全实验室检测范围的多基因评分关联扫描识别精神疾病生物标志物

Abstract

Background: Psychiatric disorders pose a significant public health burden, and their complex genetic architecture underlies multiple biological pathways, contributing to a lack of diagnostic biomarkers. Laboratory-Wide Association Studies (LabWAS) leverage electronic health record laboratory data as intermediary phenotypes to link genetic risk to physiology. Methods: Polygenic Scores (PGS) for 25 health-related, psychiatric, and substance use phenotypes were generated for individuals of African (AFR; N=10,473) and European (EUR, N=35,131) ancestry from the Penn Medicine Biobank. Laboratory data was prepared using the LabWAS pipeline, encompassing 78 laboratory tests and 6 vital signs. Linear regression models tested the association of each lab value with PGS adjusting for sex, age, and ten within-ancestry genetic principal components. Results: Four PGS were significantly associated with at least one laboratory value in AFR individuals and 22 PGS in EUR individuals. In EUR individuals, psychiatric PGS partitioned into three physiological profiles: anxiety, attention-deficit/hyperactivity disorder, major depressive disorder, and post-traumatic stress disorder shared a metabolic/inflammatory signature (higher BMI, glucose, and monocytes; lower high density lipoprotein cholesterol and oxygen saturation); anorexia nervosa, obsessive compulsive disorder, and schizophrenia were characterized by lower BMI; and bipolar disorder demonstrated a more circumscribed profile with lower electrolytes and renal makers. Substance use disorder PGS similarly clustered: tobacco use disorder and externalizing showed metabolic/inflammatory profiles; alcohol-related phenotypes showed lower red blood cell indices; and cannabis use disorder had a more circumscribed profile. Conclusions: LabWAS reveals physiologic signatures associated with genetic risk for psychiatric disorders, offering new biological insights into their pathology.

Competing Interest Statement

The authors have declared no competing interest.

Author Declarations

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IRB of University of Pennsylvania gave ethical approval for this work.

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Data Availability

The data used in this study are derived from electronic health records and cannot be made publicly available due to patient privacy and data use agreement restrictions. Analysis code are available upon reasonable request to the corresponding author.