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Open Access Highly Accessed Research article

Evidence for a heritable predisposition to Chronic Fatigue Syndrome

Frederick Albright1*, Kathleen Light2, Alan Light2, Lucinda Bateman3 and Lisa A Cannon-Albright45

Author Affiliations

1 Pharmacotherapy Outcomes Research Center, Department of Pharmacotherapy, College of Pharmacy, University of Utah, USA

2 Department of Anaesthesiology, University of Utah, USA

3 Fatigue Consultation Clinic, Salt Lake City, UT, USA

4 Division of Genetic Epidemiology, Department of Internal Medicine, School of Medicine, University of Utah, USA

5 George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, Utah, USA

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BMC Neurology 2011, 11:62  doi:10.1186/1471-2377-11-62


The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1471-2377/11/62


Received:18 January 2011
Accepted:27 May 2011
Published:27 May 2011

© 2011 Albright et al; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background

Chronic Fatigue Syndrome (CFS) came to attention in the 1980s, but initial investigations did not find organic causes. Now decades later, the etiology of CFS has yet to be understood, and the role of genetic predisposition in CFS remains controversial. Recent reports of CFS association with the retrovirus xenotropic murine leukemic virus-related virus (XMRV) or other murine leukemia related retroviruses (MLV) might also suggest underlying genetic implications within the host immune system.

Methods

We present analyses of familial clustering of CFS in a computerized genealogical resource linking multiple generations of genealogy data with medical diagnosis data of a large Utah health care system. We compare pair-wise relatedness among cases to expected relatedness in the Utah population, and we estimate risk for CFS for first, second, and third degree relatives of CFS cases.

Results

We observed significant excess relatedness of CFS cases compared to that expected in this population. Significant excess relatedness was observed for both close (p <0.001) and distant relationships (p = 0.010). We also observed significant excess CFS relative risk among first (2.70, 95% CI: 1.56-4.66), second (2.34, 95% CI: 1.31-4.19), and third degree relatives (1.93, 95% CI: 1.21-3.07).

Conclusions

These analyses provide strong support for a heritable contribution to predisposition to Chronic Fatigue Syndrome. A population of high-risk CFS pedigrees has been identified, the study of which may provide additional understanding.

Background

The Chronic Fatigue Syndrome (CFS) disease classification attempts to identify patients with a condition distinct from the fatigue of other chronic illness. It is most frequently defined by the Fukuda definition: severe, unexplained, chronic fatigue lasting at least 6 months, accompanied by 4 of 8 symptom criteria (post-exertional malaise, impaired memory or concentration, unrefreshing sleep, muscle pain, arthralgia, headaches, sore throat or, tender cervical or axillary lymph nodes)[1,2]. According to population based studies, 800,000 or more people in the US meet these criteria [3-8] or have CFS like disease [8]. The Center for Disease Control (CDC) posts that the illness costs the US $9 billion annually in lost earnings and productivity [9,10].

CFS is a complex illness that is not well understood. This applies to the genetic and environmental origins of CFS, as well as factors that may contribute to the severity of symptoms and outcomes. Despite efforts to develop standardized research criteria to define the disease, progress in CFS diagnosis and treatment has been slow, in part due to concurrence in origins, causation, lack of a standard clinical definition, and lack of specific biomarkers. A community-based screening study by the CDC indicated that only 9%-16% of individuals with CFS had been diagnosed. Variations in presentation (age of onset, sudden versus gradual onset, and co-morbid conditions) further increase the heterogeneity of CFS patients. It has been proposed that predisposition to CFS may have a genetic basis, although environmental factors, viral illnesses, stressful life events or traumas may also be implicated [4,6,8,11,12]. CFS has been described as a disorder of the brain, the immune system, or the endocrine system; studies have documented underlying pathophysiological processes involving all of these systems [13-18].

There are numerous studies suggesting that genes might play a role in the development of CFS or in its progression [19-21]. Several twin studies have examined genetic vs. environmental determinants of CFS [21-24]. These studies have shown higher concordance in monozygotic vs. dizygotic twins. A small familial aggregation study (CFS cases = 25), showed excess relative risks for CFS in first-degree relatives of CFS cases compared to controls [20].

