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 ((1)H-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.
authors.affiliation: Department of Psychology, University of New Mexico, Albuquerque, New Mexico, USA. ryeo@unm.edu
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Yeo
authors.forename: Steven W
authors.initials: SW
authors.lastname: Gangestad
authors.forename: Charles
authors.initials: C
authors.lastname: Gasparovic
authors.forename: Jingyu
authors.initials: J
authors.lastname: Liu
authors.forename: Vince D
authors.initials: VD
authors.lastname: Calhoun
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Thoma
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Mayer
authors.forename: Ravi
authors.initials: R
authors.lastname: Kalyanam
authors.forename: Kent E
authors.initials: KE
authors.lastname: Hutchison
mesh_terms: D000328:Adult; D019973:Alcohol-Related Disorders / Q000235:genetics* / Q000378:metabolism*; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D003401:Creatine / Q000378:metabolism; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D005997:Glycerylphosphorylcholine / Q000378:metabolism; D006179:Gyrus Cinguli / Q000378:metabolism*; D006801:Humans; D007294:Inositol; D008279:Magnetic Resonance Imaging / Q000379:methods; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008297:Male; D008875:Middle Aged; D010725:Phosphocreatine / Q000378:metabolism; D010767:Phosphorylcholine / Q000378:metabolism; D011522:Protons
chemical_list: D011522:Protons; D010725:Phosphocreatine; D010767:Phosphorylcholine; D001224:Aspartic Acid; D018698:Glutamic Acid; D007294:Inositol; D005997:Glycerylphosphorylcholine; C000179:N-acetylaspartate; D003401:Creatine