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

Prog Neuropsychopharmacol Biol Psychiatry. 2021 Dec 20:111:110393. doi: 10.1016/j.pnpbp.2021.110393. Epub 2021 Jul 2.

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.

Keywords: Alzheimer's disease; Cognitive functioning; Genome-wide association study; INSC; Trail making test; eQTLs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Aged
  • Alzheimer Disease* / genetics
  • Alzheimer Disease* / physiopathology
  • Cognition*
  • Cohort Studies
  • Datasets as Topic
  • Female
  • Genome-Wide Association Study*
  • Humans
  • Male
  • Mental Status and Dementia Tests
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Trail Making Test / statistics & numerical data*

Substances

  • Adaptor Proteins, Signal Transducing
  • Insc protein, human