Al-Soufi Laila, Hindley Guy, Rødevand Linn, Shadrin Alexey A, Jaholkowski Piotr, Fominykh Vera, Icick Romain, Tesfaye Markos, Costas Javier, Andreassen Ole A
Psychiatric Genetics group, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Santiago de Compostela, Galicia, Spain. Red de Investigación en Atención Primaria de Adicciones (RIAPAd).
Department of Zoology, Genetics and Physical Anthropology, Universidade de Santiago de Compostela (USC), Santiago de Compostela, Galicia, Spain.
Psychol Med. 2025 Mar 31;55:e100. doi: 10.1017/S0033291725000108.
Externalizing and internalizing pathways may lead to the development of substance use behaviors (SUBs) and substance use disorders (SUDs), which are all heritable phenotypes. Genetic correlation studies have indicated differences in the genetic susceptibility between SUBs and SUDs. We investigated whether these substance use phenotypes are differently related to externalizing and internalizing problems at a genetic level.
We analyzed data from genome-wide association studies (GWAS) of four SUBs and SUDs, five externalizing traits, and five internalizing traits using the bivariate causal mixture model (MiXeR) to estimate genetic overlap beyond genetic correlation.
Two distinct patterns were found. SUBs demonstrated high genetic overlap but low genetic correlation of shared variants with internalizing traits, suggesting a pattern of mixed effect directions of shared genetic variants. Conversely, SUDs and externalizing traits exhibited considerable genetic overlap with moderate to high positive genetic correlation of shared variants, suggesting concordant effect direction of shared risk variants.
These results highlight the importance of the externalizing pathway in SUDs as well as the limited role of the internalizing pathway in SUBs. As MiXeR is not intended for the identification of specific genes, further studies are needed to reveal the underlying shared mechanisms of these traits.
外化和内化途径可能导致物质使用行为（SUBs）和物质使用障碍（SUDs）的发展，这些都是可遗传的表型。遗传相关性研究表明，SUBs和SUDs在遗传易感性方面存在差异。我们研究了这些物质使用表型在遗传水平上与外化和内化问题的关联是否不同。
我们使用双变量因果混合模型（MiXeR）分析了来自四项SUBs和SUDs、五项外化特征和五项内化特征的全基因组关联研究（GWAS）数据，以估计超出遗传相关性的遗传重叠。
发现了两种不同的模式。SUBs表现出高遗传重叠，但共享变异与内化特征的遗传相关性低，表明共享遗传变异的效应方向混合。相反，SUDs和外化特征表现出相当大的遗传重叠，共享变异具有中度到高度的正遗传相关性，表明共享风险变异的效应方向一致。
这些结果突出了外化途径在SUDs中的重要性以及内化途径在SUBs中的有限作用。由于MiXeR并非用于识别特定基因，因此需要进一步研究以揭示这些特征潜在的共同机制。