Analysis of a heritable contribution to CFS is confounded by the newness of the diagnosis, the lack of specific diagnostic criteria or biomarkers, and high rates of co-morbidity with other syndromes. Here we report the existence of a unique, population-based resource with genealogical information linked to diagnosis data allowing analysis of the genetic relationships among 811 individuals diagnosed with CFS since 1993. The combined data have been analyzed to examine the hypothesis of a heritable contribution to CFS.

Methods

The original Utah Population Database (UPDB) represented genealogical records of Utah pioneers and their descendants. The UPDB was created from family group sheets compiled by members of the Church of Jesus Christ of Latter-day Saints (LDS) submitted to the Genealogical Society of Utah. Researchers at the University of Utah computerized these genealogical paper records of Mormon pioneers and their descendants into an electronic database [25].

The original UPDB genealogy represented approximately1.6 million individuals in genealogies up to 6 generations deep. Genealogical data added since the original derives from state records (birth, death, driver's license and others) entailing 6.5 million individuals. New individuals from these sources who link to the original genealogy data produce pedigrees up to 15 generations deep with 2.3 million individuals belonging to genealogies at least 3 generations deep.

Numerous Utah data sets have been linked to UPDB records, including Utah Cancer Registry (UCR) records. The UPDB has also been linked to individual medical data from the University of Utah Health Sciences Hospital (UUHSH) Enterprise Data Resource Center. The UUHSH Data Warehouse (DW) contains comprehensive hospital, medical, and clinical data from 1993 to present. The UUHSH serves 20% of the state's residents. The UUHSH Data Resource Center currently contains over 1.8 million patient demographic records for patients treated at the hospital and outpatient clinics. Over 1.26 million (73%) of these hospital records have been matched to a "person record" in UPDB.

CFS patients were identified by the presence in the medical record of a CFS-specific ICD-9 diagnostic code (780.71) originating from medical providers involved in the patient's care. Although in other areas of the country the rate of CFS diagnosis may be lower, it is likely that in Utah the appropriate application of the Fukuda definition and diagnosis of CFS increases the rate. This is likely related to the CFS referral clinic in the community, and the availability of CFS-specific Continuing Medical Education to community providers during the last decade. UUHSH has no clinics specifically devoted to CFS, or specialists who claim expertise in CFS.

Although all University of Utah hospital and clinic records have been linked to the UPDB genealogy, only a selected subset of these records can be accessed, due to the sensitive nature of the data. A set of randomly selected hospital patients was identified for use as controls, representing 20% of all University of Utah hospital/clinic patients who also had linked genealogy data (n~200,000). We created cohorts to which these UUHSC patients were assigned, and from which controls were selected randomly. All individuals were assigned to 1 of 132 cohorts based on sex, birth-year, and birthplace (i.e., Utah or not). All controls for the analyses performed were selected randomly from this set.

This unique resource allowed us to identify all genetic relationships between patients with a diagnosis of CFS. To examine evidence for a genetic contribution to CFS in the UPDB, two different analyses were performed: estimation of relative risks in close and distant relatives of CFS cases, and comparison of average relatedness in CFS cases to controls.

Relative Risks in Relatives

We estimated relative risk (RR) for CFS among the relatives of patients using the classical odds ratio (OR) method. Although we were able to identify all patients with a diagnosis of CFS, we were only able to identify 20% of all known UUHSC patients in any given cohort, resulting in an inability to estimate true CFS population rates. We therefore selected 5 matched (hospital) controls for each case for RR estimation. Because of the over-representation of cases in each cohort, we excluded cases from selection as controls.

