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
]. 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
]. 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
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
]. 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.