Department of Psychiatry and Behavioral Sciences,, University of Washington, Seattle, Washington, USA
Department of Medicine, University of Washington, Seattle, Washington, USA
Epidemiology-Biostatistics at the University of Illinois at Chicago and the Vietnam Era Twin Registry, Hines, Illinois, USA
Department of Medicine, University of Washington, Seattle, Washington, USA
Correspondence: Dr D. Buchwald, Harborview Medical Center, 325 Ninth Avenue, Box 359780, Seattle, WA 98104, USA. Tel: 1 206 731 8218; Fax: + 1 206 731 8247; e-mail: dedra{at}u.washington.edu
Declaration of interest None. Funding detailed in Acknowledgements.
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ABSTRACT |
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Aims To establish whether the association of chronic fatigue with psychological distress is causal or due to a common genetic or environmental factor.
Method 69 monozygotic (MZ) and 31 dizygotic (DZ) female twin pairs, with only one co-twin reporting at least 6 months of fatigue, completed questions on fatigue, the General Health Questionnaire (GHQ) and a structured psychiatric interview. We examined the effects of three progressively more stringent definitions of chronic fatigue on four GHQ sub-scales.
Results Fatigued MZ and DZ twins by all definitions were significantly more depressed, anxious, somatically preoccupied and socially dysfunctional than their non-fatigued co-twins. Intrapair differences were similar in DZ and MZ twins, but non-significant differences were observed for the somatic symptoms and anxiety/insomnia sub-scales.
Conclusions In this sample, chronic fatigue and psychological distress are strongly associated without evidence for genetic covariation, implying that the association is environmental, or due to overlapping definitions. Any genetic covariation missed is likely to involve anxiety rather than depression.
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INTRODUCTION |
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METHOD |
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A detailed account of the construction of the registry has been presented elsewhere (Buchwald et al, 1999). Briefly, all study participants completed an extensive mailed survey questionnaire that included questions on fatigue and the CFS symptom criteria according to the 1994 revised Centers for Disease Control and Prevention (CDC) working case definition (Fukuda et al, 1994). For non-fatigued twins, a control version of questions was used that did not refer to fatigue. In addition, participants were asked about their demographic characteristics and, to help determine zygosity, questions on similarity as children. A trained research assistant administered the Diagnostic Interview Schedule (DIS) version IIIA (Robins & Helzer, 1985) by telephone to all twin pairs of whom at least one twin reported fatigue of at least 6 months in duration. The DIS assigns current and life-time diagnoses using a computer algorithm based on the criteria of the DSMIIIR (American Psychiatric Association, 1987). The interview was used to assess the CDC-defined psychiatric diagnoses exclusionary to CFS.
To determine health conditions, the questionnaire contained a checklist of selfreported medical problems; twins indicated whether a condition was currently active or had resolved, and whether a physician had evaluated the condition. The application of the CDC-defined exclusionary medical conditions to the checklist was determined by consensus of two general internists, a psychiatrist with expertise in CFS, an infectious disease specialist, and an internist/ emergency room physician with knowledge of, but little exposure to, patients with CFS. Examples from the comprehensive list of exclusionary disorders included (but were not limited to) steroid-dependent asthma, infectious hepatitis, diabetes, cancer (other than skin), congestive heart failure, stroke, cirrhosis, multiple sclerosis and systemic lupus erythematosus. To assess the performance of our list of exclusionary conditions, subjects' self-reported health conditions were compared with physician confirmation of these diagnoses by chart review and telephone contact with treating physicians for a subsample of twins. Among 44 twins, we did not find any fatigued participant to be ineligible because of an exclusionary condition that was missing or inaccurately reported on the checklist. Conversely, no exclusionary conditions were observed in any twin who self-reported good health.
Definitions of fatigue
We used three progressively more stringent (but not mutually exclusive)
case definitions of chronic fatigue. The first definition, chronic
fatigue, was based on the response to the single question: Have
you been fatigued for at least 6 months? No further inclusionary or
exclusionary conditions were applied.
The second definition, chronic fatigue not explained by medical exclusions, classified all twins according to the CDC CFS research definition using data obtained solely from the mailed questionnaire. An algorithm was developed that defined chronic fatigue using both the inclusionary and medical exclusionary components of the CDC case definition (Fukuda et al, 1994). The exclusionary medical criteria were applied to both the chronically fatigued and non-fatigued twins. To be classified as having medically unexplained chronic fatigue, twins were required to report fatigue of at least 6 months' duration that was not lifelong and that resulted in a substantial reduction of occupational, educational, social or personal activities. Furthermore, subjects had to endorse the presence of four or more of eight CDC CFS symptom criteria: impaired memory or concentration, sore throat, tender glands, aching or stiff muscles, multi-joint pain, new headaches, unrefreshing sleep and post-exertional fatigue (Fukuda et al, 1994). Twins were excluded from this definition of chronic fatigue if they had a body mass index of 45 kg/m2 or more (as stipulated in the CDC criteria) or reported any of the exclusionary medical conditions.
