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Genetic Contributions to Clinical Pain and Analgesia: Avoiding Pitfalls in Genetic Research

      Abstract

      Understanding the genetic basis of human variations in pain is critical to elucidating the molecular basis of pain sensitivity, variable responses to analgesic drugs, and, ultimately, to individualized treatment of pain and improved public health. With the help of recently accumulated knowledge and advanced technologies, pain researchers hope to gain insight into genetic mechanisms of pain and eventually apply this knowledge to pain treatment.

      Perspective

      We critically reviewed the published literature to examine the strength of evidence supporting genetic influences on clinical and human experimental pain. Based on this evidence and the experience of false associations that have occurred in other related disciplines, we provide recommendations for avoiding pitfalls in pain genetic research.

      Key words

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      References

        • Abrahamsen B.
        • Zhao J.
        • Asante C.O.
        • Cendan C.M.
        • Marsh S.
        • Martinez-Barbera J.P.
        • Nassar M.A.
        • Dickenson A.H.
        • Wood J.N.
        The cell and molecular basis of mechanical, cold, and inflammatory pain.
        Science. 2008; 321: 702-705
        • Armero P.
        • Muriel C.
        • Santos J.
        • Sanchez-Montero F.J.
        • Rodriguez R.E.
        • Gonzalez-Sarmiento R.
        COMT (Val158Met) polymorphism is not associated to neuropathic pain in a Spanish population.
        Eur J Pain. 2005; 9: 229-232
        • Balding D.J.
        A tutorial on statistical methods for population association studies.
        Nat Rev Genet. 2006; 7: 781-791
        • Benjamini Y.
        • Hochberg Y.
        Controlling the false discovery rate - A practical and powerful approach to multiple testing.
        J Royal Stat Soc Ser B-Methodol. 1995; 57: 289-300
        • Bhalang K.
        • Sigurdsson A.
        • Slade G.D.
        • Maixner W.
        Associations among four modalities of experimental pain in women.
        J Pain. 2005; 6: 604-611
        • Bisgaard T.
        • Rosenberg J.
        • Kehlet H.
        From acute to chronic pain after laparoscopic cholecystectomy: a prospective follow-up analysis.
        Scand J Gastroenterol. 2005; 40: 1358-1364
        • Bjork M.
        • Gerdle B.
        • Thyberg I.
        • Peolsson M.
        Multivariate relationships between pain intensity and other aspects of health in rheumatoid arthritis-cross sectional and five year longitudinal analyses (the Swedish TIRA project).
        Disabil Rehabil. 2008; 30: 1429-1438
        • Bushnell M.C.
        • Apkarian A.V.
        Representation of pain in the brain.
        in: McMahon S. Koltzenburg M. Textbook of Pain. 5th Edition. Philadelphia, PA, Churchill Livingstone2006: 107-124
        • Cardon L.R.
        • Bell J.I.
        Association study designs for complex diseases.
        Nat Rev Genet. 2001; 2: 91-99
        • Churchill G.A.
        • Doerge R.W.
        Empirical threshold values for quantitative trait mapping.
        Genetics. 1994; 138: 963-971
        • Coghill R.C.
        • Eisenach J.
        Individual differences in pain sensitivity: implications for treatment decisions.
        Anesthesiology. 2003; 98: 1312-1314
        • Coghill R.C.
        • McHaffie J.G.
        • Yen Y.F.
        Neural correlates of interindividual differences in the subjective experience of pain.
        Proc Natl Acad Sci U S A. 2003; 100: 8538-8542
        • Dadd T.
        • Weale M.E.
        • Lewis C.M.
        A critical evaluation of genomic control methods for genetic association studies.
        Genet Epidemiol. 2009; 33: 290-298
        • Diatchenko L.
        • Slade G.D.
        • Nackley A.G.
        • Bhalang K.
        • Sigurdsson A.
        • Belfer I.
        • Goldman D.
        • Xu K.
        • Shabalina S.A.
        • Shagin D.
        • Max M.B.
        • Makarov S.S.
        • Maixner W.
        Genetic basis for individual variations in pain perception and the development of a chronic pain condition.
