S003329171800377Xjra 1..9

Background. Vulnerability to depression can be measured in different ways. We here examine how genetic risk factors are inter-related for lifetime major depression (MD), self-report current depressive symptoms and the personality trait Neuroticism. Method. We obtained data from three population-based adult twin samples (Virginia n = 4672, Australia #1 n = 3598 and Australia #2 n = 1878) to which we fitted a common factor model where risk for ‘broadly defined depression’ was indexed by (i) lifetime MD assessed at personal interview, (ii) depressive symptoms, and (iii) neuroticism. We examined the proportion of genetic risk for MD deriving from the common factor v. specific to MD in each sample and then analyzed them jointly. Structural equation modeling was conducted in Mx. Results. The best fit models in all samples included additive genetic and unique environmental effects. The proportion of genetic effects unique to lifetime MD and not shared with the broad depression common factor in the three samples were estimated as 77, 61, and 65%, respectively. A cross-sample mega-analysis model fit well and estimated that 65% of the genetic risk for MD was unique. Conclusion. A large proportion of genetic risk factors for lifetime MD was not, in the samples studied, captured by a common factor for broadly defined depression utilizing MD and selfreport measures of current depressive symptoms and Neuroticism. The genetic substrate for MD may reflect neurobiological processes underlying the episodic nature of its cognitive, motor and neurovegetative manifestations, which are not well indexed by current depressive symptom and neuroticism. The term ‘Affective Disorders’ is used for a group of mental diseases with a primary disturbance of affect from which all the other symptoms (are) . derived . The illness has a secondary characteristic: periodicity. In typical cases, . depression of mood alternates with free intervals in which there is a complete return to the normal [(Mayer-Gross et al., 1954) p. 187]. The focus of research in the genetics of major depression (MD) has shifted in recent years from genetic-epidemiological to molecular genetic designs. As the sample size requirements for genome-wide association or sequencing studies of complex psychiatric disorders like MD have become clearer (Sullivan et al., 2018), questions have arisen about the utility of proxies for the interview-based assessment of lifetime MD that could be collected more cheaply and expeditiously in very large samples. Two such potential proxies are current depressive symptoms and the personality trait of Neuroticism (Eysenck, 1953; Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium et al., 2018). Both of these measures can be easily collected by self-report and have been shown to be substantially correlated with each other and with a clinical diagnosis of MD in a range of samples (Boyd et al., 1982; Hirschfeld et al., 1983; Jardine et al., 1984; Bech et al., 1986; Fergusson et al., 1989; Kendler et al., 1993; Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium et al., 2018). For genetic studies, however, the question is not the degree of phenotypic resemblance but rather the degree to which these measures reflect genetic risk factors for MD. Prior twin and molecular genetic studies have suggested modest to moderate genetic https://doi.org/10.1017/S003329171800377X Downloaded from https://www.cambridge. org/core. UQ Library, on 22 May 2019 at 01:49:29, subject to the Cambridge Core terms of use, available at https://www.cambridge. org/core/terms. correlations between lifetime MD and neuroticism (Kendler et al., 2006; Kendler and Myers, 2010; Lo et al., 2017) and current selfreport depressive symptoms (Foley et al., 2001). Both depressive symptoms and Neuroticism are measures of negative affect which have been central to the concept of MD since its articulation as a distinct psychiatric disorder in the 19th century (Berrios, 1982, 1988; Jackson, 1986). However, as pointed out in the quote above (Mayer-Gross et al., 1954), MD has another critical dimension – its periodicity – which was central to Emil Kraepelin’s concept of manic-depressive illness from which our concept of MD derives (Kraepelin, 1990; Trede et al., 2005) and is not well captured by these self-report measures. If the genetic predisposition to experience periodic mood states (and the associated neuro-vegetative and cognitive changes) is not identical to the more generic vulnerability of negative affect, these self-report measures will not capture the full spectrum of genetic risk for MD. In this paper, we address this question using three large population-based twin samples in which lifetime MD was assessed at personal interview along with self-report levels of current depressive symptoms and Neuroticism assessed by self-report. The model that we employ (Fig. 1) assumes a latent liability to ‘Broadly Defined Depression’ which is in turn indexed by three measures: lifetime MD, depressive symptoms and Neuroticism. Results of this model permit us to decompose the sources of genetic and environmental risk for these three indices into those that arise from the shared latent liability to broad depression v. those specific to the individual measures. Our focus here is on the results for MD, that is the degree to which genetic risk factors for MD result from genetic effects specific to MD v. from genetic risk factors reflecting broad defined depression.