To estimate the RR we compared the number of CFS cases among the relatives of cases to the number of CFS cases among the relatives of 5 independently selected sets of matched UUHSC controls (relatives counted without duplication). Because of the nature of the UPDB resource, and the fact that we identify all genetic relationships between all CFS cases, this study did not require any screening of relatives; we identified all relatives of all cases (and all relatives of matched controls) using genealogy data, and then counted UUHSC CFS cases who were identified among these relatives. The significance of the test of the null hypothesis RR = 1.0 was determined by Fisher's Exact Test for the 2 × 2 table. Confidence intervals for the RR were estimated as described in Agresti [26]. This method has been applied to other disease phenotypes in the UPDB [27,28].

Genealogical Index of Familiality (GIF)

We used the Genealogical Index of Familiality (GIF) statistic to test the hypothesis of no excess relatedness among CFS cases. This statistic, developed for use with the UPDB [29,30], measures the average pair-wise relatedness of a set of individuals, and compares the measure to the average expected relatedness of a set of similar individuals in this population. In contrast to the RR, which examines close relationships between cases, the GIF analysis considers all pair-wise genetic relationships between all cases, and separately for matched controls.

The GIF relatedness measure for a pair of individuals implements the Malécot coefficient of kinship [31], which is defined as the probability that randomly selected homologous genes from the 2 individuals are identical by descent from a common ancestor. For parent/child the coefficient is 0.50 (1/2), for siblings or grandparents the coefficient is 0.25 (1/4), for avunculars the coefficient is 0.125 (1/8), and so forth. The contribution to the GIF statistic is smaller for pairs with a greater genetic distance between them.

The case-GIF statistic is defined as the average of the coefficients of kinship between all possible pairs of CFS cases (x 100,000). A control-GIF statistic is calculated as the average of the coefficients of kinship between all possible pairs in a single set of randomly selected matched controls. Comparison of the average relatedness of a set of cases to the distribution of the average relatedness statistics estimated for 1,000 independent sets of matched controls, provides an empirical test of significance.

Because both close and distant relationships are observed, the GIF statistic will show excess relatedness in the presence of genetic effects only, or environmental (familial, but non-genetic) effects only, or in the presence of a combination of both effects. The overall GIF statistic therefore tests the alternative hypothesis of no excess familial clustering of any origin. We also utilized the GIF test to examine the more specific hypothesis of a genetic contribution. To do this, the GIF statistic was estimated while ignoring all close relationships (relationships with genetic distance < 4, or closer than first cousins). We term this statistic the distant GIF (dGIF). The dGIF statistic allows a test of the hypothesis that there are significantly more distant pair-wise relationships observed among cases than would be expected, providing strong support for a familial effect that is based on shared genes.

No patient identifiers were used in this study; analysis of genetic relationships between affected individuals is non-identifiable. The University of Utah Institutional Review Board and the Utah Resource for Genetic and Epidemiological Research (RGE) approved the utilization of UPDB data in this study.

Results and Discussion

We identified 941 patients with a CFS diagnosis in the UUHSC DW from 1993 to present that also had Utah genealogy data. Age at diagnosis was estimated using the minimum admission date for a CFS diagnosis, and thus may be over estimated. Twelve percent of the cases had an age at diagnosis less than age 20 years; 28% of the cases had an age at diagnosis greater than 59 years; 653 (69%) were female. Because CFS is associated with various co-morbid conditions, with possible genetic associations, we excluded the 130 CFS cases that also had a diagnosis of cancer in the UCR. This left 811 CFS cases for analysis.

Relative Risks

Table 1 summarizes the RR estimates risk of CFS among first, second, and third degree relatives of CFS cases. For each degree of relationship considered, Table 1 shows the number of relatives considered (for cases and controls), the number of CFS cases observed among the relatives (for cases and controls), the significance for the Fisher's Exact test, the Odds Ratio (OR) estimate of RR, and the 95% confidence interval for the RR. Relative risks for first (RR = 2.70), second (RR = 2.34), and third degree (RR = 1.93) relatives were significantly elevated.

