Available at www.sciencedirect.com journal homepage: www.elsevier.com/locate/psyneuen Genetic evaluation of the serotonergic system in chronic fatigue syndrome Alicia K. Smith a , Irina Dimulescu a , Virginia R. Falkenberg a , Supraja Narasimhan a , Christine Heim b , Suzanne D. Vernon a , Mangalathu S. Rajeevan a,Ã a Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, 1600 Clifton Road, MSG41, Atlanta, GA 30333, USA b Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA Received 10 April 2007; received in revised form 22 October 2007; accepted 1 November 2007 KEYWORDS Chronic fatigue syndrome; Polymorphisms; HTR2A; Serotonin; HPA axis; TH1/E47 transcription factor Summary Chronic fatigue syndrome (CFS) is a debilitating disorder of unknown etiology with no known lesions, diagnostic markers or therapeutic intervention. The pathophysiology of CFS remains elusive, although abnormalities in the central nervous system (CNS) have been implicated, particularly hyperactivity of the serotonergic (5-hydroxytryptamine; 5-HT) system and hypoactivity of the hypothalamic–pituitary–adrenal (HPA) axis. Since alterations in 5-HT signaling can lead to physiologic and behavioral changes, a genetic evaluation of the 5-HT system was undertaken to identify serotonergic markers associated with CFS and potential mechanisms for CNS abnormality. A total of 77 polymorphisms in genes related to serotonin synthesis (TPH2), signaling (HTR1A, HTR1E, HTR2A, HTR2B, HTR2C, HTR3A, HTR3B, HTR4, HTR5A, HTR6, and HTR7), transport (SLC6A4), and catabolism (MAOA) were examined in 137 clinically evaluated subjects (40 CFS, 55 with insufficient fatigue, and 42 non-fatigued, NF, controls) derived from a population-based CFS surveillance study in Wichita, Kansas. Of the polymorphisms examined, three markers (1438G/A, C102T, and rs1923884) all located in the 5-HT receptor subtype HTR2A were associated with CFS when compared to NF controls. Additionally, consistent associations were observed between HTR2A variants and quantitative measures of disability and fatigue in all subjects. The most compelling of these associations was with the A allele of 1438G/A (rs6311) which is suggested to have increased promoter activity in functional studies. Further, in silico analysis revealed that the 1438 A allele creates a consensus binding site for Th1/E47, a transcription factor implicated in the development of the nervous system. Electrophoretic mobility shift assay supports allele-specific binding of E47 ARTICLE IN PRESS 0306-4530/$ - see front matter Published by Elsevier Ltd. doi:10.1016/j.psyneuen.2007.11.001 Ã Corresponding author. Tel.: +1 404 639 2931; fax: +1 404 639 3540. E-mail address: mor4@cdc.gov (M.S. Rajeevan). Psychoneuroendocrinology (2008) 33, 188–197