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Question
Question: To what extent are genetic and environmental risk factors shared between the nine symptomatic criteria of diagnostic and classficiation of mental diseases (DSM)-IV major depression?
People: There were 7500 adult twins (3084 twin pairs) of white ethnicity. The study included 503 identical female–female (FF) twin pairs; 346 non-identical FF twin pairs; 703 identical male–male (MM) twin pairs; 485 non-identical MM twin pairs; 1047 male–female (MF) twin pairs; and 1325 twins without their cotwin. FF twins born between 1934 and 1974 were identified using the Virginia Twin Registry, and had responded to an initial questionnaire between 1987 and 1988. MM and male-female (MF) twins born between 1940 and 1974 were sampled from the registry records and completed initial telephone interviews in 1993–1996.
Setting: Virginia Twin Registry, USA.
Risk factors: Genetic and environmental influences (shared and unique). Zygosity was assessed using discriminate function analyses based on standard twin questionnaires with validation of DNA genotype in 496 twin pairs. Multivariate twin models were used to identify which factors (additive genetic, shared and unique environment) were common to all nine DSM-IV criteria for major depression (MD).
Outcomes: Lifetime MD, as defined by the nine symptom criteria of DSM-IV (depressed mood, loss of interest/pleasure, weight or appetite change, insomnia or hypersomnia, psychomotor changes, fatigue, worthlessness/guilt, problems of concentration, suicidal ideation). Participants were assessed using the Structured Clinical Interview for DSM-III-R adapted to include DSM-IV criteria. If the participant answered affirmatively to having one or more episodes where they ‘felt depressed or down’ and/or were ‘uninterested in things or unable to enjoy things [they] used to’, individual questions were then asked about the remaining symptom criteria for MD for the episode when ‘things were at their worst’. Assessments for FF twins were made at interviews in 1992–1995; MM and MF twin assessments were conducted in 1994–1998.
Methods
Design: Prospective cohort study.
Follow-up period: FF twins, 4–8 years; MM and MF twins 1–5 years.
Main results
Just over half of the twins (n=3829, 51.1%) did screening positive for depression and were excluded from the remaining assessment. Of those who screened positively and were questioned on the remaining DSM-IV criteria, almost all reported depressed mood (96.4%) while the next most common symptoms were loss of interest/pleasure (79.8%) and insomnia or hypersomnia (71.8%). In the best-fit model, three genetic common factors, one common environmental and three unique environmental common factors, plus criterion specific unique genetic and environmental factors had influence on MD. One genetic factor had strong loadings for four psychomotor and cognitive symptoms of MD (psychomotor changes, feelings of worthlessness, difficulty concentrating and suicidal ideation). The second genetic factor had high loadings on core mood symptoms (sad mood, loss of interest/pleasure and feelings of worthlessness) and the third factor on neurovegetative-related symptoms (sleep difficulties and fatigue). The effects of shared environmental factors on the nine DSM-IV criteria were only modest.
Conclusions
Different genetic factors may influence the mood, cognitive and neurovegetative symptoms of DSM-IV major depression, rather than there being a single dimension of genetic risk.
Abstracted from
Commentary
Depression is a very common disorder that, in terms of economic burden worldwide, is surpassed only by heart disease. Unlike heart disease, there is no consensus as to how depressive disorder might usefully be classified into specific subgroups and precise knowledge about aetiology is missing. What is known is that depression shows moderate to substantial heritability and depressive episodes are often triggered by environmental adversity.
Recently, huge collaborative international efforts have been made in combining data from genome-wide association studies (GWAS) to pin down and identify specific genes that might predispose a person to depression. In contrast, with the successes of GWAS in schizophrenia and bipolar disorder, the results have been disappointingly negative.1 This has helped to reopen the debate as to whether depression is one disorder with cases differentiated only by severity, as in ‘official’ classifications such as International classification of diseases ICD-10 and DSMIV or whether, like heart disease, depressive disorder should be treated as an umbrella term for many different entities. The paper by Kendler and colleagues sheds new light on this question, and strongly suggests that there are at least three different dimensions, with somewhat independent genetic underpinnings.
This is the first study of its kind using sophisticated analysis of twin data, but it is in part supported by an earlier study of siblings that suggests independent familial dimensions.2 The current approach in treating depression with medication is crude, a ‘one size fits all’ approach; the choice of which antidepressant to use does not generally have a rational basis. This, in turn, reflects the idea that depression is a single disorder. Kendler and colleagues challenge this view, and are supported by recent findings from a multicentre European trial, genome-based therapeutic drugs for depression (GENDEP), where three dimensions of depression were found and high loadings on cognitive and observed symptoms of depression predicted response to a selective serotonin reuptake inhibitor, while neurovegetative symptoms predicted response to nortriptyline.3
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Files in this Data Supplement:
- Data supplement 1 - Online supplement
Footnotes
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Sources of funding National Institutes of Health.
Footnotes
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Competing interests None.