        Hum Mol Genet. 2005; 14: 135-143
        • Diatchenko L.
        • Nackley A.G.
        • Slade G.D.
        • Bhalang K.
        • Belfer I.
        • Max M.B.
        • Goldman D.
        • Maixner W.
        Catechol-O-methyltransferase gene polymorphisms are associated with multiple pain-evoking stimuli.
        Pain. 2006; 125: 216-224
        • Diatchenko L.
        • Nackley A.G.
        • Slade G.D.
        • Belfer I.
        • Max M.
        • Goldman D.
        • Maixner W.
        Responses to Drs. Kim and Dionne regarding comments on Diatchenko et al. Catechol-O-methyltransferase gene polymorphisms are associated with multiple pain-evoking stimuli.
        Pain. 2007; 129: 366-370
        • Diatchenko L.
        • Nackley A.G.
        • Tchivileva I.E.
        • Shabalina S.A.
        • Maixner W.
        Genetic architecture of human pain perception.
        Trends Genet. 2007; 23: 605-613
        • Dionne R.A.
        • Bartoshuk L.
        • Mogil J.
        • Witter J.
        Individual responder analyses for pain: does one pain scale fit all?.
        Trends Pharmacol Sci. 2005; 26: 125-130
        • Dostrovsky J.O.
        • Craig A.D.
        Ascending projection systems.
        in: McMahon S.B. Koltzenburg M. Wall and Melzack's Textbook of Pain. 5th Edition. Philadelphia, PA, Churchill Livingstone2006: 187-203
        • Dworkin R.H.
        • Turk D.C.
        • Wyrwich K.W.
        • Beaton D.
        • Cleeland C.S.
        • Farrar J.T.
        • Haythornthwaite J.A.
        • Jensen M.P.
        • Kerns R.D.
        • Ader D.N.
        • Brandenburg N.
        • Burke L.B.
        • Cella D.
        • Chandler J.
        • Cowan P.
        • Dimitrova R.
        • Dionne R.
        • Hertz S.
        • Jadad A.R.
        • Katz N.P.
        • Kehlet H.
        • Kramer L.D.
        • Manning D.C.
        • McCormick C.
        • McDermott M.P.
        • McQuay H.J.
        • Patel S.
        • Porter L.
        • Quessy S.
        • Rappaport B.A.
        • Rauschkolb C.
        • Revicki D.A.
        • Rothman M.
        • Schmader K.E.
        • Stacey B.R.
        • Stauffer J.W.
        • von Stein T.
        • White R.E.
        • Witter J.
        • Zavisic S.
        Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations.
        J Pain. 2008; 9: 105-121
        • Eaton M.
        Common animal models for spasticity and pain.
        J Rehabil Res Dev. 2003; 40: 41-54
        • Edwards R.R.
        • Fillingim R.B.
        • Maixner W.
        • Sigurdsson A.
        • Haythornthwaite J.
        Catastrophizing predicts changes in thermal pain responses after resolution of acute dental pain.
        J Pain. 2004; 5: 164-170
        • Fields H.L.
        • Basbaum A.I.
        • Heinricher M.M.
        Central nervous system mechanisms of pain modulation.
        in: McMahon S.B. Koltzenburg M. Wall and Melzack's Textbook of Pain. 5th Edition. Philadelphia, PA, Churchill Livingstone2006: 125-142
        • Freedman M.L.
        • Reich D.
        • Penney K.L.
        • McDonald G.J.
        • Mignault A.A.
        • Patterson N.
        • Gabriel S.B.
        • Topol E.J.
        • Smoller J.W.
        • Pato C.N.
        • Pato M.T.
        • Petryshen T.L.
        • Kolonel L.N.
        • Lander E.S.
        • Sklar P.
        • Henderson B.
        • Hirschhorn J.N.
        • Altshuler D.
        Assessing the impact of population stratification on genetic association studies.
        Nat Genet. 2004; 36: 388-393
        • Freimer N.
        • Sabatti C.
        The use of pedigree, sib-pair and association studies of common diseases for genetic mapping and epidemiology.
