Figure 1

Modeling the genetic components of variance. (a, b) The idea of the multifactorial liability-threshold model is, first, that the actual discontinuous distribution of risk (a) (estimates given for schizophrenia risk to monozygotic twins (MZ) and first and second degree relatives of affected people) can be modeled as a continuous distribution of 'liability' (b). Second, at the extreme end of the normal distribution of 'liability', the cumulative genetic burden of risk alleles suddenly passes a tipping point (from n alleles to n + 1 alleles), triggering pathogenicity (b). (c) Increased risk to relatives can be modeled with a distribution of risk allele load that is shifted to the right. If n is small (0 or 1, for example), then the idea of a threshold of burden makes sense (for example, when there are dominant or recessive alleles). If n is supposed to be in the hundreds or even the thousands, this scenario becomes rather fanciful.