognitive reserve. However, the genetic architecture and heritability for occupational attainment remain elusive. We performed a large-scale GWAS of occupational attainment with 248,847 European individuals from the UK Biobank using the proportional odds logistic mixed model method. In this analysis, we defined occupational attainment using the classified job levels formulated in the UK Standard Occupational Classification system considering the individual professional skill and academic level. We identified 30 significant loci (P < 5 × 10−8); 12 were novel variants, unassociated with other traits. Among them, four lead variants were associated with genes expressed in brain tissues by expression quantitative trait loci mapping from 10 brain regions: rs13002946, rs3741368, rs11654986, and rs1627527. The single nucleotide polymorphism (SNP)-based heritability was estimated to be 8.5% (s.e. = 0.004) and partitioned heritability was enriched in the central nervous system and brain tissues. Genetic correlation analysis showed shared genetic backgrounds between occupational attainment and multiple traits, including education, intelligence, leisure activities, life satisfaction, and neuropsychiatric disorders. In two-sample Mendelian randomization (MR) analysis, we demonstrated that high occupation levels were associated with reduced risk for Alzheimer's disease (OR = 0.78, 95% CI = 0.65–0.92 in inverse variance weighted (IVW) method; OR = 0.73, 95% CI = 0.57–0.92 in the weighted median (WM) method). This causal relationship between occupational attainment and Alzheimer's disease was robust in additional sensitivity analysis that excluded potentially pleiotropic SNPs (OR = 0.72, 95% CI = 0.57–0.91 in the IVW method; OR = 0.72, 95% CI = 0.53–0.97 in the WM method). Multivariable MR confirmed that occupational attainment had an independent effect on the risk for Alzheimer’s disease even after taking educational attainment into account (OR = 0.72, 95% CI = 0.54–0.95 in the IVW method; OR = 0.68, 95% CI = 0.48–0.97 in the WM method). Overall, our analyses provide insights into the genetic architecture of occupational attainment and demonstrate that occupational attainment is a potential causal protective factor for Alzheimer's disease as a proxy marker of cognitive reserve.

中文翻译:

职业成就的全基因组关联研究作为认知储备的代表

代表中年认知活动的职业成就是阿尔茨海默病认知储备的已知代理标志。以前的全基因组关联研究 (GWAS) 已经确定了许多遗传变异,并揭示了教育程度的遗传结构,这是认知储备的另一个标志。然而,职业成就的遗传结构和遗传性仍然难以捉摸。我们使用比例优势逻辑混合模型方法对来自英国生物银行的 248,847 名欧洲人进行了大规模的职业成就 GWAS。在此分析中,我们使用英国标准职业分类系统中制定的分类工作级别来定义职业成就,同时考虑到个人的专业技能和学术水平。我们确定了 30 个重要位点(P < 5 × 10-8);12 个是新的变体,与其他特征无关。其中,通过来自 10 个脑区的表达数量性状位点作图,四个先导变异与脑组织中表达的基因相关:rs13002946、rs3741368、rs11654986 和 rs1627527。基于单核苷酸多态性 (SNP) 的遗传力估计为 8.5% (se = 0.004),并且在中枢神经系统和脑组织中富集了分区遗传力。遗传相关性分析显示,职业成就和多种特征之间存在共同的遗传背景,包括教育、智力、休闲活动、生活满意度和神经精神疾病。在两样本孟德尔随机化 (MR) 分析中,我们证明了高职业水平与阿尔茨海默病风险降低相关(在逆方差加权 (IVW) 方法中,OR = 0.78, 95% CI = 0.65–0.92;在加权中位数中 OR = 0.73, 95% CI = 0.57–0.92 (WM)方法)。职业成就与阿尔茨海默病之间的这种因果关系在排除潜在多效性 SNP 的额外敏感性分析中是稳健的(IVW 方法中的 OR = 0.72, 95% CI = 0.57-0.91;OR = 0.72, 95% CI = 0.53-0.97 WM 方法)。多变量 MR 证实,即使将教育程度考虑在内,职业成就对阿尔茨海默病的风险也有独立影响(IVW 方法中的 OR = 0.72, 95% CI = 0.54–0.95;OR = 0.68, 95% CI = 0.48–在 WM 方法中为 0.97)。全面的,
更新日期:2021-09-16
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