Steven O. Moldin

Current perspectives on the genetics of unipolar depression

Evidence regarding the heritability of unipolar depression is evaluated. The data reviewed here support the involvement of genetic factors in the etiology of unipolar depression and its suitability for independent genetic inquiry, despite our inability to identify the mode(s) of transmission or identify a candidate locus. Continued progress in testing etiologic hypotheses requires (a) clarification of the mode of transmission; (b) resolution of phenotypic and potential genotypic heterogeneity; (c) general agreement on a “gold standard” for assessment of the unipolar phenotype; (d) the continued application of available quantitative methods to take into account the effects of ascertainment bias, sex effects, cohort effects, and variable/late age at onset; and (e) incorporation of quantitative indicators correlated with liability in multivariate analysis to improve the stability/validity of phenotypic determinations in segregation and linkage analysis. We present several recommendations regarding the extension of current methodologies in human population and quantitative genetics to help resolve these issues.

Latent structure of DSM-III-R Axis II psychopathology in a normal sample.

The Personality Disorder Examination was administered to 302 normal controls in the New York High-Risk Project in order to elicit Axis II diagnoses (revised 3rd edition of the Diagnostic and Statistical Manual of Mental Disorders; American Psychiatric Association, 1987) and quantitative dimensions of psychopathology. LISREL confirmatory factor analysis was used to evaluate the Axis II hypothesis of 3 orthogonal factors. There was considerable overlap among personality disorders. The best fitting LISREL model was of 3 oblique factors that were different for male and female subjects. Given that our choice of variables to constrain in order to mathematically identify our models was partially based on analysis of intercorrelations in our data set, our methods were not purely confirmatory. We present our results not to confirm specific hypotheses but to generate explicit hypotheses that can be tested in independent samples.

Psychometric deviance in offspring at risk for schizophrenia: I. Initial delineation of a distinct subgroup

Psychometric signs from the Minnesota Multiphasic Personality Inventory (MMPI), which measure substantive disturbances in thinking, social relatedness, volition, and affective expressivity, were evaluated as possible indicators of transmissible liability specific to schizophrenia. Children of three criterion groups in the New York High-Risk Project--offspring at high risk (HR) for schizophrenia, psychiatric comparison (PC) offspring at risk for affective disorders, and normal comparison (NC) offspring not at augmented risk for psychiatric morbidity--were tested before the expression of schizophrenic psychopathology, when the subjects ranged in age from 13 to 26 years. The rate of psychometric deviance in the HR group (23%) was significantly higher than that in either the PC (7%) or NC (2%) groups, and profile analyses showed that the HR subgroup could be delineated by qualitative distinctions in personality functioning. Our results support the utility of MMPI indicators in etiologic investigations of schizophrenia.