Genome-wide association study identified INSC gene associated with Trail Making Test Part A and Alzheimer's disease related cognitive phenotypes

Authors

KeSheng Wang
Chun Xu, The University of Texas Rio Grande Valley
Amanda Smith
Danqing Xiao, Regis College
R. Osvaldo Navia
Yongke Lu
Changchun Xie
Ubolrat Piamjariyakul

Document Type

Article

Publication Date

12-20-2021

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.

Comments

Original published version available at https://doi.org/10.1016/j.pnpbp.2021.110393

Recommended Citation

Wang, K., Xu, C., Smith, A., Xiao, D., Navia, R. O., Lu, Y., Xie, C., Piamjariyakul, U., & Alzheimer's Disease Neuroimaging Initiative (2021). 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 & biological psychiatry, 111, 110393. https://doi.org/10.1016/j.pnpbp.2021.110393

Publication Title

Progress in neuro-psychopharmacology & biological psychiatry

DOI

https://doi.org/10.1016/j.pnpbp.2021.110393