        Nat Genet. 2004; 36: 1045-1051
        • Gabriel S.B.
        • Schaffner S.F.
        • Nguyen H.
        • Moore J.M.
        • Roy J.
        • Blumenstiel B.
        • Higgins J.
        • DeFelice M.
        • Lochner A.
        • Faggart M.
        • Liu-Cordero S.N.
        • Rotimi C.
        • Adeyemo A.
        • Cooper R.
        • Ward R.
        • Lander E.S.
        • Daly M.J.
        • Altshuler D.
        The structure of haplotype blocks in the human genome.
        Science. 2002; 296: 2225-2229
        • Grupe A.
        • Germer S.
        • Usuka J.
        • Aud D.
        • Belknap J.K.
        • Klein R.F.
        • Ahluwalia M.K.
        • Higuchi R.
        • Peltz G.
        In silico mapping of complex disease-related traits in mice.
        Science. 2001; 292: 1915-1918
        • Guo Y.
        • Weller P.
        • Farrell E.
        • Cheung P.
        • Fitch B.
        • Clark D.
        • Wu S.Y.
        • Wang J.
        • Liao G.
        • Zhang Z.
        • Allard J.
        • Cheng J.
        • Nguyen A.
        • Jiang S.
        • Shafer S.
        • Usuka J.
        • Masjedizadeh M.
        • Peltz G.
        In silico pharmacogenetics of warfarin metabolism.
        Nat Biotechnol. 2006; 24: 531-536
        • Hakim A.J.
        • Cherkas L.
        • El Zayat S.
        • MacGregor A.J.
        • Spector T.D.
        The genetic contribution to carpal tunnel syndrome in women: a twin study.
        Arthritis Rheum. 2002; 47: 275-279
        • Healy D.G.
        Case-control studies in the genomic era: a clinician's guide.
        Lancet Neurol. 2006; 5: 701-707
        • Hestbaek L.
        • Iachine I.A.
        • Leboeuf-Yde C.
        • Kyvik K.O.
        • Manniche C.
        Heredity of low back pain in a young population: a classical twin study.
        Twin Res. 2004; 7: 16-26
        • Hinds D.A.
        • Stuve L.L.
        • Nilsen G.B.
        • Halperin E.
        • Eskin E.
        • Ballinger D.G.
        • Frazer K.A.
        • Cox D.R.
        Whole-genome patterns of common DNA variation in three human populations.
        Science. 2005; 307: 1072-1079
        • Kang S.C.
        • Lee D.G.
        • Choi J.H.
        • Kim S.T.
        • Kim Y.K.
        • Ahn H.J.
        Association between estrogen receptor polymorphism and pain susceptibility in female temporomandibular joint osteoarthritis patients.
        Int J Oral Maxillofac Surg. 2007; 36: 391-394
        • Kim H.
        • Neubert J.K.
        • Rowan J.S.
        • Brahim J.S.
        • Dionne R.
        Comparison of experimental and acute clinical pain responses in humans as pain phenotypes.
        J Pain. 2004; 5: 377-384
        • Kim H.
        • Neubert J.K.
        • San Miguel A.
        • Xu K.
        • Krishnaraju R.K.
        • Iadarola M.
        • Goldman D.
        • Dionne R.
        Genetic influence on variability in human pain sensitivity associated with gender, ethnicity and psychological temperament.
        Pain. 2004; 109: 488-496
        • Kim H.
        • Lee H.
        • Rowan J.
        • Brahim J.
        • Dionne R.A.
        Genetic polymorphisms in monoamine neurotransmitter systems show only weak association with acute post-surgical pain in humans.
        Mol Pain. 2006; 2: 24
        • Kim H.
        • Mittal D.P.
        • Iadarola M.J.
        • Dionne R.A.
        Genetic predictors for acute experimental cold and heat pain sensitivity in humans.
        J Med Genet. 2006; 43: e40
        • Kim H.
        • Dionne R.A.
        Lack of influence of GTP cyclohydrolase gene (GCH1) variations on pain sensitivity in humans.
        Mol Pain. 2007; 3: 6
        • Kim H.
        • Dionne R.A.
