Genetic analysis of cognitive preservation in the midwestern Amish reveals a novel locus on chromosome 2

IF 13 1区医学 Q1 CLINICAL NEUROLOGY Alzheimer's & Dementia Pub Date : 2024-10-08 DOI:10.1002/alz.14045

Leighanne R. Main, Yeunjoo E. Song, Audrey Lynn, Renee A. Laux, Kristy L. Miskimen, Michael D. Osterman, Michael L. Cuccaro, Paula K. Ogrocki, Alan J. Lerner, Jeffery M. Vance, Denise Fuzzell, Sarada L. Fuzzell, Sherri D. Hochstetler, Daniel A. Dorfsman, Laura J. Caywood, Michael B. Prough, Larry D. Adams, Jason E. Clouse, Sharlene D. Herington, William K. Scott, Margaret A. Pericak-Vance, Jonathan L. Haines

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Abstract

INTRODUCTION

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.

METHODS

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).

RESULTS

A 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.

DISCUSSION

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.

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.

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对中西部阿米什人认知能力保护的遗传分析揭示了 2 号染色体上的一个新基因座

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。确定阿尔茨海默病的保护性基因位点可能会发现新的靶点，并加快治疗方法的确定。我们研究了一个始祖群体，以确定与晚年认知能力保持相关的基因位点。

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来源期刊

Alzheimer's & Dementia 医学-临床神经学

CiteScore

14.50

自引率

5.00%

发文量

299

审稿时长

3 months

期刊介绍： Alzheimer's & Dementia is a peer-reviewed journal that aims to bridge knowledge gaps in dementia research by covering the entire spectrum, from basic science to clinical trials to social and behavioral investigations. It provides a platform for rapid communication of new findings and ideas, optimal translation of research into practical applications, increasing knowledge across diverse disciplines for early detection, diagnosis, and intervention, and identifying promising new research directions. In July 2008, Alzheimer's & Dementia was accepted for indexing by MEDLINE, recognizing its scientific merit and contribution to Alzheimer's research.