Genetic Contribution in Major Depressive Disorder

Question:

"What is the extent of genetic contribution in MDD? I thought that it was mostly a stress-induced condition."

Vladimir Maletic, MD:

Major depressive disorder (MDD) is believed to be a product of interaction between several vulnerability genes and environmental adversity (this includes stress, trauma, and also medical illness).1

There are differing opinions about the relative contribution of genes versus environment. Before one broaches the topic of etiopathogenesis, it would be prudent to clarify the definition of MDD as a diagnostic category. Recent research suggests that MDD is not a single biological entity, but rather a grouping of biologically diverse conditions with similar symptomatic manifestations. Therefore, any statement made about the origins of MDD is by necessity probabilistic: it may apply to a significant number of individuals afflicted by MDD, but certainly not to all of them.1

The body of genetic research into origins of MDD would indicate a strong influence of heritability. While estimates of heritability range from 30% to 50%, it is clear that environment has at least an equal, if not greater, contribution.2 Genetic pattern of MDD inheritance is a very complex one. Vulnerability towards MDD is conferred by interactions of multiple different genes with differing magnitude of effect. Estimates vary from dozens of genes with moderate-to-mild effect on one end, to a cumulative impact of thousands of genes with minor individual contributions at the other extreme. Research into MDD genetics is further confounded by complicated gene interactions (a process also known as epistasis): two “vulnerability” genes may have a synergistic effect, amplifying each other’s influence, or their contributions may cancel each other out!1

Relatively recent research has focused on the influence of epigenetic modulation in etiology of MDD. It appears that our life experiences have a profound impact on regulation of gene expression. Early life experience seems to be particularly influential in this regard. A study by Etringer et al.3 has found that stressful experiences in pregnancy had a profound effect on child’s hypothalamic-pituitary-adrenal function in a stressful condition, noticeable even two decades later!

—Vladimir Maletic, MD

References

1. Maletic V, Raison CL. Neurobiology of depression, fibromyalgia and neuropathic pain. Front Biosci . 2009;14:5291-5318.
2. Merikangas K, Yu K. Genetic epidemiology of bipolar disorder. Clin Neurosci Res . 2002;2(3-4):127-141.
3. Entringer S, Kumsta R, Hellhammer DH, et al. Prenatal exposure to maternal psychosocial stress and HPA axis regulation in young adults. Horm Behav . 2009;55(2):292-298.