We found the study of clinical responses to opioids by Angst et al .1to be an excellent first-of-its-kind study for distinguishing the contribution of heredity versus  environment. Much work has been done using twins to separate heredity from environment and this addition to our literature is timely.

Although the use of twins to separate nature from nurture is a long-established model, we would have appreciated more detailed analysis of the monozygotic twins. Genetically, dizygotic twins are no different from other nontwin siblings (assuming the same parents). Contrary to what was stated by the authors, monozygotic twins do not share 100% of their DNA. Copy number variants and single-nucleotide polymorphisms have been discovered, which distinguish one monozygotic twin from the other.2,3Moreover, there are differences in regulation and expression of the shared monozygotic genes. These very small and seemingly inconsequential differences probably account for the differences in disease susceptibility between monozygotic twins4–9and may be significant in their reaction to opioids.

Twins raised together do not share 100% of the same environment. Very small differences in environment such as those that occurred in the womb or even in the seemingly identical home and school environments may result in the methylation of a gene in one twin but not in the other.9–11Epigenetic variability has also been found to increase with age, which may lead to increasing differences as monozygotic twins move from infancy to adulthood.5We look forward to further investigation from the authors, which will address these additional factors.

*University of Florida College of Medicine, Gainesville, Florida. mrice@anest.ufl.edu

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
Bruder CE, Piotrowski A, Gijsbers AA, Andersson R, Erickson S, Diaz de Ståhl T, Menzel U, Sandgren J, von Tell D, Poplawski A, Crowley M, Crasto C, Partridge EC, Tiwari H, Allison DB, Komorowski J, van Ommen GJ, Boomsma DI, Pedersen NL, den Dunnen JT, Wirdefeldt K, Dumanski JP. Phenotypically concordant and discordant monozygotic twins display different DNA copy-number-variation profiles. Am J Hum Genet. 2008;82:763–71
Maiti S, Kumar KH, Castellani CA, O’Reilly R, Singh SM. Ontogenetic de novo copy number variations (CNVs) as a source of genetic individuality: Studies on two families with MZD twins for schizophrenia. PLoS ONE. 2011;6:e17125
Dempster EL, Pidsley R, Schalkwyk LC, Owens S, Georgiades A, Kane F, Kalidindi S, Picchioni M, Kravariti E, Toulopoulou T, Murray RM, Mill J. Disease-associated epigenetic changes in monozygotic twins discordant for schizophrenia and bipolar disorder. Hum Mol Genet. 2011;20:4786–96
Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, Heine-Suñer D, Cigudosa JC, Urioste M, Benitez J, Boix-Chornet M, Sanchez-Aguilera A, Ling C, Carlsson E, Poulsen P, Vaag A, Stephan Z, Spector TD, Wu YZ, Plass C, Esteller M. Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci USA. 2005;102:10604–9
Javierre BM, Fernandez AF, Richter J, Al-Shahrour F, Martin-Subero JI, Rodriguez-Ubreva J, Berdasco M, Fraga MF, O’Hanlon TP, Rider LG, Jacinto FV, Lopez-Longo FJ, Dopazo J, Forn M, Peinado MA, Carreño L, Sawalha AH, Harley JB, Siebert R, Esteller M, Miller FW, Ballestar E. Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus. Genome Res. 2010;20:170–9
Wong AH, Gottesman II, Petronis A. Phenotypic differences in genetically identical organisms: The epigenetic perspective. Hum Mol Genet. 2005;14 Spec No 1:R11–8
Stankiewicz P, Lupski JR. Structural variation in the human genome and its role in disease. Annu Rev Med. 2010;61:437–55
Halder A, Jain M, Chaudhary I, Varma B. Chromosome 22q11.2 microdeletion in monozygotic twins with discordant phenotype and deletion size. Mol Cytogenet. 2012;5:13
Ollikainen M, Craig JM. Epigenetic discordance at imprinting control regions in twins. Epigenomics. 2011;3:295–306
Bell JT, Spector TD. A twin approach to unraveling epigenetics. Trends Genet. 2011;27:116–25