American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 141B:681 (2006) Letter to the Editor Bad Luck: An Unappreciated Limitation in the Interpretation of Twin Studies Please cite this article as follows: Hardy J. 2006. Bad Luck: An Unappreciated Limitation in the Interpretation of Twin Studies. Am J Med Genet Part B 141B:681. To the Editor: The study of concordance and discordance rates for twin has been, and continues to be, a central methodology in the dissecting of the influences of nature and nurture in biology [Martin et al., 1997]. However, an assumption is often drawn from the analyses of concordance rates in monozygotic twins that the variance not attributable to genetic influence must be attributable to environmental influences. This belief pervades the genetic literature and especially the literature of psychiatric genetics. However, it is not so. If a biological process is both stochastic and self-sustaining, it could occur in one identical twin, but not the other even if their environment was the same. While this might be thought of as a rather esoteric limitation of the methodology, in fact there are several processes that may plausibly fit this description. For example, synaptic strengthening is self sustaining [Malenka and Bear, 2004] and may underlie psychiatric disorders and permissive templating, which almost certainly underlies prion disease pathogenesis [Hill and Collinge, 2003] and may underlie other amyloid deposition diseases including Alzheimer’s and Parkinson’s disease [Walker et al., 2002; Hardy, 2005] also has the potential to be both stochastic in initiation and self sustaining *Correspondence to: John Hardy, Laboratory of Neurogenetics, National Institute on Aging, Porter Neuroscience Building, 35, Convent Drive, Bethesda, MD 20892. E-mail: email@example.com Received 11 March 2006; Accepted 3 April 2006 DOI 10.1002/ajmg.b.30353 ß 2006 Wiley-Liss, Inc. in propagation. In diseases such as these, and doubtless in others, one should not interpret lack of complete concordance in monozygotic twins as necessarily signifying a role for environmental factors. However unsatisfying it may seem, bad luck may have an important but unappreciated role in the initiation of disease. John Hardy* Laboratory of Neurogenetics National Institute on Aging Bethesda, Maryland REFERENCES Hardy J. 2005. Expression of normal sequence pathogenic proteins for neurodegenerative disease contributes to disease risk: ‘Permissive templating’ as a general mechanism underlying neurodegeneration. Biochem Soc Trans 33:578–581. Hill AF, Collinge J. 2003. Subclinical prion infection. Trends Microbiol 11:578–584. Malenka RC, Bear MF. 2004. LTP and LTD: an embarrassment of riches. Neuron 44:5–21. Martin N, Boomsma D, Machin G. 1997. A twin-pronged attack on complex traits. Nat Genet 17:387–392. Walker LC, Callahan MJ, Bian F, Durham RA, Roher AE, Lipinski WJ. 2002. Exogenous induction of cerebral beta-amyloidosis in betaAPPtransgenic mice. Peptides 23:1241–1247.