Kesheng Wang1, Chun Xu2, Amanda Smith3, Danqing Xiao4, R Osvaldo Navia5, Yongke Lu6, Changchun Xie7, Ubolrat Piamjariyakul8. 1. Department of Family and Community Health, School of Nursing, Health Sciences Center, West Virginia University, Morgantown, WV 26506, USA. Electronic address: keskeng.wang@hsc.wvu.edu. 2. Department of Health and Biomedical Sciences, College of Health Affairs, University of Texas Rio Grande Valley, Brownsville, TX 78520, USA. 3. Department of Psychiatry and Behavioral Neuroscience, Morsani College of Medicine, University of South Florida, Tampa, FL 33613, USA. 4. 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. 5. Department of Medicine and Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV 26506, USA. 6. Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA. 7. Division of Biostatistics and Bioinformatics, Department of Environmental Health, University of Cincinnati, Cincinnati, OH 45267, USA. 8. School of Nursing, Health Sciences Center, West Virginia University, Morgantown, WV 26506, USA.
Abstract
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.
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.