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11q14.2 基因拷贝数变异与酒精使用障碍人群脑区体积差异的关联。

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

机构信息

The Mind Research Network, 1101 Yale blvd. NE, Albuquerque, NM 87106, USA.

出版信息

Alcohol. 2012 Sep;46(6):519-27. doi: 10.1016/j.alcohol.2012.05.002. Epub 2012 Jun 23.

Abstract

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.

摘要

本研究调查了酒精使用障碍(AUD)人群中遗传拷贝数变异与脑容量差异之间的关系。我们假设,通过区域灰质和白质脑容量的变化,拷贝数变异可能会影响个体患酒精使用障碍的风险。由于遗传对行为的影响是许多复杂相互作用的结果,我们专注于脑容量差异作为遗传变异与行为之间的假定中间表型。从参加两项 AUD 研究的 283 名受试者(199 名男性和 84 名女性)中获得了拷贝数变异、酒精使用评估和脑结构磁共振图像,并使用 Freesurfer 图像分析套件和独立成分分析进行了分析。由于脑容量随年龄而变化,我们将参与者的体积变化与来自 75 名对照受试者的体积变化进行了比较。此外,我们还回归了由长期饮酒引起的可能的脑容量变化。较小的大脑皮质、小脑和尾状核,以及较大的大脑白质和第五脑室体积与 AUD 严重程度的增加显著相关。当将这些体积变化与对照受试者的体积进行比较时;患有 AUD 的受试者的变化明显不同于正常衰老的影响。11q14.2 处的 CNV 与这些脑容量变化呈边缘相关(未校正 p<0.05),并且在控制长期饮酒后仍然如此;缺失携带者的大脑皮质、小脑、尾状核较小,大脑白质和第五脑室较大,而插入携带者或该区域无变异的受试者则相反。同样,缺失携带者的 AUD 严重程度评分也高于插入携带者或该区域无变异的受试者。这里呈现的结果表明,拷贝数变异,特别是染色体 11q14.2 的变异,可能会对脑容量变化产生影响,从而潜在地影响 AUD 行为。

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