Schizophrenia and Major Depressive Disorder

Question:

“Is it true that schizophrenia and major depressive disorder have shared genetic underpinning?"

Vladimir Maletic, MD:

Yes, it appears that schizophrenia and major depressive disorder (MDD) have some shared “vulnerability” genes. Before we continue with the discussion of the overlapping genetics of MDD and schizophrenia it is appropriate to point out that these conditions are a byproduct of an interaction between genetic predilection and environmental adversity. Schizophrenia has higher heritability than MDD (defined as portion of phenotypical variance explained by genetics). ^1,2  Heritability estimates are based on identical twin concordance rates: if one of the twins has the condition, what are the odds that the other one will also have it? Heritability estimates for schizophrenia range from 50% to 90%; usually literature quotes 70% as an approximation. ¹  Although population-based twin studies place heritability of MDD in the 30% to 40% range, a more methodologically advanced hospital-based study has found MDD heritability in excess of 70%! ^2,3

Now may be a good time to mention that “genetics” represent a complex category comprised of several interrelated processes. Genes tend to be organized into so called “genetic networks,” with interdependent activity and products (structural proteins, enzymes, etc). ³  Genes and their products tend to interact with each other through a process of genetic epistasis, either potentiating or diminishing each other’s effects. Activity of the genes can also be altered through epigenetic modulation; they can be either turned “on” by acetylation of the histone or silenced through histone methylation.

Many of the candidate genes for schizophrenia that code for products regulating monoamine signaling (catechol-O-methyltransferase [COMT], monoamine, and tyrosine hydroxylase) are also considered susceptibility genes for MDD. ^3,4,5  Monoamines have a major role in modulating gamma-aminobutyric acid (GABA) and glutamate signaling in frontal cortico-limbic circuitry, which is responsible for regulation of executive function, mood, pain, and stress response. ⁵  Additionally, genes that regulate GABA and glutamate trafficking are also on the candidate list for MDD and schizophrenia. ^4,5

Neuroplasticity allows our brains to “rewire” themselves in response to sustained change in pattern of activity in a part of neural network, often reflecting an important learning or a change in our environment. Neurotrophins, including brain-derived neurotrophic factor (BDNF), are the key regulators of neuroplasticity. Genes coding for BDNF are implicated in both schizophrenia and MDD. In order for neural signaling to flow smoothly, neurons and astroglia cells need to appropriately collaborate with each other. Aside from removing excessive neurotransmitters from the synapse (thus regulating the signal to noise ratio), glia cells also match the blood perfusion rate with the level of synaptic activity and provide nerve cells with auxiliary energy (lactate) in times of increased need. ⁵  D-serine is one of the “glia-transmitters” used in the dialogue between glia and nerve cells. It is also an important modifier of N-methyl-D-aspartate (NMDA)-mediated glutamate signaling and, indirectly, neuroplasticity. I think that you have already guessed: it has been identified as one of the genes conferring predilection for both schizophrenia and MDD. ^2,4

In summary, genes that regulate different interlinked aspects of neural function from monoamine regulation to GABA and glutamate signaling, neuroplasticity, and successful neuron-glia dialogue are implicated in both disease states. There are some more unlikely suspects as well: genes involved in immune function and regulation of inflammatory response are also considered as candidate genes in both MDD and schizophrenia. ^4,5

More recent genetic theories have focused on the role of rare copy number variants (CNVs) in pathogenesis of psychiatric illness. Structural variations reflected in loss or gain of millions of base pairs of DNA sequences are believed to represent more than 5% of human genome. ⁶  Rare CNVs have been identified in patients with schizophrenia and may be associated with elevated risk in more neurodevelopmental forms of this disease. ⁶  A better understanding of the role that CNVs play in pathogenesis of psychiatric disorders may shed light on subtypes of conditions and spectrums of disease.

Finally, whether a condition becomes manifest or not may depend on efficient silencing of nuisance genes. We have already identified methylation as an important modifier of gene expression. In order for methylation to proceed smoothly, genes regulating methyl-donor availability need to function properly. Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme determining methyl group availability. Each copy of its genetic 677T variant conveys a 35% reduction in MTHFR activity and therefore a lesser ability to silence other pesky genes. ⁷  Val copy of COMT gene is associated with more efficient breakdown of dopamine and norepinephrine in the prefrontal cortex and consequently perhaps more vulnerable executive function. It may be advantageous to keep this gene silenced.

Patients with schizophrenia homozygous for the COMT Val allele who were also misfortunate to have a dysfunctional T variant of MTHFR gene predictably performed more poorly on tests of executive function such as Wisconsin Card Sorting Task. ⁷  In a separate study, TT carriers of MTHFR gene were 22% more likely to have current or a history of depression. ⁸ Furthermore, a study of pregnant women has found that presence of MTHFR T-variant was correlated with greater severity of depression. ⁹  A greater degree of maternal depression was also associated with lesser methylation (silencing) of dysfunctional 5HTT (serotonin transporter) genes in both mothers and infants! This concerning turn of events may help us understand how  genetic epistasis  and  epigenetic modulation  may play a role in developmental programming of an infant.

–Vladimir Maletic, MD

References

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3. McGuffin P, Perroud N, Uher R, et al.  The genetics of affective disorder and suicide. Eur Psychiatry.  2010;25(5):275-277.
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