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, very 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-acetyl aspartate (NAA), creatine-phosphocreatine (Cre), glutamate/glutamine (Glx), myoinositol (mI), and phosphorylcholine-glycerol phosphorylcholine (Cho). Genetic data was collected using the Illumina 1M DuoBeadChip 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.

Increased CNV-Region deletions in mild cognitive impairment (MCI) and Alzheimer's disease (AD) subjects in the ADNI sample

“…We found a statistically significant overrepresentation of subjects with more than one CNV-Region in affected cases compared to healthy controls and we found that very large deletions >450 kb are associated with MCI and/or AD. Recent studies supported the role of the overall load of large deletions in many complex traits [29,30]. Our findings are consistent in particular with the hypothesis that links large copy number events and disease susceptibility as previously described in the context of large CNV studies of schizophrenia, autism and other psychiatric disorders [31,32]…”

The Impact of Copy Number Deletions on General Cognitive Ability and Ventricle Size in Patients with Schizophrenia and Healthy Control Subjects

“…As individual variation in general cognitive ability has been related to many different characteristics of the brain, including more efficient white matter connections [42] and formal network properties [43], there are several other candidate mechanisms awaiting future study. A particularly relevant characteristic may be greater plasticity [44], which is linked with glutamatergic activity[45], and we have found reduced glutamate/glutamine concentrations in individuals with greater deletion burden [46]. …”

Association of genetic copy number variations at 11 q14.2 with brain regional volume differences in an alcohol use disorder population

“…Similarly, deletion carriers in this region have significantly higher median loading coefficients. CNV deletions have previously been shown to have a general deleterious effect on variations in intelligence (Yeo, Gangestad, Gasparovic et al, 2011; Yeo, Gangestad, Liu et al, 2011) as well as autism risk (Pinto et al, 2010) and other neuropsychiatric diseases (Durand et al, 2007). The identified CNV region at chromosome 11 q14.2 corresponds to the ME3 gene malic enzyme which catalyzes malate to pyruvate and is involved in the glycolysis metabolic pathway.…”

“…Several regions are implicated, including the ventral striatum, precuneus and prefrontal cortex. In addition to using fMRI to find genetic associations with AUD, magnetic resonance spectroscopy has also been used to find associations between metabolite concentrations in the brain and total CNV burden in an alcohol using population (Yeo, Gangestad, Gasparovic et al, 2011; Yeo, Gangestad, Liu et al, 2011). Similar to using intermediate functional and metabolic phenotypes, intermediate structural phenotypes have also been used to study predisposed risk to AUD from alcohol dependence families (Hill et al, 2007, 2011).…”