Category: Genetics

The genetic aetiology of somatic distress

Abstract:

BACKGROUND: Somatoform disorders such as neurasthenia and chronic fatigue syndrome are characterized by a combination of prolonged mental and physical fatigue. This study aimed to investigate the heritability of somatic distress and determine whether this dimension is aetiologically distinct from measures of depression and anxiety.

METHOD: Measures of anxiety, depression, phobic anxiety, somatic distress and sleep difficulty were administered in a self-report questionnaire to a community-based sample of 3469 Australian twin individuals aged 18 to 28 years. Factor analysis using a Promax rotation, produced four factors: depression, phobic anxiety, somatic distress and sleep disturbance. Multivariate and univariate genetic analyses of the raw categorical data scores for depression, phobic anxiety and depression were then analysed in Mx1.47.

RESULTS: Univariate genetic analysis revealed that an additive genetic and non-shared environmental (AE) model best explained individual differences in depression and phobic anxiety scores, for male and female twins alike, but could not resolve whether additive genes or shared environment were responsible for significant familial aggregation in somatic distress. However, multivariate genetic analysis showed that an additive genetic and non-shared environment (AE) model best explained the covariation between the three factors. Furthermore, 33 % of the genetic variance in somatic distress was due to specific gene action unrelated to depression or phobic anxiety. In addition, 74% of the individual environmental influence on somatic distress was also unrelated to depression or phobic anxiety.

CONCLUSION: These results support previous findings that somatic symptoms are relatively aetiologically distinct both genetically and environmentally from symptoms of anxiety and depression.

 

Source: Gillespie NA, Zhu G, Heath AC, Hickie IB, Martin NG. The genetic aetiology of somatic distress. Psychol Med. 2000 Sep;30(5):1051-61. http://www.ncbi.nlm.nih.gov/pubmed/12027042

 

Cellular immunity in monozygotic twins discordant for chronic fatigue syndrome

Abstract:

Studies elsewhere have suggested that immune dysfunction may be common in patients with chronic fatigue syndrome (CFS). The objective of this study was to assess the nature and extent of abnormalities in lymphocyte cell surface markers and NK cell activity in patients with CFS while controlling for genetic factors. A co-twin control study of immune system parameters was conducted for 22 pairs of monozygotic twins discordant for CFS and 9 healthy pairs of twins.

The CFS twins had greater numbers of CD62L(+) T cells in several T cell subsets, although these differences did not achieve statistical significance. Significantly greater variability was noted in twins discordant for CFS than in the concordant healthy twins for 20 of 48 variables examined. The monozygotic co-twin control design is of unique value because of its ability to control for genetic influences on CFS; however, additional studies will be required to further assess immune dysregulation in this illness.

 

Source: Sabath DE, Barcy S, Koelle DM, Zeh J, Ashton S, Buchwald D. Cellular immunity in monozygotic twins discordant for chronic fatigue syndrome. J Infect Dis. 2002 Mar 15;185(6):828-32. Epub 2002 Feb 28. http://jid.oxfordjournals.org/content/185/6/828.long (Full article)

 

Chronic fatigue and anxiety/depression: a twin study

Abstract:

BACKGROUND: Up to three-quarters of patients with fatigue syndromes have comorbid mood or anxiety disorders, suggesting that chronic fatigue is a forme fruste of anxiety or depressive states.

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.

 

Source: Roy-Byrne P, Afari N, Ashton S, Fischer M, Goldberg J, Buchwald D. Chronic fatigue and anxiety/depression: a twin study. Br J Psychiatry. 2002 Jan;180:29-34. http://www.ncbi.nlm.nih.gov/pubmed/11772848

 

A twin study of chronic fatigue

Abstract:

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 > or =6 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 > or =6 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 =.042). The estimated heritability in liability was 19% (95% confidence interval = 0-56) for chronic fatigue > or =6 months, 30% (95% confidence interval = 0-81) for chronic fatigue not explained by medical conditions, and 51% (95% confidence interval = 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.

 

Source: Buchwald D, Herrell R, Ashton S, Belcourt M, Schmaling K, Sullivan P, Neale M, Goldberg J. A twin study of chronic fatigue. Psychosom Med. 2001 Nov-Dec;63(6):936-43. http://www.ncbi.nlm.nih.gov/pubmed/11719632

 

A twin study of the etiology of prolonged fatigue and immune activation

Abstract:

Risk factors to prolonged fatigue syndromes (PFS) are controversial. Pre-morbid and/or current psychiatric disturbance, and/or disturbed cell-mediated immunity (CMI), have been proposed as etiologic factors.

Self-report measures of fatigue and psychologic distress and three in vitro measures of CMI were collected from 124 twin pairs. Crosstwin-crosstrait correlations were estimated for the complete monozygotic (MZ; 79 pairs) and dizygotic (DZ; 45 pairs) twin groups. Multivariate genetic and environmental models were fitted to explore the patterns of covariation between etiologic factors. For fatigue, the MZ correlation was more than double the DZ correlation (0.49 versus 0.16) indicating strong genetic control of familial aggregation.

