INTRODUCTIONAlzheimer'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.METHODSGenome‐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).RESULTSA total of 12 single nucleotide polymorphisms (SNPs) demonstrated suggestive association (P ≤ 5 × 10−4) 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.DISCUSSIONA 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.Highlights 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.

中文翻译：

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中西部阿米什人认知保存的遗传分析揭示了 2 号染色体上的一个新位点


引言阿尔茨海默病 （AD） 仍然是一种使人衰弱的疾病，需要有限的治疗方法和额外的治疗靶点。鉴定 AD 保护性基因位点可以识别新靶点并加速治疗药物的鉴定。我们检查了创始人群体，以确定与高龄认知保留相关的基因座。方法对 946 名年龄在 76-95 岁之间的阿米什人进行了全基因组的关联和连锁分析，这些个体要么是认知障碍 （CU），要么是受损 （CI）。结果共有 12 个单核苷酸多态性 （SNP） 显示提示性关联 （P ≤ 5 × 10-4） 与认知保留。遗传连锁分析确定了 > 100 个显著 （比值对数 [LOD] ≥ 3.3） SNP，其中一些与关联结果重叠。在多次分析中，只有 2 号染色体上的一个基因座保持显著性。讨论 2 号染色体认知保存的一个新的重要结果包括基因 LRRTM4 和 CTNNA2。此外，先导 SNP rs1402906 会影响 POU3F2 转录因子结合亲和力，从而调节 LRRTM4 和 CTNNA2。亮点 GWAS 和连锁鉴定了 100 多个与认知保存相关的基因座。2 号染色体上的一个基因座在多次分析中保持显著性。rs1402906 附近的预测 TFBs 调节与神经认知相关的基因。