A strategy to home-in on polygenes influencing susceptibility to anxiety

Genetic influences on susceptibility to neurotic disorders appear to consis t of additive polygenes, with collective heritability of 30-50 per cent, de termining comorbidity between specific disorders rather than the latter dir ectly. Such susceptibility can be measured by questionnaire, e.g. the Eysen ck Neuroticism (N) scale. N scores show a normally distributed variation ac ross the population, with elevated values but no step change in clinical gr oups. Recent developments in allying the methods of statistical and molecul ar genetics open the way 60 the location and eventual cloning of polygenes underlying such quantitative traits. We have recently (Flint ct al., 1995, Science, 268, 1432-1435) applied these methods to a population of F-2 mice derived from two inbred strains selectively bred to display extremes on a p utative rodent homologue of human Neuroticism (emotionality), identifying t hree quantitative trait loci (QTLs) showing pleiotropic association with se veral different behavioural trait markers and collectively accounting for a ll the additive heritable variance of the trait. We aim to take this result further as follows. (1) Studies of F-2 rats will determine whether QTLs fo r emotionality in this species are syntenous to those in the mouse. (2) Stu dies of sib-pairs showing concordance versus discordance for extreme N scor es will locate human QTLs for Neuroticism and establish whether they are sy ntenous with rodent QTLs for emotionality. (3) If rodent-human synteny is e stablished, it will be feasible in principle to clone the genes and determi ne their function in rodents, although in practice this remains a difficult problem. Copyright (C) 1999 John Wiley & Sons, Ltd.