By contrast, for in vitro immune activation measures MZ and DZ correlations were similar (0.49-0.69 versus 0.42-0.53) indicating the etiologic role of shared environments. As small univariate associations were noted between prolonged fatigue and the in vitro immune measures (r = -0.07 to -0.12), multivariate models were fitted. Relevant etiologic factors included: a common genetic factor accounting for 48% of the variance in fatigue which also accounted for 4%, 6% and 8% reductions in immune activation; specific genetic factors for each of the in vitro immune measures; a shared environment factor influencing the three immune activation measures; and, most interestingly, unique environmental influences which increased fatigue but also increased markers of immune activation.

PFS that are associated with in vitro measures of immune activation are most likely to be the consequence of current environmental rather than genetic factors. Such environmental factors could include physical agents such as infection and/or psychologic stress.

 

Source: Hickie IB, Bansal AS, Kirk KM, Lloyd AR, Martin NG. A twin study of the etiology of prolonged fatigue and immune activation. Twin Res. 2001 Apr;4(2):94-102. http://www.ncbi.nlm.nih.gov/pubmed/11665341

 

Familial corticosteroid-binding globulin deficiency due to a novel null mutation: association with fatigue and relative hypotension

Abstract:

Corticosteroid-binding globulin is a 383-amino acid glycoprotein that serves a hormone transport role and may have functions related to the stress response and inflammation. We describe a 39-member Italian-Australian family with a novel complete loss of function (null) mutation of the corticosteroid-binding globulin gene. A second, previously described, mutation (Lyon) segregated independently in the same kindred. The novel exon 2 mutation led to a premature termination codon corresponding to residue -12 of the procorticosteroid-binding globulin molecule (c.121G–>A).

Among 32 family members there were 3 null homozygotes, 19 null heterozygotes, 2 compound heterozygotes, 3 Lyon heterozygotes, and 5 individuals without corticosteroid-binding globulin mutations. Plasma immunoreactive corticosteroid-binding globulin was undetectable in null homozygotes, and mean corticosteroid-binding globulin levels were reduced by approximately 50% at 18.7 +/- 1.3 microg/ml (reference range, 30-52 microg/ml) in null heterozygotes. Morning total plasma cortisol levels were less than 1.8 microg/dl in homozygotes and were positively correlated to the plasma corticosteroid-binding globulin level in heterozygotes. Homozygotes and heterozygote null mutation subjects had a high prevalence of hypotension and fatigue.

Among 19 adults with the null mutation, the systolic blood pressure z-score was 12.1 +/- 3.5; 11 of 19 subjects (54%) had a systolic blood pressure below the third percentile. The mean diastolic blood pressure z-score was 18.1 +/- 3.4; 8 of 19 subjects (42%) had a diastolic blood pressure z-score below 10.

Idiopathic chronic fatigue was present in 12 of 14 adult null heterozygote subjects (86%) and in 2 of 3 null homozygotes. Five cases met the Centers for Disease Control criteria for chronic fatigue syndrome. Fatigue questionnaires revealed scores of 25.1 +/- 2.5 in 18 adults with the mutation vs. 4.2 +/- 1.5 in 23 healthy controls (P < 0.0001).

Compound heterozygosity for both mutations resulted in plasma cortisol levels comparable to those in null homozygotes. Abnormal corticosteroid-binding globulin concentrations or binding affinity may lead to the misdiagnosis of isolated ACTH deficiency. The mechanism of the association between fatigue and relative hypotension is not established by these studies. As idiopathic fatigue disorders are associated with relatively low plasma cortisol, abnormalities of corticosteroid-binding globulin may be pathogenic.

 

Source: Torpy DJ, Bachmann AW, Grice JE, Fitzgerald SP, Phillips PJ, Whitworth JA, Jackson RV. Familial corticosteroid-binding globulin deficiency due to a novel null mutation: association with fatigue and relative hypotension. J Clin Endocrinol Metab. 2001 Aug;86(8):3692-700. http://www.ncbi.nlm.nih.gov/pubmed/11502797

 

Lack of association between HLA genotype and chronic fatigue syndrome

Abstract:

Although the aetiology of chronic fatigue syndrome is controversial, evidence that infective agents including viruses may have a role in the development of the condition has led to studies seeking an association with the immunomodulatory HLA genes.

In the present study, we sought to extend previous work using a well-characterized patient group and modern HLA genotyping techniques. Fifty-eight patients were phenotyped for HLA A and B by microcytotoxicity and genotyped for HLA DRB, DQB and DPB by PCR oligoprobing, and the frequencies of antigens so assigned were compared with those from a control group of 134. No significant differences in HLA frequencies were found between patient and control groups.

Thus, this study does not confirm previous findings of an HLA association with chronic fatigue syndrome, suggesting that neither presentation of viral antigen by HLA class I nor antigen processing genes in the HLA region is a major contributory factor in the development of the disease.

 

Source: Underhill JA, Mahalingam M, Peakman M, Wessely S. Lack of association between HLA genotype and chronic fatigue syndrome. Eur J Immunogenet. 2001 Jun;28(3):425-8. http://www.ncbi.nlm.nih.gov/pubmed/11422420

 

Is disabling fatigue in childhood influenced by genes?

