Genetic correlations suggest that the genetic relationship of alcohol use with internalizing psychopathology depends on the measure of alcohol use. Problematic alcohol use (PAU) is positively genetically correlated with internalizing psychopathology, whereas alcohol consumption ranges from not significantly correlated to moderately negatively correlated with internalizing psychopathology. To explore these different genetic relationships of internalizing psychopathology with alcohol use, we performed a multivariate genome-wide association study of four correlated factors (internalizing psychopathology, PAU, quantity of alcohol consumption, and frequency of alcohol consumption) and then assessed genome-wide and local genetic covariance between these factors. We identified 14 significant regions of local, largely positive, genetic covariance between PAU and internalizing psychopathology and 12 regions of significant local genetic covariance (including both positive and negative genetic covariance) between consumption factors and internalizing psychopathology. Partitioned genetic covariance among functional annotations suggested that brain tissues contribute significantly to positive genetic covariance between internalizing psychopathology and PAU but not to the genetic covariance between internalizing psychopathology and quantity or frequency of alcohol consumption. We hypothesize that genome-wide genetic correlations between alcohol use and psychiatric traits may not capture the more complex shared or divergent genetic architectures at the locus or tissue specific level. This study highlights the complexity of genetic architectures of alcohol use and internalizing psychopathology, and the differing shared genetics of internalizing disorders with PAU compared to consumption.

中文翻译：

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内化精神病理学和酒精使用的多变量遗传结构的新特征

遗传相关性表明，饮酒与内化精神病理学的遗传关系取决于饮酒的程度。有问题的饮酒（PAU）与内化精神病理学呈正相关，而饮酒则与内化精神病理学不显着相关到中度负相关。为了探索内化精神病理学与饮酒之间的不同遗传关系，我们对四个相关因素（内化精神病理学、PAU、饮酒量和饮酒频率）进行了多变量全基因组关联研究，然后评估了全基因组和饮酒频率。这些因素之间的局部遗传协方差。我们确定了 PAU 和内化精神病理学之间 14 个显着的局部遗传协方差区域（主要为正遗传协方差），以及消费因素和内化精神病理学之间的 12 个显着局部遗传协方差区域（包括正遗传协方差和负遗传协方差）。功能注释之间的分区遗传协方差表明，脑组织对内化精神病理学与 PAU 之间的正遗传协方差有显着贡献，但对内化精神病理学与饮酒数量或频率之间的遗传协方差没有贡献。我们假设饮酒和精神特征之间的全基因组遗传相关性可能无法在位点或组织特定水平上捕获更复杂的共享或不同的遗传结构。这项研究强调了饮酒和内化精神病理学遗传结构的复杂性，以及与饮酒相比，PAU 内化障碍的不同共同遗传学。