What is the etiology of depression (Major Depressive Disorder)?

Genetic predisposition explains the etiology of depression

Question: What is the etiology of depression (Major Depressive Disorder)?
Position1 of 3›: Depression has a biological etiology
Argument‹2 of 3›: Genetic predisposition explains the etiology of depression

Genetic researchers argue that there is an increased chance of developing depression based on one’s genetic makeup. This genetic predisposition results from specific genetic variations that are inherited from parents. Many twin, family, and adoption studies support this view.

The argument

Genetic researchers argue that genetic predisposition can explain the development of Major Depressive Disorder (MDD). A genetic predisposition to depression means an increased likelihood of developing depression based on a person’s genetic makeup. This genetic presentation results from specific genetic variations that are often inherited from a parent. These genetic variations contribute to the development of depression but do not directly cause it. Some people with a predisposing genetic variation will never get the disease while others will, even within the same family. Therefore, many psychologists lean towards gene-environment interaction. Environmental factors determine which genes are turned on and off. Genes that mediate stress response and synaptic plasticity can impact the vulnerability risk for MDD. Many family, twin, and adoption studies point to a genetic basis for depression. For example, Caspi et al. (2003) investigated the relationship between stressful life events and depression in individuals with different alleles of the 5-HTT gene. They concluded that the 5-HTT gene influences an individual’s reaction to stressful life events. Genetic predisposition can moderate a person’s reactivity to stressful life events –an instance of gene-environment interaction. Specific alleles of 5-HTT increase the vulnerability to depression. Similarly, Kendler et al. (2006) determined the level of heritability of depression through a longitudinal twin study. The estimated heritability of major depression for the entire sample was 38%. Researchers demonstrated that genes play a role in depression. They also found a sex difference in the heritability of depression; it is higher in females than in males. Overall, genetic predisposition can explain the etiology of depression. Empirical evidence shows that depression is a heritable mental disease.

Premises

[P1]A genetic predisposition—inherited genetic variations affecting stress response and synaptic plasticity—raises the likelihood of developing Major Depressive Disorder, interacting with environment to turn genes on and off. [P2] Family, twin and adoption studies support this: Caspi et al. (2003) found 5-HTT alleles influence reactivity to stressful events, and Kendler et al. (2006) estimated depression's heritability at 38%, higher in females. [C] Therefore genetic predisposition explains the etiology of depression, showing depression has a biological etiology.

Counter-arguments

The field of psychiatric genetics has failed to find common gene variants of large effect in the development of depression. Many of the family, twin, and adoption studies supporting this argument have too small patient cohorts. No findings have been consistently replicated as well. Additionally, the effects of genetic variants identified such as 5-HTT, are very weak, with odds ratios of 1.0 to 1.2. The impact of lifestyle and environmental factors seem to be larger than genetic predisposition. Risch et al. (2009) found in their meta-analysis that there is no correlation between 5-HTT variation and depression. Therefore, the reliability of Caspi et al. (2003) is very low. Establishing such a concrete relationship between genes and depression as in the argument is very problematic. It may lead to genetic determinism –the attribution of the formation of traits to genes where genes are ascribed more causal power than what scientific consensus suggests. Researchers should emphasize that the relationship is only correlational and not causal.

Rejecting the premises

[Rejecting P1] The mechanism is described in terms general enough to be compatible with almost any finding. "Inherited variations affecting stress response and synaptic plasticity" names plausible pathways rather than identified ones, and the closing clause — that genes interact with environment to switch on and off — concedes that predisposition is not doing the explaining by itself. [Rejecting P2] The two studies are weaker support than presented. The Caspi gene-environment interaction is among the best-known findings in psychiatric genetics not to have survived replication, including in the large meta-analysis the counter cites, and later genome-wide work has not supported candidate-gene results of this kind. A heritability estimate of 38% is also widely misread: it partitions variance within a population, so on its own terms it says most of the variation is not attributable to inherited differences. [Rejecting C] The conclusion overstates twice. "Explains the etiology" is not established by a partial statistical contribution, and biological etiology is the broader claim — it could be argued from neuroendocrine or inflammatory evidence that these premises never reach.

Proponents cited

Myrna Weissman
“The rates of psychopathology are highest in grandchildren of parents and grandparents with a moderately to severely impairing depression. Anxiety disorders are the early sign of psychopathology in the young grandchildren.”
Avshalom Caspi
“Individuals with one or two copies of the short allele of the 5-HTT promoter polymorphism exhibit more depressive symptoms, diagnosable depression, and suicidality in relation to stressful life events than individuals homozygous for the long allele. This epidemiological study thus provides evidence of a gene-by-environment interaction, in which an individual's response to environmental insults is moderated by his or her genetic makeup.”
Falk W. Lohoff
“Genetic factors play important roles in the development of MDD, as indicated by family, twin, and adoption studies, and may reveal important information about disease mechanisms.”
Kenneth Kendler
“In the largest sample to date, lifetime major depression was moderately heritable, with estimates similar to those in prior studies. In accord with some but not other previous investigations, this study suggests both that the heritability of major depression is higher in women than in men and that some genetic risk factors for major depression are sex-specific in their effect.”