Age and haplotype variations within FADS1 interact and associate with alterations in fatty acid composition in human male cortical brain tissue.
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Department of Genetics, McGill University, Montreal, Quebec, Canada.
Erika
E
Freemantle
Aleksandra
A
Lalovic
Naguib
N
Mechawar
Gustavo
G
Turecki
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D002525:Cerebellar Cortex / Q000378:metabolism*; D000090943:Delta-5 Fatty Acid Desaturase; D044943:Fatty Acid Desaturases / Q000235:genetics*; D005227:Fatty Acids / Q000378:metabolism*; D015870:Gene Expression; D023061:Gene Order; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics; D055815:Young Adult
D000090943:Delta-5 Fatty Acid Desaturase; D005227:Fatty Acids; D044943:Fatty Acid Desaturases; C000716847:FADS1 protein, human