The third definition, chronic fatigue not explained by medical or psychiatric exclusions, further restricted our sample on the basis of the DIS-generated psychiatric diagnoses considered exclusionary by the CDC case definition. These included life-time mania, hypomania, bipolar disorder, schizophrenia, major depression with psychotic or melancholic features, anorexia or bulimia nervosa, and current alcohol or substance abuse or dependence. Identical psychiatric exclusionary criteria were used with both fatigued and nonfatigued twins.
Determination of zygosity
Studies have shown that questions about childhood similarity in twin pairs
can be used to classify zygosity with an accuracy of 95-98% compared with
biological indicators (Torgersen,
1979; Eisen et al,
1989). Twin pairs in which both members answered affirmatively to
multiple questions about similarity in the mailed questionnaire (e.g.
When you were young, were you as alike as peas in a pod?) were
classified as monozygotic (MZ), and those pairs in which both twins denied
this degree of similarity were considered to be dizygotic (DZ).
General Health Questionnaire
The General Health Questionnaire (GHQ) is a 28-item self-report instrument
that measures psychological and somatic distress in the past few
weeks on a four-point scale
(Goldberg & Hillier,
1979). The questionnaire has been recommended by the National
Institutes of Health and the National Institutes of Health and the National
Institute of Mental Health for use in CFS research
(Schluederberg et al,
1992). The GHQ contains four sub-scales: somatic symptoms; anxiety
and insomnia; social dysfunction; and severe depression. The sub-scales are
scored by summing the values for endorsed items (higher scores suggest greater
distress). In addition, a total score cut-off can be used to determine the
sensitivity and specificity of the GHQ in various populations (e.g.
Buchwald et al,
1997).
Statistical analysis
The initial descriptive analysis examined the mean levels of each of the
four GHQ scale scores according to the three definitions of chronic fatigue.
Formal statistical analysis compared the intra-pair mean differences for each
GHQ scale score using paired t-tests. Examination of potential
genetic covariation between chronic fatigue and the GHQ scale scores compared
the magnitude of GHQ score differences between the fatigued and nonfatigued
twins within MZ and DZ pairs. This approach to analysis was based on the
methods articulated by Kendler et al
(1999).
By comparing the size of the MZ and DZ intra-pair mean differences in GHQ scores using unmatched t-tests, it is possible to gain insight into the relative magnitude of genetic and environmental influence on both chronic fatigue and psychological distress. For example, if the intra-pair difference for the GHQ severe depression score in MZ twins were zero and a large difference were noted in DZ twins, this would strongly suggest that the association between chronic fatigue and severe depression as measured by GHQ is at least partly due to a shared genetic influence. Conversely, if the effects in MZ and DZ pairs were approximately comparable, this would suggest that the phenotypic association is not due to a common genetic influence on both traits.
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RESULTS |
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The zygosity distribution of twins in all three samples was similar, with a preponderance of MZ twin pairs. Fatiguediscordant twin pairs were not different on any of the demographic characteristics at all three levels of analysis. All of the twins were White; on average, the twins were in their mid-40s, had approximately 15 years of education, and the majority were married. The fatigued twins had experienced fatigue for about 6 years with a mean severity of more than 7.5 on a 1 to 10 scale (1, none; 10, a great deal).
The means and associated 95% confidence intervals for each of the GHQ sub-scales are presented separately for MZ and DZ pairs and according to each of the three definitions of chronic fatigue in Figs 1,2,3,4.
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The data were similar across zygosity, sub-scale score and fatigue
definition. In both MZ and DZ twin pairs, regardless of definition, the
fatigued twins were more somatically preoccupied and anxious than the
non-fatigued twins (all P values 0.01). Fatigued MZ twins at all
three levels of fatigue definition were more socially dysfunctional and
depressed than their non-fatigued counterparts (all P values
0.001), whereas these differences were significant for DZ twins only in
the sample with the first and broadest definition of chronic fatigue (social
dysfunction: t=2.929, P=0.006; severe depression:
t=2.402, P=0.023). Although not significant, fatigued DZ
twins with the two more stringent definitions of fatigue were also more
socially dysfunctional and depressed than their non-fatigued counterparts.
Table 2 presents the comparisons of MZ and DZ twin pairs on the intra-pair mean differences for each GHQ sub-scale using the three increasingly stringent definitions of fatigue. None of the intra-pair GHQ scale differences was significantly different between the MZ and DZ twin pairs. However, larger intra-pair differences for the somatic symptoms and the anxiety and insomnia sub-scales were consistently noted in DZ twins. In contrast, for social dysfunction and depression, MZ intra-pair differences tended to be larger than DZ intra-pair differences.