        Comment on Diatchenko et al. Catechol-O-methyltransferase gene polymorphisms are associated with multiple pain-evoking stimuli.
        Pain 125:216-224. 2006; (Pain 129:365–366; author reply 366-370, 2007)
        • Kim H.S.
        • Neubert J.K.
        • Iadarola M.J.
        • San Miguel A.
        • Goldman D.
        • Dionne R.A.
        Genetic influence on pain sensitivity in humans: Evidence of heritability related to single nucleotide polymorphisms (SNPs) in opioid receptor genes.
        in: Dostrovsky J.O. Carr D.B. Koltzenburg M. Proceedings of the 10th World Congress on Pain, Seattle, WA2003: 513-520
        • Lariviere W.R.
        • Wilson S.G.
        • Laughlin T.M.
        • Kokayeff A.
        • West E.E.
        • Adhikari S.M.
        • Wan Y.
        • Mogil J.S.
        Heritability of nociception. III. Genetic relationships among commonly used assays of nociception and hypersensitivity.
        Pain. 2002; 97: 75-86
        • Larsson B.
        • Bille B.
        • Pedersen N.L.
        Genetic influence in headaches:a Swedish twin study.
        Headache. 1995; 35: 513-519
        • Lasky-Su J.
        • Lyon H.N.
        • Emilsson V.
        • Heid I.M.
        • Molony C.
        • Raby B.A.
        • Lazarus R.
        • Klanderman B.
        • Soto-Quiros M.E.
        • Avila L.
        • Silverman E.K.
        • Thorleifsson G.
        • Thorsteinsdottir U.
        • Kronenberg F.
        • Vollmert C.
        • Illig T.
        • Fox C.S.
        • Levy D.
        • Laird N.
        • Ding X.
        • McQueen M.B.
        • Butler J.
        • Ardlie K.
        • Papoutsakis C.
        • Dedoussis G.
        • O'Donnell C.J.
        • Wichmann H.E.
        • Celedon J.C.
        • Schadt E.
        • Hirschhorn J.
        • Weiss S.T.
        • Stefansson K.
        • Lange C.
        On the replication of genetic associations: timing can be everything!.
        Am J Hum Genet. 2008; 82: 849-858
        • Lee H.
        • Caterina M.J.
        TRPV channels as thermosensory receptors in epithelial cells.
        Pflugers Arch. 2005; 451: 160-167
        • Lee Y.
        • Kim H.
        • Wu T.
        • Wang X.
        • Dionne R.
        Genetically mediated inter-individual variation in analgesic responses to COX inhibitory drugs.
        Clin Pharmacol Ther. 2006; 79: 407-418
        • Lencz T.
        • Lambert C.
        • DeRosse P.
        • Burdick K.E.
        • Morgan T.V.
        • Kane J.M.
        • Kucherlapati R.
        • Malhotra A.K.
        Runs of homozygosity reveal highly penetrant recessive loci in schizophrenia.
        Proc Natl Acad Sci U S A. 2007; 104: 19942-19947
        • Lencz T.
        • Morgan T.V.
        • Athanasiou M.
        • Dain B.
        • Reed C.R.
        • Kane J.M.
        • Kucherlapati R.
        • Malhotra A.K.
        Converging evidence for a pseudoautosomal cytokine receptor gene locus in schizophrenia.
        Mol Psychiatry. 2007; 12: 572-580
        • Levine J.D.
        • Alessandri-Haber N.
        TRP channels: targets for the relief of pain.
        Biochim Biophys Acta. 2007; 1772: 989-1003
        • Liang D.Y.
        • Liao G.
        • Lighthall G.K.
        • Peltz G.
        • Clark D.J.
        Genetic variants of the P-glycoprotein gene Abcb1b modulate opioid-induced hyperalgesia, tolerance and dependence.
        Pharmacogenet Genomics. 2006; 16: 825-835
        • Liang D.Y.
        • Liao G.
        • Wang J.
        • Usuka J.
        • Guo Y.
        • Peltz G.
        • Clark J.D.
        A genetic analysis of opioid-induced hyperalgesia in mice.
