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bioRxiv · 10.1101/2025.07.08.663708

Identification of novel protective loci for executive function using the trail making test part B in the Long Life Family Study

Wang, L.·Tanner, K.·Andersen, S. L.·Cosentino, S.·Moghaddam, V. A.·Daw, E. W.·Anema, J. A.·Lin, S. J.·Acharya, S.·Province, M.·Wojczynski, M. K.
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Abstract

The Trail Making Test (TMT) Part B (TMT-B), a well-established assessment of cognitive function, is a frequent component of diagnostic assessments for Mild Cognitive Impairment and dementia in older adults. Identifying the genetic variants associated with the TMT-B will not only gain insights of genetic determinants of cognitive function, but also the molecular mechanisms for dementia. Published GWAS to date for TMT-B suffer from relatively low power due to the use of population level data and imputation methods. To address these deficits, we used a family-based study design to identify the genetic variants associated with the TMT-B incorporating both genome-wide linkage analysis (GWLS) and whole genome sequencing (WGS). As such, we examined the sequenced genetic determinants of TMT-B using GWLS in over 2000 participants from Long Life Family Study (LLFS). In GWLS, the estimated heritability of TMT-B was 0.29. We detected one significant linkage peak at 15q25 (LOD>3.0). Statistical fine-mapping nominated five variants including three SNPs (NTRK3-rs74031103, protective CEMIP-rs2271159, and protective AGBL1-rs4134376) and two INDELs (protective KLHL25-15:85882445:IND, and protective CEMIP-15:80893381:IND) contributing to the linkage peak. Four out of these five variants are protective for TMT-B. The rs2271159 SNP influences CEMIP expression in cerebellum and hippocampus, while the 15:80893381:IND modulates CEMIP expression in blood. Additionally, the variant rs4134376 is a basal ganglia-specific eQTL for AGBL1. In conclusion, we utilized GWLS, leveraged multi-omics data (whole genome sequence genomic data, transcriptomic data, and lipidomic data), and identified novel protective variants and genes for TMT-B performance.

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Wang, L., Tanner, K., Andersen, S. L., Cosentino, S., Moghaddam, V. A., Daw, E. W., Anema, J. A., Lin, S. J., Acharya, S., Province, M., Wojczynski, M. K.. 2025-07-12. Identification of novel protective loci for executive function using the trail making test part B in the Long Life Family Study. https://doi.org/10.1101/2025.07.08.663708

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