👤 Aleksandra Lalovic

Fatty acids (FA) play an integral role in brain function and alterations have been implicated in a variety of complex neurological disorders. Several recent genomic studies have highlighted genetic variability in the fatty acid desaturase (FADS1/2/3) gene cluster as an important contributor to FA alterations in serum lipids as well as measures of FA desaturase index estimated by ratios of relevant FAs. The contribution to alterations of FAs within the brain by local synthesis is still a matter of debate. Thus, the impact of genetic variants in FADS genes on gene expression and brain FA levels is an important avenue to investigate. Analyses were performed on brain tissue from prefrontal cortex Brodmann area 47 (BA47) of 61 male subjects of French Canadian ancestry ranging in age from young adulthood to middle age (18-58 years old), with the exception of one teenager (15 years old). Haplotype tagging SNPs were selected using the publicly available HapMap genotyping dataset in conjunction with Haploview. DNA sequencing was performed by the Sanger method and gene expression was measured by quantitative real-time PCR. FAs in brain tissue were analysed by gas chromatography. Variants in the FADS1 gene region were sequenced and analyzed for their influence on both FADS gene expression and FAs in brain tissue. Our results suggest an association of the minor haplotype with alteration in estimated fatty acid desaturase activity. Analysis of the impact of DNA variants on expression and alternative transcripts of FADS1 and FADS2, however, showed no differences. Furthermore, there was a significant interaction between haplotype and age on certain brain FA levels. This study suggests that genetic variability in the FADS genes cluster, previously shown to be implicated in alterations in peripheral FA levels, may also affect FA composition in brain tissue, but not likely by local synthesis. Show less

Studies investigating the association between low cholesterol and suicidality have generated a range of ideas about how cholesterol might play a role in influencing suicide risk, extending studies to other aspects of lipid metabolism, as well as immune response, in relation to suicide. We performed large-scale microarray gene expression analysis using the Affymetrix HG-U133 chipset and focused our investigation on the expression profile of genes related to lipid metabolism and immune response in post-mortem brains from suicide completers and comparison subjects. We used tissue from three regions of the frontal cortex (Brodmann areas (BA) 8/9, 11, and 47) from 22 male suicide completers, 15 of whom were diagnosed with major depressive disorder, and 13 male comparison subjects. Fatty acid desaturase (FADS1), leptin receptor (LEPR), phosphoinositide-3-kinase (class 2 alpha; PIK3C2A) and stearoyl-CoA desaturase (SCD) were consistently down-regulated in all three regions of the frontal cortex of depressed suicides compared to comparison subjects, and were among the genes for which significant correlations were observed between our microarray and real-time PCR data. Given the absence of a non-suicidal depressed comparison group in this study, it cannot be ascertained whether the gene expression changes identified are associated with depression or suicide. Our findings suggest a role for lipid metabolism and immune response genes in depressed suicide completers and lend further support to the relationship between lipid metabolism and suicidality. Show less