Institute for Cancer Outcomes and Survivorship, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA.
Bone Marrow Transplant. 2022 Jun;57(6):925-933. doi: 10.1038/s41409-022-01642-5. Epub 2022 Apr 4.
Cognitive impairment is prevalent in blood or marrow transplantation (BMT) recipients, albeit with inter-individual variability. We conducted a genome-wide association study of objective cognitive function assessed longitudinally in 239 adult BMT recipients for discovery and replicated in an independent cohort of 540 BMT survivors. Weighted genome-wide polygenic risk scores (PRS) were constructed using linkage disequilibrium pruned significant SNPs. Forty-four genome-wide significant SNPs were identified using additive (n = 3); codominant (n = 20) and genotype models (n = 21). Each additional copy of a risk allele was associated with a 0.28-point (p = 1.07 × 10) to a 1.82-point (p = 6.7 × 10) increase in a global deficit score. We replicated two SNPs (rs11634183 and rs12486041) with links to neural integrity. Patients in the top PRS quintile were at increased risk of cognitive impairment in discovery (RR = 1.95, 95%CI: 1.28-2.96, p = 0.002) and replication cohorts (OR = 1.84, 95%CI, 1.02-3.32, p = 0.043). Associations were stronger among individuals with lowest clinical risk for cognitive impairment. These findings support potential utility of PRS-based risk classification in the development of targeted interventions aimed at improving cognitive outcomes in BMT survivors.
认知障碍在血液或骨髓移植（BMT）受者中很常见，尽管存在个体间的差异。我们对 239 名成年 BMT 受者进行了纵向评估的客观认知功能进行了全基因组关联研究，用于发现，并在 540 名 BMT 幸存者的独立队列中进行了复制。使用连锁不平衡修剪后的显著 SNP 构建了加权全基因组多基因风险评分（PRS）。使用加性（n=3）；共显性（n=20）和基因型模型（n=21）鉴定了 44 个全基因组显著 SNP。每个风险等位基因的额外拷贝与全球缺陷评分增加 0.28 点（p=1.07×10）到 1.82 点（p=6.7×10）相关。我们复制了两个与神经完整性相关的 SNP（rs11634183 和 rs12486041）。PRS 最高五分位的患者在发现（RR=1.95，95%CI：1.28-2.96，p=0.002）和复制队列（OR=1.84，95%CI，1.02-3.32，p=0.043）中认知障碍的风险增加。在认知障碍临床风险最低的个体中，相关性更强。这些发现支持基于 PRS 的风险分类在开发针对 BMT 幸存者认知结果的靶向干预措施方面的潜在效用。
