Rare copy number deletions predict individual variation in human brain metabolite concentrations in individuals with alcohol use disorders

Ronald A. Yeo, Steven W. Gangestad, Charles Gasparovic, Jingyu Liu, Vince Daniel Calhoun, Robert J. Thoma, Andrew R. Mayer, Ravi Kalyanam, Kent E. Hutchison

Research output: Contribution to journalArticle

Abstract

Background: Although variations in neurometabolite concentrations occur in diverse neuropsychiatric and neurodegenerative disorders, little is known about the nature of underlying genetic influences. The current study investigated the importance of a specific type of genetic mutation, copy number variation (CNV), for neurometabolite concentrations in a bilateral anterior cingulate voxel. Methods: These neurometabolic signals were quantified using proton magnetic resonance spectroscopy ( 1H-MRS): N-acetylaspartate (NAA), creatine-phosphocreatine (Cre), glutamate/glutamine (Glx), myoinositol (mI), and phosphorylcholine-glycerol phosphorylcholine (Cho). Genetic data were collected using the Illumina 1MDuoBeadChip Array from a sample adults with alcohol use disorders (n = 146). Results: The number of base pairs lost through rare copy number deletions (occurring in less than 5% of our sample) predicted lower NAA, Cre, mI, and Glx. More total rare deletions also predicted lower NAA, Cre, and Glx. Principal components analyses of the five neurometabolites identified two correlated components, the first comprised of NAA, Glx, and Cre, and the second comprised of Cho, mI, and to a lesser extent, Cre. The number and length of rare deletions were correlated with the first component, capturing approximately 10% of phenotypic variance, but not the second component. Conclusions: These results suggest that mutation load affects neurometabolite concentrations, potentially increasing risk for neuropsychiatric disorders. The greater effect of CVNs on NAA, Glx, and Cre may reflect a greater sensitivity to the effects of mutations (i.e., reduced canalization) for neurometabolites related to metabolic activity and cellular energetics, due to extensive recent selection pressure on these phenotypes in the human lineage.

Original languageEnglish (US)
Pages (from-to)537-544
Number of pages8
JournalBiological Psychiatry
Volume70
Issue number6
DOIs
StatePublished - Sep 15 2011
Externally publishedYes

Fingerprint

Phosphocreatine
Creatine
Alcohols
Brain
Inositol
Phosphorylcholine
Mutation
Gyrus Cinguli
Principal Component Analysis
Glutamine
Base Pairing
Neurodegenerative Diseases
Glycerol
Glutamic Acid
N-acetylaspartate
Phenotype
Pressure

Keywords

  • Copy number variations
  • genetic
  • magnetic resonance spectroscopy
  • mutations
  • neurometabolites
  • schizophrenia

ASJC Scopus subject areas

  • Biological Psychiatry

Cite this

Rare copy number deletions predict individual variation in human brain metabolite concentrations in individuals with alcohol use disorders. / Yeo, Ronald A.; Gangestad, Steven W.; Gasparovic, Charles; Liu, Jingyu; Calhoun, Vince Daniel; Thoma, Robert J.; Mayer, Andrew R.; Kalyanam, Ravi; Hutchison, Kent E.

In: Biological Psychiatry, Vol. 70, No. 6, 15.09.2011, p. 537-544.

Research output: Contribution to journalArticle

Yeo, Ronald A. ; Gangestad, Steven W. ; Gasparovic, Charles ; Liu, Jingyu ; Calhoun, Vince Daniel ; Thoma, Robert J. ; Mayer, Andrew R. ; Kalyanam, Ravi ; Hutchison, Kent E. / Rare copy number deletions predict individual variation in human brain metabolite concentrations in individuals with alcohol use disorders. In: Biological Psychiatry. 2011 ; Vol. 70, No. 6. pp. 537-544.
@article{2dd7820b43a74c0896f993e44b758e40,
title = "Rare copy number deletions predict individual variation in human brain metabolite concentrations in individuals with alcohol use disorders",
abstract = "Background: Although variations in neurometabolite concentrations occur in diverse neuropsychiatric and neurodegenerative disorders, little is known about the nature of underlying genetic influences. The current study investigated the importance of a specific type of genetic mutation, copy number variation (CNV), for neurometabolite concentrations in a bilateral anterior cingulate voxel. Methods: These neurometabolic signals were quantified using proton magnetic resonance spectroscopy ( 1H-MRS): N-acetylaspartate (NAA), creatine-phosphocreatine (Cre), glutamate/glutamine (Glx), myoinositol (mI), and phosphorylcholine-glycerol phosphorylcholine (Cho). Genetic data were collected using the Illumina 1MDuoBeadChip Array from a sample adults with alcohol use disorders (n = 146). Results: The number of base pairs lost through rare copy number deletions (occurring in less than 5{\%} of our sample) predicted lower NAA, Cre, mI, and Glx. More total rare deletions also predicted lower NAA, Cre, and Glx. Principal components analyses of the five neurometabolites identified two correlated components, the first comprised of NAA, Glx, and Cre, and the second comprised of Cho, mI, and to a lesser extent, Cre. The number and length of rare deletions were correlated with the first component, capturing approximately 10{\%} of phenotypic variance, but not the second component. Conclusions: These results suggest that mutation load affects neurometabolite concentrations, potentially increasing risk for neuropsychiatric disorders. The greater effect of CVNs on NAA, Glx, and Cre may reflect a greater sensitivity to the effects of mutations (i.e., reduced canalization) for neurometabolites related to metabolic activity and cellular energetics, due to extensive recent selection pressure on these phenotypes in the human lineage.",
keywords = "Copy number variations, genetic, magnetic resonance spectroscopy, mutations, neurometabolites, schizophrenia",
author = "Yeo, {Ronald A.} and Gangestad, {Steven W.} and Charles Gasparovic and Jingyu Liu and Calhoun, {Vince Daniel} and Thoma, {Robert J.} and Mayer, {Andrew R.} and Ravi Kalyanam and Hutchison, {Kent E.}",
year = "2011",
month = "9",
day = "15",
doi = "10.1016/j.biopsych.2011.04.019",
language = "English (US)",
volume = "70",
pages = "537--544",
journal = "Biological Psychiatry",
issn = "0006-3223",
publisher = "Elsevier USA",
number = "6",

