Association of genetic copy number variations at 11 q14.2 with brain regional volume differences in an alcohol use disorder population.
- Authors
- Boutte, David; Calhoun, Vince D; Chen, Jiayu; Sabbineni, Amithrupa; Hutchison, Kent; Liu, Jingyu
- Year
- 2012
- Journal
- Alcohol (Fayetteville, N.Y.)
- PMID
- 22732324
- DOI
- 10.1016/j.alcohol.2012.05.002
- PMCID
- PMC4196895
This study investigates the relationship between genetic copy number variations and brain volume differences in an alcohol use disorder (AUD) population. We hypothesized that copy number variations may influence subject's risk for alcohol use disorders through variations in regional gray and white matter brain volumes. Since genetic influences upon behavior are the result of many complicated interactions we focus on differences in brain volume as a putative intermediate phenotype between genetic variation and behavior. Copy number variation, alcohol use assessments and brain structural magnetic resonance images from 283 subjects, 199 male and 84 females who were enrolled in two AUD studies were obtained and analyzed using a combination of the Freesurfer image analysis suite and independent component analysis. Because brain volume varies by age we compared participant's volume variation with that derived from a control cohort of 75 subjects. In addition we also regressed out the possible brain volume changes induced by long term alcohol consumption. Small cerebral cortex, cerebellar and caudate along with large cerebral white matter and 5th ventricle volumes are shown to be significantly associated with increased AUD severity. When these volume variations are compared with control subject volumes; the variations seen in subjects with AUD are markedly different from normal aging effects. CNVs at 11 q14.2 are marginally (p < 0.05 uncorrected) correlated with such brain volume variations and the correlation holds true after controlling for long-term alcohol consumption; deletion carriers have smaller cerebral cortex, cerebellar, caudate and larger cerebral white matter and 5th ventricle volumes than insertion carriers or subjects with no variation in this region. Similarly, deletion carriers also demonstrate higher AUD severity scores than insertion carriers or subjects with no variation. The results presented here suggest that copy number variation and in particular the variation at chromosome 11 q14.2 may have an impact in brain volume variation, potentially influencing AUD behavior.
Model of CNV influence on alcohol use.
LLM interpretation
This figure is a conceptual diagram illustrating a model of how copy number variation (CNV) influences alcohol use. It shows a direct path from CNV to Behavior, as well as an indirect path where CNV influences Brain Structure, which then influences Behavior. Additionally, an arrow indicates a feedback loop from Behavior back to Brain Structure.
AUD severity component weights linked to the brain volume component with correlation of 0.41, p < 0.05 corrected. This component explains approximately 70% of the variance present in the subjects’ AUD assessments. The component weights show large positive ADS and AUDIT weights and large negative ICSfc and ICSpc weights consistent with increased alcohol use disorder severity.
LLM interpretation
This bar chart displays the component weights of various drinking behavior metrics related to brain volume. The y-axis represents "Weight" ranging from -2 to 1.5, while the x-axis lists specific AUD assessment metrics. Positive weights are observed for ADS and AUDIT metrics (e.g., adscon, audititot, icsac), while large negative weights are seen for ICSfc and ICSpc.
Brain volume component weights for alcohol using subjects. Blue indicates small cerebella and caudate volumes and red large 5th ventricle (cavum septum pellucidum) volume. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
LLM interpretation
This figure consists of three anatomical brain MRI slices (coronal, sagittal, and axial) and a corresponding data table showing brain volume component weights for alcohol users. The MRI images use color-coding to highlight specific regions: blue indicates small cerebella and caudate volumes, while red indicates a large 5th ventricle volume. The accompanying table lists the numerical "Contribution" for various brain regions, with the most negative values associated with the cerebellum cortex and the most positive value associated with the 5th ventricle.
Volume component loading coefficient box plots for candidate CNV region at chromosome 11 q14.2. There are 12 homozygous deletion carriers, 6 hemizygous insertion carriers and 265 subjects with no variation in this region. Deletion carriers have significantly, p < 0.05, higher median loading coefficients indicating these subjects have small cerebellar and caudate volumes and large 5th ventricle volume relative to insertion carriers and subjects with no variation. Similarly, insertion carriers have significantly, p < 0.05, lower median loading coefficients indicating they have large cerebellar and caudate volumes and small 5th ventricle volumes relative to deletion carriers or subjects with no variation. The central mark or each box represents the median with edges representing the 25th and 75th percentile respectively. The whiskers extend to the extreme non-outlier points. Whiskers coincide with the box edges for hemizygous insertions.
LLM interpretation
This figure consists of three notched box plots showing volume loading coefficients for three groups at chromosome 11 q14.2: homozygous deletions, neutral (no variation), and hemizygous insertions. The y-axis represents the volume loading coefficient, with the homozygous deletion group exhibiting the highest median value and the hemizygous insertion group exhibiting the lowest. The neutral group shows the widest distribution of data, including several outliers indicated by red crosses.
Alcohol component loading coefficient box plots for candidate CNV region at chromosome 11 q14.2. Deletion carriers have significantly, p < 0.05, higher median loading coefficients indicating these subjects contribute more to the alcohol use disorder severity component than insertion carriers or subjects with no variation. Similarly, insertion carriers have significantly, p < 0.05, lower loading coefficients indicating these subjects contribute less to the alcohol use disorder severity component than deletion carriers or subjects with no variation. Whiskers coincide with the box edges for hemizygous insertions.
LLM interpretation
This figure consists of notched box plots showing drinking behavior loading coefficients for three groups at chromosome 11 q14.2: homozygous deletions, neutral, and hemizygous insertions. The y-axis represents the loading coefficient, with the homozygous deletion group exhibiting the highest median value and the hemizygous insertion group exhibiting the lowest. The neutral group shows the widest distribution of data, while the hemizygous insertion group includes two red outlier markers.
Percent change in weights of subjects with AUD compared with control subjects. The change was calculated as subjects with AUD weights minus control weights normalized by the control weights. Positive values indicate larger volumes in subjects with AUD versus control subjects and negative values indicate smaller volumes. The change in weights was a significant difference, p < 0.05, in left cerebellum cortex, right caudate, left and right overall white matter and 5th ventricle.
LLM interpretation
This bar chart displays the percent change in weights of brain components between subjects with alcohol use disorder (AUD) and control subjects. The y-axis represents the percent change in weights, while the x-axis lists specific brain regions, including the cerebral white matter, cerebellum cortex, caudate, and 5th ventricle. Positive changes are observed in the cerebral white matter and 5th ventricle, while negative changes are seen in the cerebellum cortex and caudate.
Volume component loading coefficient box plots for candidate CNV region at chromosome 11 q14.2 after correcting for each subject’s duration of drinking. Deletion carriers still have significantly, p < 0.05, higher median loading coefficients than insertion carriers or subjects with no variation.
LLM interpretation
This figure consists of notched box plots showing volume component loading coefficients for three groups at chromosome 11 q14.2: homozygous deletions, neutral, and hemizygous insertions. The y-axis represents the volume loading coefficient, with the homozygous deletion group exhibiting the highest median value compared to the neutral and hemizygous insertion groups. Red markers indicate outliers in the neutral and hemizygous insertion groups.
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