title: Serum cholesterol and variant in cholesterol-related gene CETP predict white matter microstructure.
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.
authors.affiliation: Imaging Genetics Center, Institute for Neuroimaging and Informatics, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
authors.forename: Nicholus M
authors.initials: NM
authors.lastname: Warstadt
authors.affiliation: Imaging Genetics Center, Institute for Neuroimaging and Informatics, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
authors.forename: Emily L
authors.initials: EL
authors.lastname: Dennis
authors.affiliation: Imaging Genetics Center, Institute for Neuroimaging and Informatics, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
authors.forename: Neda
authors.initials: N
authors.lastname: Jahanshad
authors.affiliation: Department of Neurology, UCLA School of Medicine, Los Angeles, CA, USA.
authors.forename: Omid
authors.initials: O
authors.lastname: Kohannim
authors.affiliation: Imaging Genetics Center, Institute for Neuroimaging and Informatics, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
authors.forename: Talia M
authors.initials: TM
authors.lastname: Nir
authors.affiliation: Centre for Advanced Imaging, University of Queensland, Brisbane, Australia.
authors.forename: Katie L
authors.initials: KL
authors.lastname: McMahon
authors.affiliation: School of Psychology, University of Queensland, Brisbane, Australia.
authors.forename: Greig I
authors.initials: GI
authors.lastname: de Zubicaray
authors.affiliation: Queensland Institute of Medical Research Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
authors.affiliation: Queensland Institute of Medical Research Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Anjali K
authors.initials: AK
authors.lastname: Henders
authors.affiliation: Queensland Institute of Medical Research Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Martin
authors.affiliation: Queensland Institute of Medical Research Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: John B
authors.initials: JB
authors.lastname: Whitfield
authors.affiliation: Department of Radiology, Mayo Clinic and Foundation, Rochester, MN, USA.
authors.forename: Clifford R
authors.initials: CR
authors.lastname: Jack
authors.affiliation: Department of Radiology, Mayo Clinic and Foundation, Rochester, MN, USA.
authors.forename: Matt A
authors.initials: MA
authors.lastname: Bernstein
authors.affiliation: Department of Radiology and Biomedical Imaging, UCSF School of Medicine, San Francisco, CA, USA; Veteran Affairs Medical Center, San Francisco, CA, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Weiner
authors.affiliation: Laboratory of Neuro Imaging, Institute for Neuroimaging and Informatics, USC Keck School of Medicine, Los Angeles, CA, USA.
authors.forename: Arthur W
authors.initials: AW
authors.lastname: Toga
authors.affiliation: School of Psychology, University of Queensland, Brisbane, Australia; Queensland Institute of Medical Research Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Margaret J
authors.initials: MJ
authors.lastname: Wright
authors.affiliation: 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.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Thompson
mesh_terms: D000328:Adult; D000375:Aging; D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics*; D016880:Anisotropy; D002784:Cholesterol / Q000097:blood*; D053480:Cholesterol Ester Transfer Proteins / Q000235:genetics*; D038524:Diffusion Magnetic Resonance Imaging; D005260:Female; D005500:Follow-Up Studies; D005544:Forecasting; D006801:Humans; D008297:Male; D009186:Myelin Sheath / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D066127:White Matter / Q000473:pathology*; D055815:Young Adult
chemical_list: C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D002784:Cholesterol
keywords: Aging; Brain structure; Cholesterol; DTI; Development; Imaging genetics