}

TY - JOUR

T1 - Rare copy number deletions predict individual variation in human brain metabolite concentrations in individuals with alcohol use disorders

AU - Yeo, Ronald A.

AU - Gangestad, Steven W.

AU - Gasparovic, Charles

AU - Liu, Jingyu

AU - Calhoun, Vince Daniel

AU - Thoma, Robert J.

AU - Mayer, Andrew R.

AU - Kalyanam, Ravi

AU - Hutchison, Kent E.

PY - 2011/9/15

Y1 - 2011/9/15

N2 - Background: Although variations in neurometabolite concentrations occur in diverse neuropsychiatric and neurodegenerative disorders, little is known about the nature of underlying genetic influences. The current study investigated the importance of a specific type of genetic mutation, copy number variation (CNV), for neurometabolite concentrations in a bilateral anterior cingulate voxel. Methods: These neurometabolic signals were quantified using proton magnetic resonance spectroscopy ( 1H-MRS): N-acetylaspartate (NAA), creatine-phosphocreatine (Cre), glutamate/glutamine (Glx), myoinositol (mI), and phosphorylcholine-glycerol phosphorylcholine (Cho). Genetic data were collected using the Illumina 1MDuoBeadChip Array from a sample adults with alcohol use disorders (n = 146). Results: The number of base pairs lost through rare copy number deletions (occurring in less than 5% of our sample) predicted lower NAA, Cre, mI, and Glx. More total rare deletions also predicted lower NAA, Cre, and Glx. Principal components analyses of the five neurometabolites identified two correlated components, the first comprised of NAA, Glx, and Cre, and the second comprised of Cho, mI, and to a lesser extent, Cre. The number and length of rare deletions were correlated with the first component, capturing approximately 10% of phenotypic variance, but not the second component. Conclusions: These results suggest that mutation load affects neurometabolite concentrations, potentially increasing risk for neuropsychiatric disorders. The greater effect of CVNs on NAA, Glx, and Cre may reflect a greater sensitivity to the effects of mutations (i.e., reduced canalization) for neurometabolites related to metabolic activity and cellular energetics, due to extensive recent selection pressure on these phenotypes in the human lineage.

AB - Background: Although variations in neurometabolite concentrations occur in diverse neuropsychiatric and neurodegenerative disorders, little is known about the nature of underlying genetic influences. The current study investigated the importance of a specific type of genetic mutation, copy number variation (CNV), for neurometabolite concentrations in a bilateral anterior cingulate voxel. Methods: These neurometabolic signals were quantified using proton magnetic resonance spectroscopy ( 1H-MRS): N-acetylaspartate (NAA), creatine-phosphocreatine (Cre), glutamate/glutamine (Glx), myoinositol (mI), and phosphorylcholine-glycerol phosphorylcholine (Cho). Genetic data were collected using the Illumina 1MDuoBeadChip Array from a sample adults with alcohol use disorders (n = 146). Results: The number of base pairs lost through rare copy number deletions (occurring in less than 5% of our sample) predicted lower NAA, Cre, mI, and Glx. More total rare deletions also predicted lower NAA, Cre, and Glx. Principal components analyses of the five neurometabolites identified two correlated components, the first comprised of NAA, Glx, and Cre, and the second comprised of Cho, mI, and to a lesser extent, Cre. The number and length of rare deletions were correlated with the first component, capturing approximately 10% of phenotypic variance, but not the second component. Conclusions: These results suggest that mutation load affects neurometabolite concentrations, potentially increasing risk for neuropsychiatric disorders. The greater effect of CVNs on NAA, Glx, and Cre may reflect a greater sensitivity to the effects of mutations (i.e., reduced canalization) for neurometabolites related to metabolic activity and cellular energetics, due to extensive recent selection pressure on these phenotypes in the human lineage.

KW - Copy number variations

KW - genetic

KW - magnetic resonance spectroscopy

KW - mutations

KW - neurometabolites

KW - schizophrenia

UR - http://www.scopus.com/inward/record.url?scp=80052031904&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80052031904&partnerID=8YFLogxK

U2 - 10.1016/j.biopsych.2011.04.019

DO - 10.1016/j.biopsych.2011.04.019

M3 - Article

C2 - 21684527

AN - SCOPUS:80052031904

VL - 70

SP - 537

EP - 544

JO - Biological Psychiatry

JF - Biological Psychiatry

SN - 0006-3223

IS - 6

ER -