Publications
APS Bulletin • Volume 18, Number 3, 2008
Special Interest Groups
David Williams, PhD, Department Editor
Pain Genetics and Genome-Wide Association Studies
Editor’s note: Prior to his death, APS Bulletin talked with Mitchell Max, to discuss genetics and pain—a topic of particular interest to the APS Genetics and Pain Special Interest Group.
In Memoriam
APS mourns the recent, sudden passing of long-time member and friend Mitchell Max, MD, who died on October 22, 2008, at age 59. Max was an anesthesiology professor and director of the molecular epidemiology of pain program (MEPP) at the University of Pittsburgh’s Center for Pain Research. A prolific speaker and writer, Max was a leading authority on the genetic basis of chronic pain and the mechanisms and treatment of neuropathic pain. Prior to joining the University of Pittsburgh, Max directed the pain clinic at the National Institutes of Health (NIH) where he conducted research for more than 20 years. He was also chief of the clinical pain research section at the National Institute of Dental and Craniofacial Research (NIDCR). Max was a graduate of Harvard Medical School, a fellow of the American Neurological Association, and recipient of many distinctions including the NIH Director’s Award, the U.S. Public Health Service Citation Award, and the Wilbert E. Fordyce Clinical Investigator Award and Lecture. In addition to his professional accomplishments, Max was a jazz musician and Jewish scholar. He is survived by his wife, Lisa, and two daughters, Rachel and Laura, of Garrett Park, MD; his mother, Charlotte Max of Summit, NJ; and a sister, Lily Siegel of Chester Springs, PA. Funeral services were held on Sunday, October 26, 2008, in Bethesda, MD. Memorial contributions may be made to the Laura and Rachel Max College Fund, PO Box 394, Garrett Park, MD 20896. |
Q: What are genome-wide association studies (GWAS)?
We’ve all seen recent reports on new GWAS and the discovery of novel mediators of diseases including diabetes, Crohn’s disease, macular degeneration, obesity, sudden cardiac death, and multiple sclerosis, as well as breast, prostate, and lung cancer. These studies, and the work involved in cataloging human genetic variation, represents a multibillion dollar research investment. Unfortunately, pain researchers are not yet sharing in this bounty. By the end of 2009, about 400 GWAS will be published and, although pain treatment represents up to 20% of medical activities and costs, it’s a safe bet that none of these studies will concern pain.
That’s unfortunate because GWAS can help identify novel mediators of pain beyond the few hundred molecules discussed in neurobiology literature. They can also help us prioritize among the many existing pain targets for physiological studies and drug development with human data; extract up to 50% of the variance from studies of nongenetic factors that affect pain; understand pain risks, mechanisms, and treatments of individual patients; and better classify pain disorders.
Q: How can GWAS advance pain research and treatment?
The association study is perhaps the simplest analysis that geneticists perform. They are usually carried out in unrelated people to compare the frequency or average magnitude of a trait in individuals with one form of a gene to those with other gene variants. It’s essentially the same procedure used to analyze the effects of an active versus a control treatment on a disorder—and it uses methods such as t-tests, contingency tables, analysis of variance, or regression. In the past, most association studies were done at one gene locus at a time. In human pain genetics, singlegene studies center on COMT [catechol-O-methyltransferase], GCH1, IL6, OPRM, and genes responsible for metabolizing analgesic drugs.
Q: Explain how GWAS would facilitate pain research and treatment.
First, GWAS can identify entirely new mediators of disease, essentially revolutionizing the basic and clinical research in a disease. For example, recent GWAS find that several members of the interleukin family are implicated in Crohn’s disease and multiple sclerosis—and this gives a new focus to all immunological research on these disorders.
Second, GWAS can shed a spotlight on drug-development programs. Most drug companies interested in analgesics are faced with a host of potential targets. Traditionally they have relied on animal models of pain for most of the development phase, adding human data only after the investment of tens of millions of dollars. However, GWAS are too new to have a track record of proof of principle for new drugs. Demonstrating that a polymorphism, the presence of at least two versions of a gene, affects the severity of pain implies that this pathway is a necessary mediator of human pain. With this knowledge, a drug company may choose to invest in developing this class of drug rather than other classes that lack such evidence. This approach is not necessarily applicable to all analgesic classes, however. If there are no common variants of the genes that affect the function of the target pathway, association studies will not be informative.
Q: What are some findings from GWAS?
Patterns of findings have varied across the common diseases, depending upon their “genetic architecture,” such as how the total heritability of the disease is divided among the common variants in the genome. For example, the common genes with relatively large effects on risk have been replicated in Alzheimer’s disease, Crohn’s disease, and macular degeneration. But GWAS have not been successful in every disease. Psychiatric disorders have been the most frustrating, in that twin studies have suggested high levels of heritability of schizophrenia and bipolar illness, yet GWAS have not yet persuasively replicated any loci. Unipolar disorder has been even more unrevealing.
Similar difficulties might be experienced in trying to study pains that develop in the absence of a tissue injury. Some types of pain, particularly those caused by a rather uniform peripheral injury, avoid these liabilities. Clinical drug trials show that standard pain measures are quite sensitive to modest biochemical effects, pain is mediated by a well-characterized set of peripheral nerve and spinal cord systems, and pains caused by a uniform peripheral injury have very similar environmental influences.
Q: How can pain researchers compete for funding for GWAS?
The success of GWAS has created new difficulties—namely that everyone wants to apply these methods in their own disease. But with costs of many million dollars per study, most applications must be rejected. Pain genomics grants are often judged in competition with genomics grants from other diseases, and suffer several disadvantages. First, the 10- to 20-year lead time that has accrued to genetic investigators in many common diseases provides much greater proof of principle and methodological validation to our competitors’ proposals. Second, many grants are rated for innovation. You might think that it’s an advantage to adapt the best of proven methods from other diseases to pain, but this may be viewed as ‘not innovative.’
Q: How to overcome these disadvantages?
First, pain researchers should try to influence funding agencies to consider pain genomics grants as competing only against each other, and judged by reviewers familiar with pain research. Many have rigorously counted the number of NIH grants devoted to pain to show that the current system has put pain research at a disadvantage. Second, clinical pain researchers should increase their coordination, such as by selecting several conditions for targets of GWAS and working together to decide on the phenotype and optimizing the methods of assessing any nongenetic variables that may contribute to the pain outcome.
Third, pain researchers should study the current shortcomings of GWAS in other diseases and seek to leap ahead of them, like the Japanese when they bested American automakers after a late start. Current reviews of GWAS suggest there has been a “rush to quantity,” with too little attention to crucial issues like measurement of environmental exposures, or heterogeneity of the disease process.
Successful pain genomics efforts will require large numbers of collaborating researchers with expertise not yet found in the pain field. Epidemiology and genetics are the two most obvious such disciplines. However, we cannot rely upon the wisdom of governmental funding agencies alone to ensure that meritorious pain GWAS proposals are funded. The pharmaceutical and biotechnology sectors are well aware of the unsatisfied market needs in pain. At present, they spend at least 10 times as much on pain research as governmental agencies. Because they will be major beneficiaries of better identification of analgesic targets, drug companies may be essential funders, co-funders, or policy advocates for moving pain genetics into the GWA study era.
Dr. Max was Director, Molecular Epidemiology of Pain Program, Center for Pain Research, and Visiting Professor of Anesthesiology and Medicine at the University of Pittsburgh, PA.