Brain white matter development is associated with a human-specific haplotype increasing the synthesis of long chain fatty acids.
The genetic and molecular pathways driving human brain white matter (WM) development are only beginning to be discovered. Long chain polyunsaturated fatty acids (LC-PUFAs) have been implicated in myelination in animal models and humans. The biosynthesis of LC-PUFAs is regulated by the fatty acid desaturase (FADS) genes, of which a human-specific haplotype is strongly associated with ω-3 and ω-6 LC-PUFA concentrations in blood. To investigate the relationship between LC-PUFA synthesis and human brain WM development, we examined whether this FADS haplotype is associated with age-related WM differences across the life span in healthy individuals 9-86 years of age (n = 207). Diffusion tensor imaging was performed to measure fractional anisotropy (FA), a putative measure of myelination, of the cerebral WM tracts. FADS haplotype status was determined with a single nucleotide polymorphism (rs174583) that tags this haplotype. Overall, normal age-related WM differences were observed, including higher FA values in early adulthood compared with childhood, followed by lower FA values across older age ranges. However, individuals homozygous for the minor allele (associated with lower LC-PUFA concentrations) did not display these normal age-related WM differences (significant age × genotype interactions, p(corrected) < 0.05). These findings suggest that LC-PUFAs are involved in human brain WM development from childhood into adulthood. This haplotype and LC-PUFAs may play a role in myelin-related disorders of neurodevelopmental origin.
Division of Psychiatry Research, Zucker Hillside Hospital, Glen Oaks, New York 11004, Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, Toronto, Ontario M5T 1R8, Canada, Institute of Medical Science, University of Toronto, Toronto, Ontario M5S 1A8, Canada, Department of Psychiatry, University of Toronto, Toronto, Ontario M5T 1R8, Canada, Center for Psychiatric Neuroscience, Feinstein Institute for Medical Research, Manhasset, New York 11030, and Department of Communication Sciences and Disorders, School of Applied Sciences, University of Mississippi, University, Mississippi 38766.
Bart D
BD
Peters
Aristotle N
AN
Voineskos
Philip R
PR
Szeszko
Tristram A
TA
Lett
Pamela
P
DeRosse
Saurav
S
Guha
Katherine H
KH
Karlsgodt
Toshikazu
T
Ikuta
Daniel
D
Felsky
Majnu
M
John
David J
DJ
Rotenberg
James L
JL
Kennedy
Todd
T
Lencz
Anil K
AK
Malhotra
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016880:Anisotropy; D001921:Brain / Q000033:anatomy & histology* / Q000098:blood supply / Q000254:growth & development; D002648:Child; D044943:Fatty Acid Desaturases / Q000235:genetics*; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D005838:Genotype; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009413:Nerve Fibers, Myelinated / Q000502:physiology*; D010100:Oxygen / Q000097:blood; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D055815:Young Adult
D005227:Fatty Acids; D044943:Fatty Acid Desaturases; C533241:FADS2 protein, human; D010100:Oxygen
brain development; diffusion tensor imaging; fatty acid desaturase genes; myelin; polyunsaturated fatty acids; white matter