        Anesthesiology. 2006; 104: 1054-1062
        • Lin P.I.
        • Vance J.M.
        • Pericak-Vance M.A.
        • Martin E.R.
        No gene is an island: the flip-flop phenomenon.
        Am J Hum Genet. 2007; 80: 531-538
        • Lotsch J.
        • Geisslinger G.
        Current evidence for a modulation of nociception by human genetic polymorphisms.
        Pain. 2007; 132: 18-22
        • Lötsch J.
        • Belfer I.
        • Kirchhof A.
        • Mishra B.K.
        • Max M.B.
        • Doehring A.
        • Costigan M.
        • Woolf C.J.
        • Geisslinger G.
        • Tegeder I.
        Reliable screening for a pain-protective haplotype in the GTP cyclohydrolase 1 gene (GCH1) through the use of 3 or fewer single nucleotide polymorphisms.
        Clin Chem. 2007; 53: 1010-1015
        • MacGregor A.J.
        The heritability of pain in humans.
        in: Mogil J. The genetics of pain. Ist Edition. IASP Press, Seattle, WA2004: 151-170
        • MacGregor A.J.
        • Andrew T.
        • Sambrook P.N.
        • Spector T.D.
        Structural, psychological, and genetic influences on low back and neck pain: a study of adult female twins.
        Arthritis Rheum. 2004; 51: 160-167
        • Marchini J.
        • Cardon L.R.
        • Phillips M.S.
        • Donnelly P.
        The effects of human population structure on large genetic association studies.
        Nat Genet. 2004; 36: 512-517
        • Max M.
        Assessing pain candidate gene studies.
        Pain. 2004; 109: 1-3
        • Michalowicz B.S.
        • Pihlstrom B.L.
        • Hodges J.S.
        • Bouchard Jr., T.J.
        No heritability of temporomandibular joint signs and symptoms.
        J Dent Res. 2000; 79: 1573-1578
        • Mishra B.K.
        • Wu T.
        • Belfer I.
        • Hodgkinson C.A.
        • Cohen L.G.
        • Kiselycznyk C.
        • Kingman A.
        • Keller R.B.
        • Yuan Q.
        • Goldman D.
        • Atlas S.J.
        • Max M.B.
        Do motor control genes contribute to interindividual variability in decreased movement in patients with pain?.
        Mol Pain. 2007; 3: 20
        • Mogil J.
        • Ritchie J.
        • Strasburg K.
        • Kaplan L.
        • Wallace M.R.
        • Romberg R.
        • Bijl H.
        • Sarton E.
        • Fillingim R.
        Melanocortin-1 receptor gene variants affect pain and mu-opioid analgesia in mice and humans.
        J Med Genetics. 2005; 42: 583-587
        • Mogil J.S.
        • Wilson S.G.
        • Bon K.
        • Lee S.E.
        • Chung K.
        • Raber P.
        • Pieper J.O.
        • Hain H.S.
        • Belknap J.K.
        • Hubert L.
        • Elmer G.I.
        • Chung J.M.
        • Devor M.
        Heritability of nociception II. ‘Types’ of nociception revealed by genetic correlation analysis.
        Pain. 1999; 80: 83-93
        • Mogil J.S.
        • Wilson S.G.
        • Bon K.
        • Lee S.E.
        • Chung K.
        • Raber P.
        • Pieper J.O.
        • Hain H.S.
        • Belknap J.K.
        • Hubert L.
        • Elmer G.I.
        • Chung J.M.
        • Devor M.
        Heritability of nociception I: responses of 11 inbred mouse strains on 12 measures of nociception.
        Pain. 1999; 80: 67-82
        • Moher D.
        • Schulz K.F.
        • Altman D.G.
        The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomised trials.
        Lancet. 2001; 357: 1191-1194
        • Nackley A.G.
        • Shabalina S.A.
        • Tchivileva I.E.
        • Satterfield K.
        • Korchynskyi O.
        • Makarov S.S.
        • Maixner W.
        • Diatchenko L.
        Human catechol-O-methyltransferase haplotypes modulate protein expression by altering mRNA secondary structure.
