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The Genetics of Pain and Pain Inhibition: Where to From Here?

This meeting was funded by the Mayday Fund, New York

June 22-25, 2014

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Why the Meeting was held
Chronic pain is the most prevalent human health problem, with a lifetime prevalence of one in two. Susceptibility to developing chronic pain disorders, as well as pain intensity and response to analgesics, have been shown to have moderate-to-high heritability. Many neuropathic pain syndromes are classic gene x environment interactions, whereby nerve damage is required but only produces neuropathic pain in a small subset of individuals.
It is now 10 years since the first human genetic association studies of pain began appearing in the literature, and association studies and exome sequencing studies of chronic pain disorders are also now being published. As with other complex traits, replicability is poor, and the percentage of trait variance being explained is small. At the same time, progress has been made in identifying rare genetic variants responsible for monogenic pain disorders, both loss-of-function (congenital insensitivity to pain) and gain-of-function (e.g., erythromelalgia). Mindful of the experience of migraine geneticists, the relevance of these genes to more common pain traits is unclear.
Thus the time was right for a meeting to address the relative merits of the association studies and single-gene approaches for the study of chronic pain, along with various current practices in the field.


Organizers
Jeffrey Mogil, McGill University. Montreal, Canada
Clifford Woolf, Harvard University, Boston


Meeting Report
(contributed by P. McCaffrey)
The recent conference on pain genetics pulled together a varied roster of research leaders from the pain field and beyond. The presence of top investigators in migraine genetics brought together two groups—chronic and neuropathic pain researchers and headache researchers—who normally operate in independent spheres. The result was an open and fertile discussion of the progress, pitfalls and future avenues most likely to create new understanding of the causes and new treatments for chronic pain. Importantly, by the end of the sessions, several conferees had found new opportunities for collaborative studies.
After two and a half days of presentations and discussion, working groups offered up assessments of four aspects of genetics research related to pain: mutants, genome wide association studies (GWAS), model organisms, and epigenetics. Highlights of each discussion are summarized below.

Mutants

    The discovery of rare inherited familial pain syndromes including congenital insensitivity to pain or paroxysmal pain syndromes has led to the identification of important pain genes, and led to multiple therapeutic targets, including voltage-gated sodium channels, nerve growth factor (NGF) and its receptor (TRKA1) and several others. The group recommended extending this approach by collecting and analyzing additional cohorts and seeking out a diversity of clinical presentations.
    To identify another set of pain genes, participants advocated the study of outliers, people whose pain phenotypes are at the extreme ends of normal. One study underway involves the one percent of women who display high pain tolerance and do not require analgesia during childbirth, for example.  

GWAS

    The GWAS discussion group acknowledged the limitations of GWAS, which identifies common genetic variants that contribute to individual differences in phenotype. In many conditions, common variants explain only a fraction of individual variance. The GWAS approach is difficult to apply to pain conditions that are highly heterogeneous. Because of funding and difficulty of getting homogenous cohorts, new GWAS studies in pain may be limited. However, the possibility for reusing existing genotyping data was discussed. Large migraine GWAS cohorts have been assembled, and they may be useful for add-on studies querying the clinical data or study participants for other pain phenotypes.
    Pain phenotypes remain a challenge. Chronic pain is not one disease, but many. Cohorts exist for chronic back pain, osteoarthritis, and other chronic pain conditions, but they are heterogeneous. Endophenotypes may be useful to overcome this heterogeneity. In the OPPERA study, for example, a combination of deep phenotyping, subgroup analysis, and a candidate gene approach has revealed common variants and potential treatment targets for chronic jaw pain.  
    The definition of continuous pain-related traits, rather than a condition-specific case-control approach, may aid in uncovering genetic bases for chronic pain. Such traits would ideally incorporate individual differences in both pain processing or modulation. For example, measuring sensitivity to pain in the cold pressor test show has the advantages of being highly heritable and predictive of clinical pain. Another useful heritable phenotype may be widespread pain, which may allow differentiation of genetic factors that contribute to pain versus pain spreading.

Model organisms

    Lower organisms (zebra fish, Drosophila) provide insight into mechanisms of nociception, but the group concurred they may not offer useful models for chronic pain. Mice were considered a good model, but with some limitations. A major issue is the prevailing reliance on measures of evoked pain in rodent models, although the field is currently very active in developing other, possibly more relevant, behavioral measures of pain.  The veterinary field may offer additional possibilities for pain models, where some animals develop conditions (arthritis, cancer pain) that mimic human pain diseases.

Epigenetics

    Epigenetics, defined as the stable, long-term non-coding alterations to the genome, are particularly important in pain, where environmental factors that alter the genome profoundly influence the development of chronic pain. Assessing  the  epigenetic contribution requires multiple data sets, including analysis of DNA methylation, histone modifications, noncoding RNAs, and protein and metabolomics profiles.
    To understand the predisposition to chronic pain and individual variability, it will be necessary to look at known factors that affect epigenetics, for example, pollutants, and then take those into account in any studies. An open question remains whether analyzing blood cells, rather than nervous tissue, may be acceptable for these studies.
    A possible human model of epigenetic changes could be chemotherapy-induced painful neuropathy, where a known epigenetic challenge begins at a defined time and results in chronic neuropathic pain. Post-operative chronic pain offers another potential human model. In both cases, there may be the opportunity to collect and analyze affected tissues.  