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DISCUSSION |
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Nature of the fatiguedistress association
The co-twin control study provides a unique approach to exploring the
nature of the association between chronic fatigue and psychological distress.
The design controls for the potential confounding influence of genetic and
early environmental factors in a way that is not possible using standard
research designs. Our results are clear regarding the absence of a common
genetic factor for chronic fatigue and various domains of psychological
distress, and consistent with evidence from a prospective primary care study
that fatigue causes depression (odds ratio of 1.4;
Hickie et al,
1999a). This finding is at variance with results from a
previous study that found two genetic factors common to fatigue and distress
(Hickie et al,
1999b), suggesting that the association between fatigue
and distress is more likely to be environmental in origin. However, it is
possible that our small sample size accounted for our failure to find genetic
covariation between fatigue and measures of psychological distress. We also
used a less age-restricted twin sample, and more refined and multiple
definitions of fatigue, which may account for some of the disparities in
results.
Association of fatigue with anxiety v. depression
Although our results did not demonstrate significant genetic covariation,
there was an interesting pattern of differences across the four GHQ
sub-scales. For somatic and anxiety symptoms, the larger intra-pair
differences in the DZ twins suggest that some portion of these measures may be
due to genetic covariation that was not detected owing to small sample size.
Conversely, for severe depression, the MZ intra-pair difference was larger
than that observed for DZ pairs (regardless of the stringency of the chronic
fatigue definition), which argues against a common genetic influence. This is
consistent with previous speculations that chronic fatigue most closely
resembles atypical depression with its prominent anxiety and
somatic symptoms, tendency to cortisol hyposecretion, and poor response to
conventional antidepressant pharmacotherapy
(Gold et al, 1995;
Terman et al,
1998).
The evidence for a genetic influence on depression is abundant from numerous twin and family studies (Moldin et al, 1991; Kendler et al, 1993; Lyons et al, 1998). However, the role of genetic effects in fatigue, more specifically chronic fatigue, is less well documented and has only recently emerged. Studying Australian twins, researchers demonstrated a significant heritability (44%) for a continuous measure of fatigue (Hickie et al, 1999b). Importantly, a component of both unique and shared (with depression) genetic influence on chronic fatigue was observed. Other investigators also have described a significant genetic influence on fatigue (54%) in a British sample of young twins (Farmer et al, 1999). However, neither the Australian nor the British studies attempted to define a discrete illness phenotype of chronic fatigue. Using the twins from the registry described here, we found a significant heritable influence on a CFS-like illness (51%), defined according to the CDC 1994 criteria (Buchwald et al, 2001).
Limitations
This study has several limitations. First, the method used to identify the
CFS twins was not ideal. Solicitation by advertisement resulted in a volunteer
sample of twin pairs with the potential for ascertainment biases. However, the
more desirable strategy of systematically identifying twins with chronic
fatigue and CFS from a well-defined, truly population-based twin registry is
not readily accomplished in the USA. Likewise, the selected nature of the
sample, which had more female-female twin pairs and a long duration of
fatigue, may have increased the probability of comorbid psychiatric illness,
therefore inflating GHQ score differences between fatigued and non-fatigued
twins. However, the rates of mood and anxiety disorders among our twins were
comparable to those observed in clinical samples
(Katon & Walker, 1993). Second, the number of DZ twins and the overall number of twins discordant for
chronic fatigue that were identified were not large. Finally, we relied on
self-report to define and measure fatigue and exclusionary medical conditions.
However, we closely followed the CFS symptom and psychiatric criteria as
articulated by CDC. In addition, our three definitions of fatigue were
consistent with those used in several recent epidemiological studies
(Nisenbaum et al,
1998; Steele et al,
1998; Jason et al,
1999).
Despite these shortcomings, this study makes several contributions to the field. Using three discrete definitions of fatigue, we have provided evidence that prolonged fatigue is the critical factor in the association of psychological distress with chronic fatigue. In addition, the absence of a common genetic factor for fatigue and various domains of psychological distress suggests that the relationship between fatigue and distress is largely, if not exclusively, environmental, although the direction of effect is unknown. The contribution of overlapping definitions to this relationship is unknown, but must also be acknowledged. If there is any small genetic relationship between fatigue and distress, the pattern of differences between various measures of distress and fatigue suggests this is most likely to involve anxiety and somatisation rather than depression, suggesting a relationship between fatigue and atypical (i.e. anxious) forms of depression.
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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REFERENCES |
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Received for publication February 12, 2001. Revision received June 18, 2001. Accepted for publication July 20, 2001.
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