Departments of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio, USA.
Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
Alzheimers Dement. 2024 Nov;20(11):7453-7464. doi: 10.1002/alz.14045. Epub 2024 Oct 8.
Alzheimer's disease (AD) remains a debilitating condition with limited treatments and additional therapeutic targets needed. Identifying AD protective genetic loci may identify new targets and accelerate identification of therapeutic treatments. We examined a founder population to identify loci associated with cognitive preservation into advanced age.
Genome-wide association and linkage analyses were performed on 946 examined and sampled Amish individuals, aged 76-95, who were either cognitively unimpaired (CU) or impaired (CI).
A total of 12 single nucleotide polymorphisms (SNPs) demonstrated suggestive association (P ≤ 5 × 10) with cognitive preservation. Genetic linkage analyses identified > 100 significant (logarithm of the odds [LOD] ≥ 3.3) SNPs, some which overlapped with the association results. Only one locus on chromosome 2 retained significance across multiple analyses.
A novel significant result for cognitive preservation on chromosome 2 includes the genes LRRTM4 and CTNNA2. Additionally, the lead SNP, rs1402906, impacts the POU3F2 transcription factor binding affinity, which regulates LRRTM4 and CTNNA2.
GWAS and linkage identified over 100 loci associated with cognitive preservation. One locus on Chromosome 2 retained significance over multiple analyses. Predicted TFBSs near rs1402906 regulate genes associated with neurocognition.
阿尔茨海默病（AD）仍然是一种使人衰弱的疾病，治疗方法有限，需要更多的治疗靶点。确定 AD 的保护性遗传基因座可能会确定新的靶点，并加速治疗方法的确定。我们研究了一个创始人群，以确定与认知保护相关的基因座，使其能进入老年。
对 946 名接受检查和抽样的年龄在 76-95 岁的阿米什人进行全基因组关联和连锁分析，这些人要么认知正常（CU），要么认知受损（CI）。
共有 12 个单核苷酸多态性（SNPs）与认知保护呈显著关联（P≤5×10）。遗传连锁分析确定了 100 多个显著的（对数优势[LOD]≥3.3）SNP，其中一些与关联结果重叠。只有一个位于染色体 2 上的基因座在多个分析中保持显著。
染色体 2 上认知保护的一个新的显著结果包括 LRRTM4 和 CTNNA2 基因。此外，主要 SNP rs1402906 影响了 POU3F2 转录因子结合亲和力，从而调节了 LRRTM4 和 CTNNA2。
全基因组关联和连锁分析确定了 100 多个与认知保护相关的基因座。染色体 2 上的一个基因座在多个分析中保持显著。rs1402906 附近的预测 TFBS 调节与神经认知相关的基因。