        Science. 2006; 314: 1930-1933
        • Neddermeyer T.J.
        • Fluhr K.
        • Lotsch J.
        Principle components analysis of pain thresholds to thermal, electrical, and mechanical stimuli suggests a predominant common source of variance.
        Pain. 2008; 138: 286-291
        • Nielsen C.S.
        • Stubhaug A.
        • Price D.D.
        • Vassend O.
        • Czajkowski N.
        • Harris J.R.
        Individual differences in pain sensitivity: genetic and environmental contributions.
        Pain. 2008; 136: 21-29
        • Pan P.H.
        • Coghill R.
        • Houle T.T.
        • Seid M.H.
        • Lindel W.M.
        • Parker R.L.
        • Washburn S.A.
        • Harris L.
        • Eisenach J.C.
        Multifactorial preoperative predictors for postcesarean section pain and analgesic requirement.
        Anesthesiology. 2006; 104: 417-425
        • Patsopoulos N.A.
        • Tatsioni A.
        • Ioannidis J.P.
        Claims of sex differences: an empirical assessment in genetic associations.
        JAMA. 2007; 298: 880-893
        • Price A.L.
        • Patterson N.J.
        • Plenge R.M.
        • Weinblatt M.E.
        • Shadick N.A.
        • Reich D.
        Principal components analysis corrects for stratification in genome-wide association studies.
        Nat Genet. 2006; 38: 90490-90499
        • Price D.D.
        Psychological mechanisms of pain and analgesia.
        Ist Edition. IASP Press, Seattle, WA1999
        • Rakvag T.T.
        • Klepstad P.
        • Baar C.
        • Kvam T.M.
        • Dale O.
        • Kaasa S.
        • Krokan H.E.
        • Skorpen F.
        The Val158Met polymorphism of the human catechol-O-methyltransferase (COMT) gene may influence morphine requirements in cancer pain patients.
        Pain. 2005; 116: 73-78
        • Reyes-Gibby C.C.
        • Shete S.
        • Rakvag T.
        • Bhat S.V.
        • Skorpen F.
        • Bruera E.
        • Kaasa S.
        • Klepstad P.
        Exploring joint effects of genes and the clinical efficacy of morphine for cancer pain: OPRM1 and COMT gene.
        Pain. 2007; 130: 25-30
        • Rolke R.
        • Baron R.
        • Maier C.
        • Tolle T.R.
        • Treede R.D.
        • Beyer A.
        • Binder A.
        • Birbaumer N.
        • Birklein F.
        • Botefur I.C.
        • Braune S.
        • Flor H.
        • Huge V.
        • Klug R.
        • Landwehrmeyer G.B.
        • Magerl W.
        • Maihofner C.
        • Rolko C.
        • Schaub C.
        • Scherens A.
        • Sprenger T.
        • Valet M.
        • Wasserka B.
        Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): standardized protocol and reference values.
        Pain. 2006; 123: 231-243
        • Ross J.R.
        • Riley J.
        • Taegetmeyer A.B.
        • Sato H.
        • Gretton S.
        • du Bois R.M.
        • Welsh K.I.
        Genetic variation and response to morphine in cancer patients: catechol-o-methyltransferase and multidrug resistance-1 gene polymorphisms are associated with central side effects.
        Cancer. 2008; 112: 1390-1403
        • Ruby J.G.
        • Jan C.H.
        • Bartel D.P.
        Intronic microRNA precursors that bypass Drosha processing.
        Nature. 2007; 448: 83-86
        • Salonen J.T.
        • Uimari P.
        • Aalto J.M.
        • Pirskanen M.
        • Kaikkonen J.
        • Todorova B.
        • Hypponen J.
        • Korhonen V.P.
        • Asikainen J.
        • Devine C.
        • Tuomainen T.P.
        • Luedemann J.
        • Nauck M.
        • Kerner W.
        • Stephens R.H.
        • New J.P.
        • Ollier W.E.
        • Gibson J.M.
        • Payton A.
        • Horan M.A.
        • Pendleton N.
        • Mahoney W.
        • Meyre D.
        • Delplanque J.
        • Froguel P.
