Khan Yousef, Davis Christal N, Jinwala Zeal, Feuer Kyra L, Toikumo Sylvanus, Hartwell Emily E, Sanchez-Roige Sandra, Peterson Roseann E, Hatoum Alexander S, Kranzler Henry R, Kember Rachel L
Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA 19104.
Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; Mental Illness Research, Education and Clinical Center, Crescenz VAMC, Philadelphia, PA 19104.
Biol Psychiatry. 2025 May 7. doi: 10.1016/j.biopsych.2025.04.021.
Substance use disorders (SUDs) and psychiatric disorders frequently co-occur, and their etiology likely reflects both transdiagnostic (i.e., common/shared) and disorder-level (i.e., independent/nonshared) genetic influences. Understanding the genetic influences that are shared and those that operate independently of the shared risk could enhance precision in diagnosis, prevention, and treatment, but this remains underexplored, particularly in non-European ancestry groups.
We applied genomic structural equation modeling to examine the common and independent genetic architecture among SUDs and psychotic, mood, and anxiety disorders using summary statistics from genome-wide association studies (GWAS) conducted in European- (EUR) and African-ancestry (AFR) individuals. To characterize the biological and phenotypic associations, we used FUMA, conducted genetic correlations, and performed phenome-wide association studies (PheWAS).
In EUR individuals, transdiagnostic genetic factors represented SUDs, psychotic, and mood/anxiety disorders, with GWAS identifying two novel lead single-nucleotide polymorphisms (SNPs) for the mood factor. In AFR individuals, genetic factors represented SUDs and psychiatric disorders, and GWAS identified one novel lead SNP for the SUD factor. In EUR individuals, second-order factor models showed phenotypic and genotypic associations with a broad range of physical and mental health traits. Finally, genetic correlations and PheWAS highlighted how common and independent genetic factors for SUD and psychotic disorders were differentially associated with psychiatric, sociodemographic, and medical phenotypes.
Combining transdiagnostic and disorder-level genetic approaches can improve our understanding of co-occurring conditions and increase the specificity of genetic discovery, which is critical for identifying more effective prevention and treatment strategies to reduce the burden of these disorders.
物质使用障碍（SUDs）与精神疾病常常同时出现，其病因可能反映了跨诊断（即共同/共享）和疾病水平（即独立/非共享）的遗传影响。了解共享的遗传影响以及独立于共享风险起作用的遗传影响，可提高诊断、预防和治疗的精准度，但这方面仍未得到充分探索，尤其是在非欧洲血统人群中。
我们应用基因组结构方程模型，利用在欧洲血统（EUR）和非洲血统（AFR）个体中进行的全基因组关联研究（GWAS）的汇总统计数据，来检验SUDs与精神病性、心境和焦虑症之间的共同和独立遗传结构。为了描述生物学和表型关联，我们使用了FUMA，进行了遗传相关性分析，并开展了全表型组关联研究（PheWAS）。
在欧洲血统个体中，跨诊断遗传因素代表SUDs、精神病性障碍和心境/焦虑症，GWAS识别出两个与心境因素相关的新的领先单核苷酸多态性（SNP）。在非洲血统个体中，遗传因素代表SUDs和精神疾病，GWAS识别出一个与SUD因素相关的新的领先SNP。在欧洲血统个体中，二阶因素模型显示出与广泛的身心健康特征的表型和基因型关联。最后，遗传相关性分析和PheWAS突出了SUD和精神病性障碍的共同和独立遗传因素如何与精神、社会人口统计学和医学表型存在差异关联。
结合跨诊断和疾病水平的遗传方法，可以增进我们对共病情况的理解，并提高遗传发现的特异性，这对于确定更有效的预防和治疗策略以减轻这些疾病的负担至关重要。
