[Note: Abstracts of the CDC studies can be found at http://cfids-cab.org/MESA/pharmacogenomics.htm .] Science 5 May 2006: Vol. 312. no. 5774, pp. 669 - 671 DOI: 10.1126/science.312.5774.669 News of the Week BIOMEDICINE: Genes and Chronic Fatigue: How Strong Is the Evidence? Jocelyn Kaiser The U.S. Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, announced last month that it has cracked a medical mystery: Chronic fatigue syndrome (CFS) has a biological and genetic basis. CDC Director Julie Gerberding called the study "groundbreaking" and also hailed its novel methodology. These claims have attracted widespread media attention. But, like most aspects of CFS, the study and its findings are controversial. Some scientists think the agency is overstating the case for a link between the syndrome and genetic mutations. "Most complex-trait geneticists would interpret [these] findings more cautiously than the authors have," says Patrick Sullivan, a psychiatric geneticist at the University of North Carolina, Chapel Hill. CFS is defined as severe fatigue lasting more than 6 months, accompanied by symptoms such as muscle pain and memory problems. It is thought to afflict at least 1 million Americans, mostly women. The lack of specific diagnostic criteria since CFS was first defined 20 years ago has led to debate over whether the cause could be an infectious agent, psychiatric, or something else--and made research funding for the disorder highly political. In 2000, a CDC division director lost his job after the agency diverted $12.9 million that Congress had instructed CDC to spend on CFS research to other infectious disease studies (Science, 7 January 2000, p. 22). The agency agreed to restore the money over 4 years and launch a major study. [Photo: Roots of fatigue. CDC Director Julie Gerberding applauds new study on chronic fatigue syndrome. One part divided 111 women into subgroups that correspond to different gene-expression patterns.] The new project, led by William Reeves, CDC's lead CFS researcher (who had blown the whistle on the diverted funds), took an unusual approach. Instead of recruiting patients already diagnosed with CFS, CDC surveyed one-quarter of the population of Wichita, Kansas, by phone to find people suffering from severe fatigue. Several thousand then underwent screening at a clinic for CFS. The population-based aspect is "a big plus" because it avoids the possible bias in tapping a pool of patients seeking treatment for their problems, says Simon Wessely, who studies CFS and a similar disorder, Gulf War illness, at King's College London. Out of this survey, 172 people, most of them white middle-aged women, were deemed to fit the criteria for CFS (58) or CFS-like illness (114). A total of 227 people, including 55 controls, then underwent an extensive 2-day battery of clinical measurements, including sleep studies, cognitive tests, biochemical analyses, and gene-expression studies on blood cells. This part of the study alone cost upward of $2 million, says Reeves. In another unusual step, CDC's Suzanne Vernon then handed this massive data set to four teams of outside epidemiologists, mathematicians, physicists, and other experts. They spent 6 months examining statistical patterns in the data. For instance, one group analyzed patient characteristics such as obesity, sleep disturbance, and depression and grouped them into four to six distinct subtypes; they also looked for different gene-expression patterns in these categories. Some groups also looked for associations between CFS and 43 common mutations in 11 genes involved in the hypothalamic-pituitary-adrenal axis, which controls the body's reaction to stress. The 14 papers were published last month in the journal Pharmacogenomics. The results, which include the finding that the patterns of expression of about two dozen genes involved in immune function, cell signaling, and other roles are different in CFS patients, provide what Harvard University CFS researcher Anthony Komaroff calls "solid evidence" for a biological basis of CFS. They dispel the notion that "this is a bunch of hysterical upper-class professional white women," says Reeves. Other scientists are much more cautious. The gene-expression results, says Jonathan Kerr of Imperial College London, are "meaningless" because they don't demonstrate conclusively, using the polymerase chain reaction, that the genes' RNA is indeed expressed. After this step, says Kerr, 30% to 40% of genes could drop out. The most controversial assertion, however, is that the Wichita study has tied CFS to particular mutations in three genes, including the glucocorticoid receptor and one affecting serotonin levels. Genetic epidemiologists are skeptical for two reasons. First, the team looked for associations with just 43 gene variants; some other set of genes might have correlated just as closely, notes Nancy Cox of the University of Chicago in Illinois. Second, the researchers studied no more than 100 or so individuals with fatigue. The results, although they meet the threshold for statistical significance, are "very likely not robust," says Sullivan. (Sullivan himself has co-authored twin studies finding a "modest" genetic component for CFS, although without pointing to a particular gene.) Reeves doesn't disagree: "One of our caveats is that it is a small study," he says. CDC researchers are now planning to repeat the study with 100 CFS patients. Vernon says her group is also validating the gene-expression results and will hold another computational exercise next month at Duke University in Durham, North Carolina, with a larger data set. Meanwhile, Gerberding has suggested that the same multipronged approach could be applied to seek genetic links to other complex diseases such as autism. That's already being done for many other diseases, from cancer to schizophrenia, notes Sullivan, although the studies use much larger samples and search the entire genome for disease markers. That scale may never be possible for relatively uncommon diseases such as CFS, he says. And he and other human geneticists warn that it's unclear whether any conclusions can be drawn from gene hunts carried out on such very small sample sizes.