Table 1. Estimated RRs for first-, second-, and third-degree relatives in the 811 CFS cases

Genealogical Index of Familiality

Table 2 shows the results of the GIF test for excess relatedness in the 811 CFS cases, including the average relatedness of the cases, the mean average relatedness for 1000 sets of matched controls, the empirical significance of the overall test for excess relatedness, and the empirical significance of the dGIF. The average relatedness of CFS cases was significantly greater than expected when all relationships were considered (p <0.001), showing strong evidence for excess familial clustering (due to either shared environment, or shared genes, or a combination). When close relationships (genetic distance <4) were ignored, the significant excess was still present (p = 0.010). Figure 1 displays the GIF test graphically. It shows the contribution to the GIF statistic (y-axis) by the relationship (x-axis; genetic distance) between all pairs for CFS cases (and controls). This observation of significant excess relationships observed at almost all degrees of relationship strongly supports a genetic contribution to predisposition to CFS.

Table 2. GIF test for excess relatedness among 811 CFS cases

thumbnailFigure 1. Contribution to the GIF statistic, measuring average relatedness. Contribution to the GIF statistic (y-axis) by genetic relationship (genetic distance, x axis) between all pairs of related CFS cases compared to all pairs of related controls. Genetic distance 1 = parent/offspring, 2-siblings or grandparent/grandchild, 3 = avunculars, and so forth).

Conclusions

The existence of a Utah resource combining up to 15 generations of genealogy data with medical diagnosis data from 1993 has allowed testing of the hypothesis of a heritable contribution to CFS. The methods used in this study have previously provided evidence for a heritable component to many diseases, including: prostate cancer, influenza mortality, aneurysm, cancer, rotator cuff disease, asthma mortality, and diabetes, among others [28,32-34]. Studies of Utah high-risk pedigrees identified in the UPDB have lead to the discovery of multiple cancer predisposition genes including BRCA1, BRCA2, p16, and HPC2/ELAC2 [35-38]. The UPDB data analyzed represents a homogeneous population that has been shown to be genetically representative of Northern Europe, with normal U.S. inbreeding levels [39,40].

Significantly increased risks among first degree relatives are often referred to as providing evidence for a "genetic" contribution to disease. However, given the sharing among close relatives of their genes, lifestyle, and environment, increased first degree risk may simply indicate familial clustering, it does not provide evidence for a genetic contribution. However, significant excess risks in second and third degree relatives strongly indicates a genetic contribution to disease, given the much lower likelihood of these relatives sharing common risks and environments.

Analysis of CFS in a large Utah resource shows clear evidence of significant excess familial clustering and significantly elevated risks for CFS among first, second, and third degree relatives of CFS cases. The results strongly support a genetic contribution to predisposition to CFS as it is currently defined and diagnosed by clinicians in Utah. Although a genetic predisposition to CFS has been suggested in the literature, this is the first population-based analysis to comprehensively support this claim.

This study used a uniform, consistent source for all diagnoses, and is not limited by bias introduced by study designs involving selected ascertainment of cases or requiring recall for diagnoses. The most significant limitation of this analysis is the narrow window of view to identify individuals diagnosed with CFS. This results from the relatively short period of time for which this diagnosis has existed, and the limited time-period of diagnosis data available (1993-present). These effects limit our ability to identify cases who might be related across different generations (e.g. grandparent/grandchild or avunculars). Although CFS cases may have been censored from our observation in this resource, cases are uniformly censored across the resource, leading to conservative, but unbiased, estimates of familiality.

We excluded CFS cases with a cancer diagnosis, which might have been a cause of CFS symptoms in these cases. Other potential confounders could not be considered: including other heritable predisposing conditions (e.g., depression), or risk factors that are familial, but not genetic (e.g., occupation, socioeconomic factors, or healthcare access).

This study of CFS heritability does not allow determination of the mechanisms that lead to predisposition to CFS. We have identified multiple pedigrees with a significant excess of CFS cases. We propose study of these pedigrees to identify the gene(s) predisposing to CFS, as well as to better understand mechanisms and potential environmental factors and triggers.

Studies reporting an association of CFS with XMRV and MLV-related viruses have provided conflicting results [41-44]. While association of CFS with an infectious-like syndrome at onset is recognized, and many microbial and viral infections have been implicated as possible triggers, no single agent has been associated with a large fraction of cases. It might be hypothesized that a heritable predisposition to virus infection explains both our findings and the complex virus associations that have been recognized.

