Peripheral and central inflammation in progressive supranuclear palsy syndrome: an immunological and imaging neuroinflammation study.

Approximately one in eight people worldwide live with a mental disorder, and this number continues to rise. According to studies by the Global Burden of Disease, neuropsychiatric disorders are among the leading causes of disability and are important risk factors for premature mortality. These disorders have profound psychological and psychiatric effects on the workforce and impose a substantial economic burden on society. Neuropsychiatric disorders such as schizophrenia (SCZ), major depressive disorder (MDD), bipolar disorder (BIP), autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) are characterized by their moderate heritability and peak age at onset in childhood or adolescence. Despite this, the underlying biological mechanisms remain poorly understood, limiting progress in early detection and effective treatment. Twin studies have provided empirical evidence of the genetic contributions to neuropsychiatric disorders and genome-wide association studies (GWAS) have identified hundreds of genetic loci associated with multiple neuropsychiatric disorders. However, most associated variants lie in non-coding regions, making it difficult to infer their regulatory roles or downstream biological effects. Genetic variants associated with neuropsychiatric disorders may influence disease risk through regulatory mechanisms, including effects on DNA methylation and gene expression, captured by methylation quantitative trait loci (meQTLs) and expression quantitative trait loci (eQTLs). Integrative approaches that combine genetic and functional genomic data can help bridge this gap by mapping genetic risk to molecular mechanisms. Mendelian randomization (MR) further enables the inference of putative causal relationships between these molecular intermediates and disease outcomes, leveraging genetic instruments to move beyond correlation toward causal insight. Although neuropsychiatric disorders primarily affect the brain, increasing evidence suggests that peripheral tissues, especially blood, can provide meaningful molecular insights into psychiatric risk. This is particularly relevant for disorders with known immune involvement, such as SCZ, MDD, BIP, ASD and ADHD. Multiple studies have reported systemic inflammation and immune dysregulation in these disorders, and GWAS have consistently implicated immune-related pathways, especially in SCZ and MDD. Blood-based methylation and gene expression profiles can reflect such systemic immune alterations and may capture upstream regulatory mechanisms that affect both peripheral and central systems. Moreover, blood-derived molecular QTLs are highly accessible and scalable for population-based research, particularly in adolescents, where brain tissue is not available. While blood may not fully represent brain-specific mechanisms, it offers a valuable proxy for identifying peripheral biomarkers and genetically anchored regulatory pathways with potential relevance to neurodevelopmental and psychiatric conditions.