University of Oulu

Sliz, E., Shin, J., Syme, C. et al. A variant near DHCR24 associates with microstructural properties of white matter and peripheral lipid metabolism in adolescents. Mol Psychiatry (2020). https://doi.org/10.1038/s41380-019-0640-9

A variant near DHCR24 associates with microstructural properties of white matter and peripheral lipid metabolism in adolescents

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Author: Sliz, Eeva1,2,3; Shin, Jean1,2; Syme, Catriona1,2;
Organizations: 1The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
2Departments of Physiology and Nutritional Sciences, University of Toronto, Toronto, ON, Canada
3Center for Life-Course Health Research and Computational Medicine, Faculty of Medicine, University of Oulu, and Biocenter Oulu, Oulu, Finland
4Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, Toronto, ON, Canada
5Department of Health Sciences, Université du Québec à Chicoutimi, Chicoutimi, QC, Canada
6Clinical Lipidology and rare lipid disorders Unit, Community Genetic Medicine Center, Department of Medicine, Université de Montréal, ECOGENE-21, Chicoutimi, QC, Canada
7Neural Regeneration Laboratory, Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON, Canada
8Departments of Psychology and Psychiatry, University of Toronto, Toronto, ON, Canada
Format: article
Version: accepted version
Access: open
Online Access: PDF Full Text (PDF, 1.3 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2020041416504
Language: English
Published: Springer Nature, 2020
Publish Date: 2020-07-03
Description:

Abstract

Visceral adiposity has been associated with altered microstructural properties of white matter in adolescents. Previous evidence suggests that circulating phospholipid PC(16:0/2:0) may mediate this association. To investigate the underlying biology, we performed a genome-wide association study (GWAS) of the shared variance of visceral fat, PC(16:0/2:0), and white matter microstructure in 872 adolescents from the Saguenay Youth Study. We further studied the metabolomic profile of the GWAS-lead variant in 931 adolescents. Visceral fat and white matter microstructure were assessed with magnetic resonance imaging. Circulating metabolites were quantified with serum lipidomics and metabolomics. We identified a genome-wide significant association near DHCR24 (Seladin-1) encoding a cholesterol-synthesizing enzyme (rs588709, p = 3.6 × 10−8); rs588709 was also associated nominally with each of the three traits (white matter microstructure: p = 2.1 × 10−6, PC(16:0/2:0): p = 0.005, visceral fat: p = 0.010). We found that the metabolic profile associated with rs588709 resembled that of a TM6SF2 variant impacting very low-density lipoprotein (VLDL) secretion and was only partially similar to that of a HMGCR variant. This suggests that the effect of rs588709 on VLDL lipids may arise due to altered phospholipid rather than cholesterol metabolism. The rs588709 was also nominally associated with circulating concentrations of omega-3 fatty acids in interaction with visceral fat and PC(16:0/2:0), and these fatty acid measures showed robust associations with white matter microstructure. Overall, the present study provides evidence that the DHCR24 locus may link peripheral metabolism to brain microstructure, an association with implications for cognitive impairment.

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Series: Molecular psychiatry
ISSN: 1359-4184
ISSN-E: 1476-5578
ISSN-L: 1359-4184
Volume: In press
DOI: 10.1038/s41380-019-0640-9
OADOI: https://oadoi.org/10.1038/s41380-019-0640-9
Type of Publication: A1 Journal article – refereed
Field of Science: 1184 Genetics, developmental biology, physiology
3111 Biomedicine
Subjects:
Funding: The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS.
Dataset Reference: The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 04/01/2019 and dbGaP accession number phs000424.v7.p2 on 04/01/2019.
Copyright information: © The Author(s), under exclusive licence to Springer Nature Limited 2020. This is a post-peer-review, pre-copyedit version of an article published in Mol Psychiatry. The final authenticated version is available online at https://doi.org/10.1038/s41380-019-0640-9.