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Research Paper|Volume 11, Issue 5|pp 1440—1456

Genetic variation underlying cognition and its relation with neurological outcomes and brain imaging

Maria J. Knol1, Alis Heshmatollah1,2, Lotte G.M. Cremers1,3, M. Kamran Ikram1,2, André G. Uitterlinden4, Cornelia M. van Duijn1, Wiro J. Niessen3,5,6, Meike W. Vernooij1,3, M. Arfan Ikram1, Hieab H.H. Adams1,3
  • 1Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands
  • 2Department of Neurology, Erasmus MC University Medical Center, Rotterdam, the Netherlands
  • 3Department of Radiology and Nuclear Medicine, Erasmus MC University Medical Center, Rotterdam, the Netherlands
  • 4Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, the Netherlands
  • 5Department of Medical Informatics, Erasmus MC University Medical Center, Rotterdam, the Netherlands
  • 6Faculty of Applied Sciences, Delft University of Technology, Delft, the Netherlands

* * Equal contribution

Received: November 28, 2018Accepted: February 21, 2019Published: March 4, 2019
https://doi.org/10.18632/aging.101844

Copyright: © 2019 Knol et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Cognition in adults shows variation due to developmental and degenerative components. A recent genome-wide association study identified genetic variants for general cognitive function in 148 independent loci. Here, we aimed to elucidate possible developmental and neurodegenerative pathways underlying these genetic variants by relating them to functional, clinical and neuroimaging outcomes. This study was conducted within the population-based Rotterdam Study (N=11,496, mean age 65.3±9.9 years, 58.0% female). We used lead variants for general cognitive function to construct a polygenic score (PGS), and additionally excluded developmental variants at multiple significance thresholds. A higher PGS was related to more years of education (β=0.29, p=4.3x10-7) and a larger intracranial volume (β=0.05, p=7.5x10-4). To a smaller extent, the PGS was associated with less cognitive decline (βΔG-factor=0.03, p=1.3x10-3), which became non-significant after adjusting for education (p=1.6x10-2). No associations were found with daily functioning, dementia, parkinsonism, stroke or microstructural white matter integrity. Excluding developmental variants attenuated nearly all associations. In conclusion, this study suggests that the genetic variants identified for general cognitive function are acting mainly through the developmental pathway of cognition. Therefore, cognition, assessed cross-sectionally, seems to have limited value as a biomarker for neurodegeneration.