Kochunov, Peter, Glahn, David C., Nichols, Thomas E., Winkler, Anderson M., Hong, Elliot L., Holcomb, Henry H., Stein, Jason L., Thompson, Paul M., Curran, Joanne E., Carless, Melanie A., Olvera, Rene L., Johnson, Matthew P., Cole, Shelley A., Kochunov, Valeria, Kent, Jack and Blangero, John (2011) Genetic analysis of cortical thickness and fractional anisotropy of water diffusion in the brain. Frontiers in Neuroscience, Vol.5 . p. 120. doi:10.3389/fnins.2011.00120

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Abstract

Objectives: The thickness of the brain’s cortical gray matter (GM) and the fractional
anisotropy (FA) of the cerebral white matter (WM) each follow an inverted U-shape trajectory
with age. The two measures are positively correlated and may be modulated by
common biological mechanisms. We employed four types of genetic analyses to localize
individual genes acting pleiotropically upon these phenotypes. Methods: Whole-brain
and regional GM thickness and FA values were measured from high-resolution anatomical
and diffusion tensor MR images collected from 712, Mexican American participants (438
females, age=47.9±13.2 years) recruited from 73 (9.7±9.3 individuals/family) large families.
The significance of the correlation between two traits was estimated using a bivariate
genetic correlation analysis. Localization of chromosomal regions that jointly influenced
both traits was performed using whole-genome quantitative trait loci (QTL) analysis. Gene
localization was performed using SNP genotyping on Illumina 1M chip and correlation with
leukocyte-based gene-expression analyses. The gene-expressions were measured using
the Illumina BeadChip. These data were available for 371 subjects. Results: Significant
genetic correlationwas observed amongGMthickness and FA values. Significant logarithm
of odds (LOD≥3.0) QTLs were localized within chromosome 15q22–23. More detailed
localization reported no significant association (p <5·10−5) for 1565 SNPs located within
the QTLs. Post hoc analysis indicated that 40% of the potentially significant (p ≤10−3)
SNPs were localized to the related orphan receptor alpha (RORA) and NARG2 genes. A
potentially significant association was observed for the rs2456930 polymorphism reported
as a significant GWAS finding in Alzheimer’s disease neuroimaging initiative subjects. The
expression levels for RORA and ADAM10 genes were significantly (p <0.05) correlated
with both FA and GM thickness. NARG2 expressions were significantly correlated with
GM thickness (p <0.05) but failed to show a significant correlation (p =0.09) with FA. Discussion:
This study identified a novel, significant QTL at 15q22–23. SNP correlation with
gene-expression analyses indicated that RORA, NARG2, and ADAM10 jointly influenceGM
thickness and WM–FA values.

Item Type:	Journal Article
Subjects:	Q Science > QH Natural history > QH426 Genetics
Divisions:	Faculty of Science > Statistics Faculty of Science > WMG (Formerly the Warwick Manufacturing Group)
Library of Congress Subject Headings (LCSH):	Brain -- Physiology, Human genetics
Journal or Publication Title:	Frontiers in Neuroscience
Publisher:	Frontiers Media S.A
ISSN:	1662-4548
Official Date:	19 October 2011
Dates:	Date Event 19 October 2011 Published
Volume:	Vol.5
Page Range:	p. 120
DOI:	10.3389/fnins.2011.00120
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Open Access
Funder:	National Institute of Biomedical Imaging and Bioengineering (U.S.) (NIBIB), National Institute of Mental Health (U.S.) (NIMH)
Grant number:	EB006395 (NIBIB), MH078111 (NIMH), MH0708143 (NIMH), MH083824 (NIMH)

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