Identification of CFS predisposition genes, and increased understanding of how these genes affect health could allow identification of predisposed individuals at an earlier age, prophylactic screening for at-risk individuals, improved healthcare standards to reduce risk of CFS development, all leading to identification of treatments or medications that could prevent or delay onset of symptoms in those impaired by this debilitating disease.

Competing interests

No authors have any financial involvement or affiliation with any organization whose financial interests may be affected by material in the manuscript or which might potentially bias it.

Authors' contributions

Each author contributed equally to the development and ensuing research of the project. Each author made significant and substantial written contributions in this manuscript. All authors read and approved the final version of the manuscript.

Acknowledgements

Support includes R01 NLM009331 (to LACA) and R21 NS057821 (KCL), Partial support for all datasets within the Utah Population Database (UPDB) provided by the University of Utah Huntsman Cancer Institute. The authors also acknowledge support from the Huntsman Cancer Foundation and a University of Utah Catalyst grant.

References

  1. Chronic fatigue Syndrome - The Revised Case Definition (abridged version) [http://www.cdc.gov/cfs/general/case_definition/abridged.html] webcite

  2. Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A: The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group.

    Ann Intern Med 1994, 121(12):953-959. PubMed Abstract | Publisher Full Text OpenURL

  3. Jason LA, Benton MC, Valentine L, Johnson A, Torres-Harding S: The Economic impact of ME/CFS: Individual and societal costs.

    Dyn Med 2008, 7:6. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text OpenURL

  4. Jason LA, Richman JA, Rademaker AW, Jordan KM, Plioplys AV, Taylor RR, McCready W, Huang CF, Plioplys S: A community-based study of chronic fatigue syndrome.

    Arch Intern Med 1999, 159(18):2129-2137. PubMed Abstract | Publisher Full Text OpenURL

  5. Jason LA, Taylor R, Wagner L, Holden J, Ferrari JR, Plioplys AV, Plioplys S, Lipkin D, Papernik M: Estimating rates of chronic fatigue syndrome from a community-based sample: a pilot study.

    Am J Community Psychol 1995, 23(4):557-568. PubMed Abstract | Publisher Full Text OpenURL

  6. Jason LA, Taylor RR, Kennedy CL, Song S, Johnson D, Torres S: Chronic fatigue syndrome: occupation, medical utilization, and subtypes in a community-based sample.

    J Nerv Ment Dis 2000, 188(9):568-576. PubMed Abstract | Publisher Full Text OpenURL

  7. Jason LA, Taylor SL: Monitoring chronic fatigue syndrome.

    J Nerv Ment Dis 1994, 182(4):243-244. PubMed Abstract | Publisher Full Text OpenURL

  8. Jason LAT-HS, Njoku MGC: The face of CFS in the US.

    CFIDS Chronicle16-21.

    The Science & Research of CFS: A Special Issue of the CFIDS Chronicle edn; 2005-2006

    OpenURL

  9. Reynolds KJ, Vernon SD, Bouchery E, Reeves WC: The economic impact of chronic fatigue syndrome.

    Cost Eff Resour Alloc 2004, 2(1):4. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text OpenURL

  10. Reyes M, Nisenbaum R, Hoaglin DC, Unger ER, Emmons C, Randall B, Stewart JA, Abbey S, Jones JF, Gantz N, et al.: Prevalence and incidence of chronic fatigue syndrome in Wichita, Kansas.

    Arch Intern Med 2003, 163(13):1530-1536. PubMed Abstract | Publisher Full Text OpenURL

  11. Steele L, Dobbins JG, Fukuda K, Reyes M, Randall B, Koppelman M, Reeves WC: The epidemiology of chronic fatigue in San Francisco.

    Am J Med 1998, 105(3A):83S-90S. PubMed Abstract OpenURL

  12. Boneva RS, Decker MJ, Maloney EM, Lin JM, Jones JF, Helgason HG, Heim CM, Rye DB, Reeves WC: Higher heart rate and reduced heart rate variability persist during sleep in chronic fatigue syndrome: a population-based study.

