Objective: The etiology of chronic fatigue syndrome is unknown, but genetic influences may be important in its expression. Our objective was to assess the role of genetic and environmental factors in unexplained chronic fatigue. Methods: A classic twin study was conducted using 146 female-female twin pairs, of whom at least one member reported Ն6 months of fatigue. After completing questionnaires on symptoms, zygosity, physical health, and a psychiatric interview, twins were classified using three increasingly stringent definitions: 1) chronic fatigue for Ն6 months, 2) chronic fatigue not explained by exclusionary medical conditions, and 3) idiopathic chronic fatigue not explained by medical or psychiatric exclusionary criteria of the chronic fatigue syndrome case definition. Concordance rates in monozygotic and dizygotic twins were calculated for each fatigue definition along with estimates of the relative magnitude of genetic and environmental influences on chronic fatigue. Results: The concordance rate was higher in monozygotic than dizygotic twins for each definition of chronic fatigue. For idiopathic chronic fatigue, the concordance rates were 55% in monozygotic and 19% in dizygotic twins (p ϭ .042). The estimated heritability in liability was 19% (95% confidence interval ϭ 0 -56) for chronic fatigue Ն6 months, 30% (95% confidence interval ϭ 0 -81) for chronic fatigue not explained by medical conditions, and 51% (95% confidence interval ϭ 7-96) for idiopathic chronic fatigue. Conclusions: These results provide evidence supporting the familial aggregation of fatigue and suggest that genes may play a role in the etiology of chronic fatigue syndrome.

OBJECTIVES: Chronically fatiguing illness, defined as fatigue for at least 6 months, has been associated with various physical health conditions. Our objective was to determine whether there is a significant relationship between chronically fatiguing illness and 10 clinical conditions that frequently appear to be associated with fatigue, adjusting for the potentially confounding effects of psychiatric illness. DESIGN: A co‐twin control study controlling for genetic and many environmental factors by comparing chronically fatigued twins with their nonfatigued co‐twins. SETTING: A nationally distributed volunteer twin registry. PARTICIPANTS: The study included 127 twin pairs in which one member of the pair experienced fatigue of at least 6 months' duration and the co‐twin was healthy and denied chronic fatigue. Fatigued twins were classified into 3 levels using increasingly stringent diagnostic criteria. MEASUREMENTS AND MAIN RESULTS: Twins reported on a history of fibromyalgia, irritable bowel syndrome, multiple chemical sensitivities, temporomandibular disorder, interstitial cystitis, postconcussion syndrome, tension headache, chronic low back pain, chronic pelvic pain (women), and chronic nonbacterial prostatitis (men). The prevalence of these comorbid clinical conditions was significantly higher in the fatigued twins compared to their nonfatigued co‐twins. Most notably, compared to their nonfatigued co‐twins, the chronically fatigued twins had higher rates of fibromyalgia (>70% vs <10%) and irritable bowel syndrome (>50% vs <5%). The strongest associations were observed between chronic fatigue and fibromyalgia (odds ratios >20), irritable bowel syndrome, chronic pelvic pain, multiple chemical sensitivities, and temporomandibular disorder (all with odds ratios ≥4). Regression analysis suggested that the number of comorbid clinical conditions associated with chronic fatigue could not be attributed solely to psychiatric illness. CONCLUSIONS: Chronically fatiguing illnesses were associated with high rates of many other clinical conditions. Thus, patients with chronic fatigue may present a complex clinical picture that poses diagnostic and management challenges. Nonetheless, clinicians should assess such patients for the presence of comorbid clinical conditions. Future research should provide a better understanding of the temporal relationship of the onset of fatigue and these conditions, and develop strategies for early intervention.