Stress, negative life experiences, and existing pain are all important factors that raise the risk of chronic pain, and may have epigenetic effects. The group recognized the need for broad-based measures to assess injury, and other life stressors including sexual abuse, as well as exposure to chemicals, recreational drugs, tobacco and other environmental factors for both epigenetic and genetic studies. This was seen as a place where existing genetic data and cohorts such as the migraine studies could possibly be reused, if the subjects could be further queried for these environmental factors.

Program Sessions and Topics

Session 1: Introductory Session

Clifford Woolf, Boston Children’s Hospital, Boston, Massachusetts:
    Why pain genes?
Jeffrey Mogil, McGill University, Montreal, Canada:
    History of pain genetics

Session 2: Lessons from Other Fields
Tilo Grosser, University of Pennsylvania, Philadelphia, Pennsylvania:
    Pharmacogenetics
Anne Bowcock, National Heart & Lung Institute, London, United Kingdom:
    Molecular genetics of inflammatory diseases

Session 3: Single Gene Pain Trait Session
Geoff Woods, Cambridge Institute for Medical Research, Cambridge, United Kingdom:
    SCN9A loss-of-function
Stephen Waxman, Yale University, New Haven, Connecticut:
    SCN9A gain-of-function
Michel Ferrari, Leiden University, Leiden, The Netherlands:
    FHM genes
Inna Belfer, University of Pittsburgh, Pittsburgh, Pennsylvania:
    COMT: a complex story

Session 4: Complex Pain Genetics Session
Luda Diatchenko, McGill University, Montreal, Canada:
    Complex pain genetics: progress so far
William Maixner, University of North Carolina, Chapel Hill, North Carolina:
    OPPERA update
Verneri Anttila, Harvard University, Boston, Massachusetts:
    Migraine GWAS

Session 5: Translational Pain Genetics Session
Arn van den Maagdenberg, Leiden University Medical Centre, Leiden, The Netherlands:
    Transgenic mouse models of single-gene disorders: migraine as the example
Gary Peltz, Stanford University, Stanford, California:
    Haplotype mapping in mice
Michael Costigan, Harvard University, Boston, Massachusetts:
    Expression profiling and target validation

Session 6: Phenotyping Session
Greg Neely, Garvin Institute of Medical Research, Sydney, Australia:
    Pain genetics in non-mammalian organisms
Christopher Nielsen, Norwegian Institute of Public Health, Oslo, Norway:
    What can/should be measured in large cohorts?
Vania Apkarian, Northwestern University, Chicago, Illinois:
    Brain imaging and genetic studies

Session 7: Breakout Groups:  What is the Best Way Forward?:
    Four breakout groups to discuss future research

Session 8: New Approaches
David Bennett, University of Oxford, Oxford, United Kingdom:
    Applying RNAseq to both animal and human pain models
Rajiv Ratan, Burke Medical Research Institute, White Plains, New York:
    Epigenetics

Session 9: Conclusions
Reports by breakout groups to the meeting
Group review, conclusion and summary
 
Participants

 Verneri Anttila
Harvard University
USA 
A. Apkarian
Northwestern University
USA  
Inna Belfer
University of Pittsburgh
USA
 David Bennett
University of Oxford
United Kingdom
Anne Bowcock
Imperial College London
United Kingdom
Michael Costigan
Harvard University
USA
 Luda Diatchenko
McGill University
Canada
 Michel Ferrari
Leiden University Medical Center
The Netherlands
Tilo Grosser
University of Pennsylvania
USA
 Roy Levitt
Miller School of Medicine
USA
Jorn Lotsch
University of Frankfurt
Germany
 William Maixner
University of North Carolina
USA
Pat McCaffrey
Pain Research Forum
USA
Jeffrey Mogil
McGill University
Canada
Greg Neely
Garvan Institute
Australia
Christopher  Nielsen
Norwegian Institute of Public Health
Norway
Gary Peltz
Stanford University
USA
Rajiv Ratan
Burke Medical Research Institute
USA
Christina Spellman
Mayday Fund
USA
Pamela Thye
Mayday Fund
USA
Arn van den Maagdenberg
Leiden University
The Netherlands
Stephen Waxman
Yale University
USA
C. Geoffrey Woods
University of Cambridge
United Kingdom
Clifford Woolf
Harvard University
USA


The Meeting 
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M. Ferrari, D. Bennett, J. Mogil

C. Spellman, P. Thye, C. Stebbins

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J Watson

I Belfer, V Apkarian

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S Waxman, V Apkarian, C Woolf

A Bowcock

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V Antilla
J Witkowski, P Thye