Abstract:

BACKGROUND: Medically unexplained chronic fatigue in childhood may cause considerable disability and (by definition) its cause remains unclear. A study of fatigue in healthy twins has been undertaken to examine whether or not genetic factors play a part.

METHOD: A questionnaire survey of the main carers of an epidemiological population-based sample of 670 twin pairs who were asked about periods of unexplained and disabling fatigue in their twins. Out of 1340 individuals a period of disabling fatigue was reported for 92 (6.9%). Thirty-three (2.5%) reported disabling fatigue for more than 1 month. Zygosity could be confidently assigned in 98% of the sample providing 278 monozygotic (MZ) and 378 dizygotic (DZ) pairs. These data were analysed using a structural equation modelling approach.

RESULTS: The results showed that disabling fatigue in childhood is highly familial with an MZ tetrachoric correlation (rMZ) of 0.81 and a DZ tetrachoric correlation (rDZ) of 0.59, for fatigue lasting at least a week. The most acceptable model using Akaike’s information criteria, was one containing additive genetic effects (A) and shared environment (C) plus residual (or non-shared) environment (E). For fatigue lasting at least a month rMZ was 0.75 and rDZ 0.47. The most acceptable model included just A and E. However, the role of shared environment could not be conclusively rejected.

CONCLUSIONS: Unexplained disabling fatigue in childhood is substantially familial. Both genetic and shared environmental factors are worth further exploration in a search for the causes.

 

Source: Farmer A, Scourfield J, Martin N, Cardno A, McGuffin P. Is disabling fatigue in childhood influenced by genes? Psychol Med. 1999 Mar;29(2):279-82. http://www.ncbi.nlm.nih.gov/pubmed/10218919

 

Unique genetic and environmental determinants of prolonged fatigue: a twin study

Abstract:

BACKGROUND: Prolonged fatigue syndromes have been proposed as prevalent and disabling forms of distress that occur independently of conventional notions of anxiety and depression.

METHODS: To investigate the genetic and environmental antecedents of common forms of psychological and somatic distress, we measured fatigue, anxiety, depression and psychological distress in 1004 normal adult twin pairs (533 monozygotic (MZ), 471 dizygotic (DZ)) over 50 years of age.

RESULTS: Familial aggregation of psychological distress, anxiety and fatigue appeared to be due largely to additive genetic factors (MZ:DZ ratios of 2.12-2.69). The phenotypic correlations between the psychological measures (distress, anxiety and depression) were moderate (0.67-0.79) and higher than that between fatigue and psychological distress (0.38). Multivariate genetic modelling revealed a common genetic factor contributing to the development of all the observed phenotypes (though most strongly for the psychological forms), a second independent genetic factor also influenced anxiety and depression and a third independent genetic factor made a major contribution to fatigue alone. In total, 44% (95% CI 25-60%) of the genetic variance for fatigue was not shared by the other forms of distress. Similarly, the environmental factor determining psychological distress made negligible contributions to fatigue, which was underpinned largely by its own independent environmental factor.

CONCLUSION: This study supports the aetiological independence of prolonged fatigue and, therefore, argues strongly for its inclusion in classification systems in psychiatry.

 

Source: Hickie I, Kirk K, Martin N. Unique genetic and environmental determinants of prolonged fatigue: a twin study. Psychol Med. 1999 Mar;29(2):259-68. http://www.ncbi.nlm.nih.gov/pubmed/10218917

 

Dysfunction of natural killer activity in a family with chronic fatigue syndrome

Abstract:

A family was identified with 5 of 6 siblings and 3 other immediate family members who had developed chronic fatigue syndrome (CFS) as adults. All 8 met criteria for the CFS case definition as recommended by the Centers for Disease Control and Prevention.

Sixty-eight blood samples were obtained over a period of 2 years from 20 family members (8 affected, 12 unaffected) and 8 normal controls. All blood samples were tested for NK activity in 4-h 51Cr-release assays and for the number of circulating CD3-CD56(+) and CD3-CD16(+) by flow cytometry.

NK activity of the affected immediate family members (cases, n = 8) was significantly lower (P = 0.006, two-sided) than that of the concurrently tested normal controls. The results for unaffected family members were intermediate between these two groups, and the pairwise comparison of unaffected family members to either cases or controls showed no statistically significant difference (P = 0.29, two-sided). No differences were seen between the groups in the absolute number of CD3-CD56(+) or CD3-CD16(+) lymphocytes in the peripheral blood.

Familial CFS was associated with persistently low NK activity, which was documented in 6/8 cases and in 4/12 unaffected family members. In the family with 5 of 6 siblings who had documented CFS, 2 of their offspring had pediatric malignancies. Low NK activity in this family may be a result of a genetically determined immunologic abnormality predisposing to CFS and cancer.

 

Source: Levine PH, Whiteside TL, Friberg D, Bryant J, Colclough G, Herberman RB. Dysfunction of natural killer activity in a family with chronic fatigue syndrome. Clin Immunol Immunopathol. 1998 Jul;88(1):96-104. http://www.ncbi.nlm.nih.gov/pubmed/9683556