Anesthesiology:
doi: 10.1097/ALN.0b013e318278e4e4
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Angst, Martin S. M.D.*; Clark, J. David M.D., Ph.D.

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We thank Drs. Greek and Rice for their interest in our pharmacogenomic twin study reporting heritability estimates for aversive and reinforcing opioid effects.1 Studies on monozygotic and dizygotic twins are almost uniquely positioned to examine to what extent genetic variations contribute to disease susceptibility and pharmacologic variance.2 The classical twin study paradigm compares phenotypical resemblance of monozygotic and dizygotic twins and infers heritability if monozygotic twins resemble each other more than dizygotic twins do. Inherent to the analysis of such data is the assumption that monozygotic twins are genetically identical, whereas dizygotic twins share 50% of their genome on average. The twin study paradigm also allows examining the relative importance of the shared familial environment by assuming that monozygotic and dizygotic twins share the same environment. Twin studies have significantly advanced our understanding of the genetic and familial contributions to disease burden by indicating that outlined assumptions, although not entirely correct, are very reasonable.3–5
Monozygotic twins share the overwhelming portion of their DNA. However, small portions may indeed vary. Studies examining phenotypical dissimilarities rather than similarities in monozygotic twin pairs (discordant twins) exploit this very fact and have received significant recent attention as the odds of correctly attributing phenotypical differences to structural differences in DNA are favorable.6 Although appealing in concept, the overall utility of discordant twin studies for identifying mechanisms underlying complex traits or pharmacologic responses has not yet been established.
The primary aim of our study was to examine the overall genetic contribution to interindividual differences in analgesic, aversive and reinforcing opioid effects.1,7 Our results suggest that genetics clearly matter, thereby justifying future and more detailed studies examining molecular mechanisms underlying observed differences. We agree with Drs. Greek and Rice that studying discordant monocytic twin pairs is a plausible approach to unravel some of these mechanisms.
Martin S. Angst, M.D.,* J. David Clark, M.D., Ph.D.
*Stanford University School of Medicine, Stanford, California. ang@stanford.edu
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References

1. Angst MS, Lazzeroni LC, Phillips NG, Drover DR, Tingle M, Ray A, Swan GE, Clark JD. Aversive and reinforcing opioid effects: A pharmacogenomic twin study. ANESTHESIOLOGY. 2012;117:22–37

2. Boomsma D, Busjahn A, Peltonen L. Classical twin studies and beyond. Nat Rev Genet. 2002;3:872–82

3. Martin N, Boomsma D, Machin G. A twin-pronged attack on complex traits. Nat Genet. 1997;17:387–92

4. Tsuang MT, Bar JL, Harley RM, Lyons MJ. The Harvard Twin Study of Substance Abuse: What we have learned. Harv Rev Psychiatry. 2001;9:267–79

5. Faraone SV, Doyle AE. The nature and heritability of attention-deficit/hyperactivity disorder. Child Adolesc Psychiatr Clin N Am. 2001;10:299–316 viii–ix

6. Zwijnenburg PJ, Meijers-Heijboer H, Boomsma DI. Identical but not the same: The value of discordant monozygotic twins in genetic research. Am J Med Genet B Neuropsychiatr Genet. 2010;153B:1134–49

7. Angst MS, Phillips NG, Drover DR, Tingle M, Ray A, Swan GE, Lazzeroni LC, Clark JD. Pain sensitivity and opioid analgesia: A pharmacogenomic twin study. Pain. 2012;153:1397–409

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