Sliz E, et al. Mol Psychiatry. 2020 Jan 3.
Sliz E, et al., conducted a study to perform a genome-wide association study (GWAS) of the shared variance of visceral fat, phospholipid PC (16:0/2:0), and white matter microstructure in 872 participants from the Saguenay Youth Study (SYS). The metabolomic profile of the GWAS-lead variant in 931 participants was also further investigated.
Visceral fat and white matter microstructure were correlated with magnetic resonance imaging. Circulating metabolites were measured with serum lipidomics and metabolomics.
The GWAS of PC1 observed a genome-wide significant locus in 1p32.3 (rs588709; p=3.58 × 10−8). The GWAS-lead variant was also nominally correlated with each of the 3 variables in the SYS participants when assessed individually (WMT1W-SI: p=2.1 × 10−6; PC (16:0/2:0): p= 0.005; VF: p=0.010). The rs588709 portion of an ~41 kb linkage disequilibrium block overlaying with the 3′- untranslated region of DHCR24 (Figure 1).
Figure 1: The genome-wide significant locus on chromosome 1 near DHCR24.
DHCR24 rs588709-G was correlated with reduced circulating level of apoB-containing lipoprotein particles (Figure 2).
Figure 2: Expression of DHCR24 during lifespan. Cerebrocortical mRNA expression of DHCR24 was acquired from five postmortem human databases (Allen Human Brain Atlas, AHBA; BrainCloud; BRAINEAC; BrainSpan; and Genotype-Tissue Expression project; GTEx) with a total of 572 donors. Within each database, mRNA expression was scaled by region and all scaled values were pooled by cortical lobe. Donor age (x-axis) was regressed on lobar expression (y-axis) adjusting for sex as a fixed effect and donor ID as a random effect.
The rs588709-G was correlated with reduced triglycerides in all the six VLDL subfractions, reduced phospholipids in XXL-M VLDL subfractions, cholesteryl esters in XXL-L VLDL subfractions, and reduced free cholesterol in XXL-S VLDL subfractions. Consistent decrease in total serum triglycerides (p= 0.00048) and VLDL triglycerides (p=0.00051) were also observed (Figure 3).
Figure 3: The effects of the DHCR24 rs588709-G on particle concentration of 14 lipoprotein subclasses and the lipid fractions within the 14 subclasses. Error bars indicate 95% confidence intervals. Statistical significance was considered at p < 0.002 (0.05/29) to account for testing of 29 independent metabolic measures. VLDL very low-density lipoprotein, IDL intermediate-density lipoprotein, LDL low-density lipoprotein, HDL high-density lipoprotein, XXL extremely large, XL very large, L large, M medium, S small, XS very small.
The rs588709-G demonstrated the firmest impact on amino acids leucine (p=0.0015) and glycine (p=0.0013), and a slight significant effect (p=0.0081) on glycoprotein acetylation, a marker of systemic inflammation from the nonlipid measures (Figure 4).
Figure 4: The effects of the DHCR24 rs588709-G on lipoprotein particle size, apolipoproteins, cholesterol, triglycerides, phospholipids, amino acids, and glycoprotein acetylation. VLDL very low-density lipoprotein, LDL low-density lipoprotein, HDL high-density lipoprotein, ApoB apolipoprotein B, ApoA-I apolipoprotein A-I, C cholesterol, TG triglyceride, PG phosphoglyceride, PC phosphatidylcholine, SM sphingomyelin, GlycA glycoprotein acetylation.
DHCR24 rs588709-G determined a matching correlation profile with the TM6SF2 rs58542926-T (Figure 5, R2 = 0.74).
Figure 5: The overall similarities of the metabolomic effects of DHCR24 rs588709-G versus TM6SF2 rs58542926-T or HMGCR rs12916-T. The dashed line indicates the linear fit of the effect estimates on 111 metabolic measures that were available in both studies. The shaded area denotes the 95% confidence interval for the line. R2 indicates the goodness of fit.
Thus, the present study offers evidence that the DHCR24 locus may be associated with peripheral metabolism to brain microstructure, a correlation with implications for cognitive impairment.
