Background: Postural orthostatic tachycardia syndrome (POTS) is a complex disorder with serious health consequences, while its etiology remains largely elusive. Objective: To investigate the genetic landscape of POTS using genomic approaches in a unique pediatric cohort. Methods: We conducted a combined genome wide genotyping and whole exome sequencing (WES) study to systemically examine the molecular mechanisms of POTS pathogenesis. The patients for were genotyped as two independent cohorts, a family cohort of 100 complete families and a case control cohort of 207 unrelated European cases and 4,063 ethnicity-matched controls. The WES component consisted of a subset of the genotyped subjects, including 87 unrelated European cases and 2,719 unrelated European controls. Results: Due to the heterogeneous phenotype of POTS, unlike traditional phenotypes for association study, it is unlikely that any loci will reach genome-wide significance. Instead, we conducted an over-representation analysis (ORA) by considering all genes that showed nominal significance. The ORA identified gene sets linked to Cell-Cell Junction, Early Estrogen Response, and Substance-Related Disorders, with statistical significance. Moreover, WES revealed 55 genes with genome-wide significance through rare variant burden analysis, harboring 92 variants classified as pathogenic or likely pathogenic by ClinVar. Conclusions and Relevance: This study showcases the complex interplay between common and rare genetic variants in POTS development, marking an pioneering step forward in deciphering its complex etiologies. The insights gained from this research enriches our understanding of POTS, offering new avenues for precise treatment strategies and highlighting the need for continued research in this area.

The authors have declared no competing interest.

This study was funded in part by donation from the Esther Feigenbaum Foundation, The Siemer Family Foundation, by an Endowed Chair in Genomic Research (HH) and by an Institutional Development Award to the Center for Applied Genomics from The Children's Hospital of Philadelphia.

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The Institutional Review Board (IRB) of the Children's Hospital of Philadelphia (CHOP) approved this study.

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