Genetic analysis of cortical thickness and fractional anisotropy of water diffusion in the brain

Peter Kochunov, David C. Glahn, Thomas E. Nichols, Anderson M. Winkler, Elliot L. Hong, Henry H. Holcomb, Jason L. Stein, Paul M. Thompson, Joanne E. Curran, Melanie A. Carless, Rene L Olvera, Matthew P. Johnson, Shelley A. Cole, Valeria Kochunov, Jack Kent, John Blangero

Research output: Contribution to journalArticle

47 Citations (Scopus)

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 correlation was observed among GM thickness 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 influence GM thickness and WM-FA values.

Original languageEnglish (US)
Article numberArticle 120
JournalFrontiers in Neuroscience
Issue numberOCT
DOIs
StatePublished - 2011

Fingerprint

Anisotropy
Single Nucleotide Polymorphism
Water
Brain
Quantitative Trait Loci
Gene Expression
Genes
Genome-Wide Association Study
Neuroimaging
Gray Matter
Alzheimer Disease
Leukocytes
Chromosomes
Genome
Phenotype

Keywords

  • ADAM10
  • Cortical thickness
  • Genetic correlation
  • GWAS
  • Imaging genetics
  • QTL
  • RORA
  • WM integrity

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Kochunov, P., Glahn, D. C., Nichols, T. E., Winkler, A. M., Hong, E. L., Holcomb, H. H., ... Blangero, J. (2011). Genetic analysis of cortical thickness and fractional anisotropy of water diffusion in the brain. Frontiers in Neuroscience, (OCT), [Article 120]. https://doi.org/10.3389/fnins.2011.00120

Genetic analysis of cortical thickness and fractional anisotropy of water diffusion in the brain. / 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; Blangero, John.

In: Frontiers in Neuroscience, No. OCT, Article 120, 2011.

Research output: Contribution to journalArticle

Kochunov, P, Glahn, DC, Nichols, TE, Winkler, AM, Hong, EL, Holcomb, HH, Stein, JL, Thompson, PM, Curran, JE, Carless, MA, Olvera, RL, Johnson, MP, Cole, SA, Kochunov, V, Kent, J & Blangero, J 2011, 'Genetic analysis of cortical thickness and fractional anisotropy of water diffusion in the brain', Frontiers in Neuroscience, no. OCT, Article 120. https://doi.org/10.3389/fnins.2011.00120
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 ; Blangero, John. / Genetic analysis of cortical thickness and fractional anisotropy of water diffusion in the brain. In: Frontiers in Neuroscience. 2011 ; No. OCT.
@article{fefc9eeebffa42d19ed4f34d92ae2f89,
title = "Genetic analysis of cortical thickness and fractional anisotropy of water diffusion in the brain",
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 correlation was observed among GM thickness 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 influence GM thickness and WM-FA values.",
keywords = "ADAM10, Cortical thickness, Genetic correlation, GWAS, Imaging genetics, QTL, RORA, WM integrity",
author = "Peter Kochunov and Glahn, {David C.} and Nichols, {Thomas E.} and Winkler, {Anderson M.} and Hong, {Elliot L.} and Holcomb, {Henry H.} and Stein, {Jason L.} and Thompson, {Paul M.} and Curran, {Joanne E.} and Carless, {Melanie A.} and Olvera, {Rene L} and Johnson, {Matthew P.} and Cole, {Shelley A.} and Valeria Kochunov and Jack Kent and John Blangero",
year = "2011",
doi = "10.3389/fnins.2011.00120",
language = "English (US)",
journal = "Frontiers in Neuroscience",
issn = "1662-4548",
publisher = "Frontiers Research Foundation",
number = "OCT",

}

TY - JOUR

T1 - Genetic analysis of cortical thickness and fractional anisotropy of water diffusion in the brain

AU - Kochunov, Peter

AU - Glahn, David C.

AU - Nichols, Thomas E.

AU - Winkler, Anderson M.

AU - Hong, Elliot L.

AU - Holcomb, Henry H.

AU - Stein, Jason L.

AU - Thompson, Paul M.

AU - Curran, Joanne E.

AU - Carless, Melanie A.

AU - Olvera, Rene L

AU - Johnson, Matthew P.

AU - Cole, Shelley A.

AU - Kochunov, Valeria

AU - Kent, Jack

AU - Blangero, John

PY - 2011

Y1 - 2011

N2 - 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 correlation was observed among GM thickness 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 influence GM thickness and WM-FA values.

AB - 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 correlation was observed among GM thickness 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 influence GM thickness and WM-FA values.

KW - ADAM10

KW - Cortical thickness

KW - Genetic correlation

KW - GWAS

KW - Imaging genetics

KW - QTL

KW - RORA

KW - WM integrity

UR - http://www.scopus.com/inward/record.url?scp=84861880052&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84861880052&partnerID=8YFLogxK

U2 - 10.3389/fnins.2011.00120

DO - 10.3389/fnins.2011.00120

M3 - Article

C2 - 22028680

AN - SCOPUS:84861880052

JO - Frontiers in Neuroscience

JF - Frontiers in Neuroscience

SN - 1662-4548

IS - OCT

M1 - Article 120

ER -