    Auton Neurosci 2007, 137(1-2):94-101. PubMed Abstract | Publisher Full Text OpenURL

  13. Chapman CR, Tuckett RP, Song CW: Pain and stress in a systems perspective: reciprocal neural, endocrine, and immune interactions.

    J Pain 2008, 9(2):122-145. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  14. Cleare AJ: The HPA axis and the genesis of chronic fatigue syndrome.

    Trends Endocrinol Metab 2004, 15(2):55-59. PubMed Abstract | Publisher Full Text OpenURL

  15. Skowera A, Cleare A, Blair D, Bevis L, Wessely SC, Peakman M: High levels of type 2 cytokine-producing cells in chronic fatigue syndrome.

    Clin Exp Immunol 2004, 135(2):294-302. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  16. Light AR, White AT, Hughen RW, Light KC: Moderate exercise increases expression for sensory, adrenergic, and immune genes in chronic fatigue syndrome patients but not in normal subjects.

    J Pain 2009, 10(10):1099-1112. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  17. White AT, Light AR, Hughen RW, Bateman L, Martins TB, Hill HR, Light KC: Severity of symptom flare after moderate exercise is linked to cytokine activity in chronic fatigue syndrome.

    Psychophysiology 2010. OpenURL

  18. Hampton T: Researchers find genetic clues to chronic fatigue syndrome.

    JAMA 2006, 295(21):2466-2467. PubMed Abstract | Publisher Full Text OpenURL

  19. Kaiser J: Biomedicine. Genes and chronic fatigue: how strong is the evidence?

    Science 2006, 312(5774):669-671. PubMed Abstract | Publisher Full Text OpenURL

  20. Walsh CM, Zainal NZ, Middleton SJ, Paykel ES: A family history study of chronic fatigue syndrome.

    Psychiatr Genet 2001, 11(3):123-128. PubMed Abstract | Publisher Full Text OpenURL

  21. 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, 63(6):936-943. PubMed Abstract | Publisher Full Text OpenURL

  22. 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, 4(2):94-102. PubMed Abstract | Publisher Full Text OpenURL

  23. Schur E, Afari N, Goldberg J, Buchwald D, Sullivan PF: Twin analyses of fatigue.

    Twin Res Hum Genet 2007, 10(5):729-733. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  24. Sullivan PF, Evengard B, Jacks A, Pedersen NL: Twin analyses of chronic fatigue in a Swedish national sample.

    Psychol Med 2005, 35(9):1327-1336. PubMed Abstract | Publisher Full Text OpenURL

  25. Skolnick M: The Utah genealogical database: A resource for genetic epidemiology. In Banbury Report No 4; Cancer Incidence in Defined Populations. Edited by Cairns J LJ, Skolnick M. New York: Cold Spring Harbor; 1980:285-297. PubMed Abstract | Publisher Full Text OpenURL

  26. Agresti A: Categorical Data Analysis. John Wiley & Sons; 1990.

  27. Tashjian RZ, Farnham JM, Albright FS, Teerlink CC, Cannon-Albright LA: Evidence for an inherited predisposition contributing to the risk for rotator cuff disease.

    J Bone Joint Surg Am 2009, 91(5):1136-1142. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  28. Albright FS, Orlando P, Pavia AT, Jackson GG, Cannon Albright LA: Evidence for a heritable predisposition to death due to influenza.

    J Infect Dis 2008, 197(1):18-24. PubMed Abstract | Publisher Full Text OpenURL

  29. Cannon Albright LA: Utah family-based analysis: past, present and future.

    Hum Hered 2008, 65(4):209-220. PubMed Abstract | Publisher Full Text OpenURL

  30. Hill JR: A survey of cancer sites by kinship in the Utah Mormon population. In Banbury Report No 4; Cancer Incidence in Defined Populations. Edited by Cairns J LJ, Skolnick M. New York: Cold Spring Harbor; 1980:299-318. PubMed Abstract | Publisher Full Text OpenURL

  31. Malécot G: Les mathématiques de l'hérédité. Paris,: Masson; 1948.

  32. Cannon Albright LA, Camp NJ, Farnham JM, MacDonald J, Abtin K, Rowe KG: A genealogical assessment of heritable predisposition to aneurysms.

