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Neurobiol Aging. 2014 Nov;35(11):2504-2513. doi: 10.1016/j.neurobiolaging.2014.05.024. Epub 2014 Jun 2.

Serum cholesterol and variant in cholesterol-related gene CETP predict white matter microstructure.

Author information

1
Imaging Genetics Center, Institute for Neuroimaging and Informatics, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
2
Department of Neurology, UCLA School of Medicine, Los Angeles, CA, USA.
3
Centre for Advanced Imaging, University of Queensland, Brisbane, Australia.
4
School of Psychology, University of Queensland, Brisbane, Australia.
5
Queensland Institute of Medical Research Berghofer Medical Research Institute, Brisbane, Australia.
6
Department of Radiology, Mayo Clinic and Foundation, Rochester, MN, USA.
7
Department of Radiology and Biomedical Imaging, UCSF School of Medicine, San Francisco, CA, USA; Veteran Affairs Medical Center, San Francisco, CA, USA.
8
Laboratory of Neuro Imaging, Institute for Neuroimaging and Informatics, USC Keck School of Medicine, Los Angeles, CA, USA.
9
School of Psychology, University of Queensland, Brisbane, Australia; Queensland Institute of Medical Research Berghofer Medical Research Institute, Brisbane, Australia.
10
Imaging Genetics Center, Institute for Neuroimaging and Informatics, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA; Department of Neurology, UCLA School of Medicine, Los Angeles, CA, USA. Electronic address: pthomp@usc.edu.

Abstract

Several common genetic variants influence cholesterol levels, which play a key role in overall health. Myelin synthesis and maintenance are highly sensitive to cholesterol concentrations, and abnormal cholesterol levels increase the risk for various brain diseases, including Alzheimer's disease. We report significant associations between higher serum cholesterol (CHOL) and high-density lipoprotein levels and higher fractional anisotropy in 403 young adults (23.8 ± 2.4 years) scanned with diffusion imaging and anatomic magnetic resonance imaging at 4 Tesla. By fitting a multi-locus genetic model within white matter areas associated with CHOL, we found that a set of 18 cholesterol-related, single-nucleotide polymorphisms implicated in Alzheimer's disease risk predicted fractional anisotropy. We focused on the single-nucleotide polymorphism with the largest individual effects, CETP (rs5882), and found that increased G-allele dosage was associated with higher fractional anisotropy and lower radial and mean diffusivities in voxel-wise analyses of the whole brain. A follow-up analysis detected white matter associations with rs5882 in the opposite direction in 78 older individuals (74.3 ± 7.3 years). Cholesterol levels may influence white matter integrity, and cholesterol-related genes may exert age-dependent effects on the brain.

KEYWORDS:

Aging; Brain structure; Cholesterol; DTI; Development; Imaging genetics

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