FIGURE 1 | Liability threshold model and disease discordance in monozygotic twins.

From the following article:

The continuing value of twin studies in the omics era

Jenny van Dongen, P. Eline Slagboom, Harmen H. M. Draisma, Nicholas G. Martin & Dorret I. Boomsma

Nature Reviews Genetics 13, 640-653 (September 2012)

doi:10.1038/nrg3243

The continuing value of twin studies in the omics era

The liability threshold model assumes that multifactorial diseases result from an underlying continuous character (that is, liability) that is normally distributed in the population123. If the combined effects of genetic and environmental influences push an individual's liability across a certain threshold level, the individual is affected. In the population, the proportion of individuals with a liability above the threshold is reflected in the disease prevalence. In discordant monozygotic (MZ) twin pairs, only one twin has a liability above the threshold, although the liability of the unaffected twin may also be high. The black arrow displays the potential range of liabilities of affected twins from discordant MZ twin pairs, and the grey arrow displays the potential range of liabilities of unaffected twins. A comparison of MZ twins who were discordant for congenital diaphragmatic hernia and oesophageal atresia found no differences in genomic structural variation between co-twins39. However, structural events in relevant genomic regions that may have contributed to the genetic predisposition of both twins were detected in several pairs; these events were rarely observed in individuals from a healthy control population. A metabolomic study of MZ twins who were discordant for schizophrenia found that, relative to healthy individuals in concordant pairs, the unaffected twins from discordant female pairs showed similar (although smaller) metabolic changes than the affected co-twins124. These examples demonstrate that the liability of unaffected twins from discordant pairs may also be elevated. However, this feature does not argue against the value of studying discordant MZ twin pairs to search for the molecular events that caused the affected twin to pass the threshold or events that protected the unaffected twin. Of interest, a study of neurofibromatosis type 1 (NF1) in MZ twins with the same causal mutation in the NF1 gene but highly variable disease phenotypes revealed considerable variation between twins in DNA methylation at the NF1 gene125.

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