        • Luzzatto O.
        • Yakir B.
        • Darvasi A.
        Type 2 diabetes whole-genome association study in four populations: the DiaGen consortium.
        Am J Hum Genet. 2007; 81: 338-345
        • Scuteri A.
        • Sanna S.
        • Chen W.M.
        • Uda M.
        • Albai G.
        • Strait J.
        • Najjar S.
        • Nagaraja R.
        • Orru M.
        • Usala G.
        • Dei M.
        • Lai S.
        • Maschio A.
        • Busonero F.
        • Mulas A.
        • Ehret G.B.
        • Fink A.A.
        • Weder A.B.
        • Cooper R.S.
        • Galan P.
        • Chakravarti A.
        • Schlessinger D.
        • Cao A.
        • Lakatta E.
        • Abecasis G.R.
        Genome-Wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits.
        PLoS Genet. 2007; 3: e115
        • Shifman S.
        • Bhomra A.
        • Smiley S.
        • Wray N.R.
        • James M.R.
        • Martin N.G.
        • Hettema J.M.
        • An S.S.
        • Neale M.C.
        • van den Oord E.J.
        • Kendler K.S.
        • Chen X.
        • Boomsma D.I.
        • Middeldorp C.M.
        • Hottenga J.J.
        • Slagboom P.E.
        • Flint J.
        A whole genome association study of neuroticism using DNA pooling.
        Mol Psychiatry. 2008; 13: 302-312
        • Skol A.D.
        • Scott L.J.
        • Abecasis G.R.
        • Boehnke M.
        Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studies.
        Nat Genet. 2006; 38: 209-213
        • Slade G.D.
        • Diatchenko L.
        • Bhalang K.
        • Sigurdsson A.
        • Fillingim R.B.
        • Belfer I.
        • Max M.B.
        • Goldman D.
        • Maixner W.
        Influence of psychological factors on risk of temporomandibular disorders.
        J Dent Res. 2007; 86: 1120-1125
        • Smith S.B.
        • Marker C.L.
        • Perry C.
        • Liao G.
        • Sotocinal S.G.
        • Austin J.S.
        • Melmed K.
        • Clark J.D.
        • Peltz G.
        • Wickman K.
        • Mogil J.S.
        Quantitative trait locus and computational mapping identifies Kcnj9 (GIRK3) as a candidate gene affecting analgesia from multiple drug classes.
        Pharmacogenet Genomics. 2008; 18: 231-241
        • Storey J.D.
        A direct approach to false discovery rates.
        J Royal Stat Soc Ser B-Methodol. 2002; 64: 479-498
        • Storey J.D.
        • Tibshirani R.
        Statistical significance for genomewide studies.
        Proc Natl Acad Sci U S A. 2003; 100: 9440-9445
        • Sullivan P.F.
        • Purcell S.
        Analyzing genome-wide association study data: a tutorial using PLINK.
        in: Neale B.M. Ferreira M.A. Medland S.E. Posthuma D. Statistical Genetics, Gene Mapping Through Linkage and Association. Ist Edition. Taylor & Francis, New York2007: 355-394
        • Tegeder I.
        • Costigan M.
        • Griffin R.S.
        • Abele A.
        • Belfer I.
        • Schmidt H.
        • Ehnert C.
        • Nejim J.
        • Marian C.
        • Scholz J.
        • Wu T.
        • Allchorne A.
        • Diatchenko L.
        • Binshtok A.M.
        • Goldman D.
        • Adolph J.
        • Sama S.
        • Atlas S.J.
        • Carlezon W.A.
        • Parsegian A.
        • Lotsch J.
        • Fillingim R.B.
        • Maixner W.
        • Geisslinger G.
        • Max M.B.
        • Woolf C.J.
        GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence.
        Nat Med. 2006; 12: 1269-1277
        • Tegeder I.
        • Adolph J.
        • Schmidt H.
        • Woolf C.J.
        • Geisslinger G.
        • Lotsch J.
        Reduced hyperalgesia in homozygous carriers of a GTP cyclohydrolase 1 haplotype.
        Eur J Pain. 2008; 12: 1069-1077
        • Thomas D.C.