    J Neurosurg 2003, 99(4):637-643. PubMed Abstract | Publisher Full Text OpenURL

  33. Teerlink CC, Hegewald MJ, Cannon-Albright LA: A genealogical assessment of heritable predisposition to asthma mortality.

    Am J Respir Crit Care Med 2007, 176(9):865-870. PubMed Abstract | Publisher Full Text OpenURL

  34. Weires MB, Tausch B, Haug PJ, Edwards CQ, Wetter T, Cannon-Albright LA: Familiality of diabetes mellitus.

    Exp Clin Endocrinol Diabetes 2007, 115(10):634-640. PubMed Abstract | Publisher Full Text OpenURL

  35. Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, Liu Q, Cochran C, Bennett LM, Ding W, et al.: A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1.

    Science 1994, 266(5182):66-71. PubMed Abstract | Publisher Full Text OpenURL

  36. Kamb A, Shattuck-Eidens D, Eeles R, Liu Q, Gruis NA, Ding W, Hussey C, Tran T, Miki Y, Weaver-Feldhaus J, et al.: Analysis of the p16 gene (CDKN2) as a candidate for the chromosome 9p melanoma susceptibility locus.

    Nat Genet 1994, 8(1):23-26. PubMed Abstract | Publisher Full Text OpenURL

  37. Tavtigian SV, Simard J, Rommens J, Couch F, Shattuck-Eidens D, Neuhausen S, Merajver S, Thorlacius S, Offit K, Stoppa-Lyonnet D, et al.: The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds.

    Nat Genet 1996, 12(3):333-337. PubMed Abstract | Publisher Full Text OpenURL

  38. Tavtigian SV, Simard J, Teng DH, Abtin V, Baumgard M, Beck A, Camp NJ, Carillo AR, Chen Y, Dayananth P, et al.: A candidate prostate cancer susceptibility gene at chromosome 17p.

    Nat Genet 2001, 27(2):172-180. PubMed Abstract | Publisher Full Text OpenURL

  39. Jorde LB: Inbreeding in the Utah Mormons: an evaluation of estimates based on pedigrees, isonymy, and migration matrices.

    Ann Hum Genet 1989, 53(Pt 4):339-355. PubMed Abstract OpenURL

  40. McLellan T, Jorde LB, Skolnick MH: Genetic distances between the Utah Mormons and related populations.

    Am J Hum Genet 1984, 36(4):836-857. PubMed Abstract | PubMed Central Full Text OpenURL

  41. Erlwein O, Kaye S, McClure MO, Weber J, Wills G, Collier D, Wessely S, Cleare A: Failure to detect the novel retrovirus XMRV in chronic fatigue syndrome.

    PLoS ONE 2010, 5(1):e8519. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  42. Lo SC, Pripuzova N, Li B, Komaroff AL, Hung GC, Wang R, Alter HJ: Detection of MLV-related virus gene sequences in blood of patients with chronic fatigue syndrome and healthy blood donors.

    Proc Natl Acad Sci USA 2010. OpenURL

  43. Lombardi VC, Ruscetti FW, Das Gupta J, Pfost MA, Hagen KS, Peterson DL, Ruscetti SK, Bagni RK, Petrow-Sadowski C, Gold B, et al.: Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome.

    Science 2009, 326(5952):585-589. PubMed Abstract | Publisher Full Text OpenURL

  44. Switzer WM, Jia H, Hohn O, Zheng H, Tang S, Shankar A, Bannert N, Simmons G, Hendry RM, Falkenberg VR, et al.: Absence of evidence of xenotropic murine leukemia virus-related virus infection in persons with chronic fatigue syndrome and healthy controls in the United States.

    Retrovirology 2010, 7:57. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text OpenURL

Pre-publication history

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