Genetic analysis of cognitive preservation in the midwestern Amish reveals a novel locus on chromosome 2.
Genetic analysis of cognitive preservation in the midwestern Amish reveals a novel locus on chromosome 2.
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对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基因座。
DOI：
10.1101/2023.12.13.23299932
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Dorfsman,Daniel
中科院分区：
文献类型：
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作者：
Main,LeighanneR;Song,YeunjooE;Lynn,Audrey;Laux,ReneeA;Miskimen,KristyL;Osterman,MichaelD;Cuccaro,MichaelL;Ogrocki,PaulaK;Lerner,AlanJ;Vance,JefferyM;Fuzzell,MDenise;Fuzzell,SaradaL;Hochstetler,SherriD;Dorfsman,Daniel
引言阿尔茨海默病（AD）仍然是一个衰弱的条件与有限的治疗和额外的治疗目标的需要。识别AD保护性遗传基因座可以识别新的靶点并加速治疗性治疗的识别。我们检查了一个创始人人口，以确定与认知保存到先进的age. METHODS基因组关联和连锁分析进行了946检查和抽样的阿米什人，年龄76-95，结果表明，12个单核苷酸多态性（SNPs）与认知功能受损（CI）或认知功能未受损（CU）相关，（P≤ 5 × 10−4），具有认知保护。遗传连锁分析确定了> 100个显著的（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，2号染色体上只有一个位点保持了显著性。此外，前导SNP rs 1402906影响POU 3F 2转录因子结合亲和力，POU 3F 2转录因子结合亲和力调节LRRTM 4和CTNNA 2。突出显示GWAS和连锁发现超过100个与认知保护相关的位点。2号染色体上的一个位点在多次分析中保持显著性。预测rs 1402906附近的TFBS调节与神经认知相关的基因。
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 genesLRRTM4andCTNNA2. Additionally, the lead SNP, rs1402906, impacts the POU3F2 transcription factor binding affinity, which regulatesLRRTM4andCTNNA2.HighlightsGWAS 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.