        Are we ready for genome-wide association studies?.
        Cancer Epidemiol Biomarkers Prev. 2006; 15: 595-598
        • Treloar S.A.
        • Martin N.G.
        • Heath A.C.
        Longitudinal genetic analysis of menstrual flow, pain, and limitation in a sample of Australian twins.
        Behav Genet. 1998; 28: 107-116
        • Turk D.C.
        • Dworkin R.H.
        • Allen R.R.
        • Bellamy N.
        • Brandenburg N.
        • Carr D.B.
        • Cleeland C.
        • Dionne R.
        • Farrar J.T.
        • Galer B.S.
        • Hewitt D.J.
        • Jadad A.R.
        • Katz N.P.
        • Kramer L.D.
        • Manning D.C.
        • McCormick C.G.
        • McDermott M.P.
        • McGrath P.
        • Quessy S.
        • Rappaport B.A.
        • Robinson J.P.
        • Royal M.A.
        • Simon L.
        • Stauffer J.W.
        • Stein W.
        • Tollett J.
        • Witter J.
        Core outcome domains for chronic pain clinical trials: IMMPACT recommendations.
        Pain. 2003; 106: 337-345
        • Vargas-Alarcon G.
        • Fragoso J.M.
        • Cruz-Robles D.
        • Vargas A.
        • Lao-Villadoniga J.I.
        • Garcia-Fructuoso F.
        • Ramos-Kuri M.
        • Hernandez F.
        • Springall R.
        • Bojalil R.
        • Vallejo M.
        • Martinez-Lavin M.
        Catechol-O-methyltransferase gene haplotypes in Mexican and Spanish patients with fibromyalgia.
        Arthritis Res Ther. 2007; 9: R110
        • Wall J.D.
        • Pritchard J.K.
        Haplotype blocks and linkage disequilibrium in the human genome.
        Nat Rev Genet. 2003; 4: 587-597
        • Wang J.
        • Liao G.
        • Usuka J.
        • Peltz G.
        Computational genetics: from mouse to human?.
        Trends Genet. 2005; 21: 526-532
        • Wang X.M.
        • Wu T.X.
        • Hamza M.
        • Ramsay E.S.
        • Wahl S.M.
        • Dionne R.A.
        Rofecoxib modulates multiple gene expression pathways in a clinical model of acute inflammatory pain.
        Pain. 2007; 128: 136-147
        • Weedon M.N.
        • Lettre G.
        • Freathy R.M.
        • Lindgren C.M.
        • Voight B.F.
        • Perry J.R.
        • Elliott K.S.
        • Hackett R.
        • Guiducci C.
        • Shields B.
        • Zeggini E.
        • Lango H.
        • Lyssenko V.
        • Timpson N.J.
        • Burtt N.P.
        • Rayner N.W.
        • Saxena R.
        • Ardlie K.
        • Tobias J.H.
        • Ness A.R.
        • Ring S.M.
        • Palmer C.N.
        • Morris A.D.
        • Peltonen L.
        • Salomaa V.
        • Smith G.D.
        • Groop L.C.
        • Hattersley A.T.
        • McCarthy M.I.
        • Hirschhorn J.N.
        • Frayling T.M.
        A common variant of HMGA2 is associated with adult and childhood height in the general population.
        Nat Genet. 2007; 39: 1245-1250
        • Westfall P.H.
        • Young S.S.
        Resampling-based multiple testing: examples and methods for p-value adjustment.
        Ist Edition. John Wiley and Song, New York, NY1993
        • Zang Y.
        • Zhang H.
        • Yang Y.
        • Zheng G.
        Robust genomic control and robust delta centralization tests for case-control association studies.
        Hum Hered. 2007; 63: 187-195
        • Zubieta J.K.
        • Heitzeg M.M.
        • Smith Y.R.
        • Bueller J.A.
        • Xu K.
        • Xu Y.
        • Koeppe R.A.
        • Stohler C.S.
        • Goldman D.
        COMT val158met genotype affects mu-opioid neurotransmitter responses to a pain stressor.
        Science. 2003; 299: 1240-1243