Genome-wide association study identified INSC gene associated with Trail Making Test Part A and Alzheimer's disease related cognitive phenotypes,Progress in Neuro-Psychopharmacology and Biological Psychiatry

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Genome-wide association study identified INSC gene associated with Trail Making Test Part A and Alzheimer's disease related cognitive phenotypes
Progress in Neuro-Psychopharmacology and Biological Psychiatry ( IF 5.3 ) Pub Date : 2021-07-02 , DOI: 10.1016/j.pnpbp.2021.110393
Kesheng Wang ₁ , Chun Xu ₂ , Amanda Smith ₃ , Danqing Xiao ₄ , R Osvaldo Navia ₅ , Yongke Lu ₆ , Changchun Xie ₇ , Ubolrat Piamjariyakul ₈ ,

Affiliation

Department of Family and Community Health, School of Nursing, Health Sciences Center, West Virginia University, Morgantown, WV 26506, USA.
Department of Health and Biomedical Sciences, College of Health Affairs, University of Texas Rio Grande Valley, Brownsville, TX 78520, USA.
Department of Psychiatry and Behavioral Neuroscience, Morsani College of Medicine, University of South Florida, Tampa, FL 33613, USA.
Department of STEM, School of Arts and Sciences, Regis College, Weston, MA 02493, USA; Neuroimaging Center, McLean Hospital, Belmont, MA 02478, USA; School of Arts and Sciences, MCPHS University, Boston, MA 02115, USA.
Department of Medicine and Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV 26506, USA.
Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA.
Division of Biostatistics and Bioinformatics, Department of Environmental Health, University of Cincinnati, Cincinnati, OH 45267, USA.
School of Nursing, Health Sciences Center, West Virginia University, Morgantown, WV 26506, USA.

Background

The Trail Making Test (TMT) Part A (TMT-A) is a good measure of performance on cognitive processing speed. This study aimed to perform a genome-wide association study of TMT-A in Alzheimer's disease (AD).

Methods

A total of 757 individuals with TMT-A phenotypes and 620,901 single nucleotide polymorphisms (SNPs) were extracted from the Alzheimer's Disease Neuroimaging Initiative 1 (ADNI-1) cohort. AD related cognitive phenotypes include TMT-A, TMT-B, Functional Activities Questionnaire (FAQ), Clinical Dementia Rating Sum of Boxes (CDR-SB), and Alzheimer's Disease Assessment Scale–Cognitive Subscale 13 (ADAS13). Multivariable linear regression analysis of TMT-A was conducted using PLINK software. The most TMT-A associated gene was tested with Color Trails Test 1 Form A (CTTA), a culturally fair analog of the TMT-A. Functional annotation of SNPs was performed using the RegulomeDB and Genotype-Tissue Expression (GTEx) databases.

Results

The best signal with TMT-A was rs1108010 (p = 4.34 × 10⁻⁸) at 11p15.2 within INSC gene, which was also associated with TMT-B, FAQ, CDR-SB, and ADAS13 (p = 2.47 × 10⁻⁴, 8.56 × 10⁻³, 0.0127 and 0.0188, respectively). Furthermore, suggestive loci were identified such as FOXD2 and CLTA with TMT-A, GBP1/GBP3 with TMT-B, GRIK2 with FAQ, BAALC and CCDC146 with CDR-SB, BAALC and NKAIN2 with ADAS13. Additionally, the best SNP within INSC associated with CTTA was rs7931705 (p = 6.15 × 10⁻⁵). Several SNPs had significant eQTLs using GTEx.

Conclusions

We identified several genes/loci associated with TMT-A and AD related phenotypes. These findings offer the potential for new insights into the pathogenesis of cognitive function and Alzheimer's disease.

中文翻译：

全基因组关联研究确定了与 Trail Making Test Part A 和阿尔茨海默病相关的认知表型相关的 INSC 基因

背景

Trail Making Test (TMT) Part A (TMT-A) 是衡量认知处理速度表现的良好指标。本研究旨在对阿尔茨海默病 (AD) 中的 TMT-A 进行全基因组关联研究。

方法

从阿尔茨海默病神经影像学倡议 1 (ADNI-1) 队列中提取了总共 757 名具有 TMT-A 表型和 620,901 个单核苷酸多态性 (SNP) 的个体。AD 相关的认知表型包括 TMT-A、TMT-B、功能活动问卷 (FAQ)、临床痴呆症评定总和 (CDR-SB) 和阿尔茨海默病评估量表 - 认知分量表 13 (ADAS13)。使用 PLINK 软件对 TMT-A 进行多变量线性回归分析。与 TMT-A 最相关的基因通过颜色轨迹测试 1 型 A (CTTA) 进行了测试，CTTA 是一种文化上公平的 TMT-A 类似物。使用 RegulomeDB 和基因型组织表达 (GTEx) 数据库对 SNP 进行功能注释。

结果

TMT-A 的最佳信号是 rs1108010 ( p = 4.34 × 10 ^-8 ) 在 INSC 基因内的 11p15.2，这也与 TMT-B、FAQ、CDR-SB 和 ADAS13 相关 ( p = 2.47 × 10 ^{- 4、8.56} × 10 ^-3、0.0127 和 0.0188 分别）。此外，还鉴定了提示性位点，例如带有 TMT-A 的 FOXD2 和 CLTA、带有 TMT-B 的 GBP1/GBP3、带有 FAQ 的 GRIK2、带有 CDR-SB 的 BAALC 和 CCDC146、带有 ADAS13 的 BAALC 和 NKAIN2。此外，INSC 内与 CTTA 相关的最佳 SNP 是 rs7931705 ( p = 6.15 × 10 ^-5 )。几个 SNP 使用 GTEx 具有显着的 eQTL。