The nascent field of epigenetics has been helpful in elucidating upon other polygenic traits and diseases. Thus it only seems logical to apply it to the study of schizophrenia, a chronic and debilitating illness with a sundry of risk factors. In his widely cited 2013 article, Dr. Thomas Insel defines schizophrenia as “a collection of signs and symptoms of unknown aetiology, predominantly defined by observed signs of psychosis.” The NIMH estimates it affects 1 out of 100 people. Yet in spite of its costs to society, the unfathomable suffering it inflicts upon those who live with it, and the steady progress researchers have made in the last two decades, its exact causes are still not certain.
Depending on which study one chooses to cite, monozygotic twin concordance for schizophrenia falls somewhere between 41% and 65%. Although high, one would expect the numbers to approach 100% if schizophrenia was entirely hereditary. This confirms earlier findings by Fraga and Ballestar regarding epigenetic changes in twins. While their methylation profiles are normally quite similar at birth, over time, markers change thanks to chance and environment. Presumably, however, they are living in the same house, eating the same meals and being exposed to very similar stimuli. This means chance may play a larger role than environment. Alas, in spite of science’s unquenchable thirst for identical twins reared apart, it is still a tragically uncommon occurrence. Petronus and Oh speculate that the changes in transcription and translation is “stochastic.” They even go so far as to assert that stochastic epigenetic changes may be a more important cause of phenotypic differences than environmental effects. The implications of this thought go well beyond the study of schizophrenia, but that is a topic for another day.
Increasingly, researchers are interested in the influence the intrauterine environment has on the aetiology of neurodevelopmental disorders like schizophrenia. This can be quite different for two fetuses, even for two sharing the same womb. Folate has been singled out as especially important in the epigenetic imprinting of cells and organs. As Kim wrote in his paper on this venerable B vitamin, “embryonic and fetal exposure to nutrients, which are mainly maternally-derived, can affect this dramatic epigenetic phenomenon, thereby affecting fetal development and even later life health status.” Most people begin experiencing symptoms between the ages of 16 and 30 (most commonly between 18 and 25). Onset in people over 45 and under 16 is rare. Can subtle (or not so subtle) events during gestation predispose one twin to a neurodevelopmental disorder while leaving the other unaffected? If so, is it possible to screen for these events during adolescence? Will it be possible to prevent? Remember, epigenetic changes are reversible (compared with the sequences themselves, anyway).
The neurology of schizophrenia is becoming better understood. Gogtay and Sporn observed a dramatic loss of cortical brain matter in children with early onset SZ. This pruning process is long and normally not complete until one’s mid-twenties. The prefrontal cortex, the seat of our better judgment, is the last region to mature. Rapoport found “a significant decrease in cortical gray matter volume [in] healthy controls in the frontal (2.6%) and parietal (4.1%) regions.” The child schizophrenics, however, showed decreases of 10.9% and 8.5% in these regions. SZ sufferers often miss developmental milestones growing up. The IQ’s of SZ patients is measurably lower at an early age. Growing up they consistently lag behind their peers “on tests indexing processing speed, attention, visual-spatial problem solving ability, and working memory.” This is not surprising given the relationship between schizophrenia and genes associated with neuronal proliferation and synapse formation. Guilmatre indicted a number of rare copy number (CNV) variations in the development of autism spectrum disorders, schizophrenia and certain mental handicaps. Though these findings are far from conclusive, perhaps similar pathways are involved in the genesis of more than one disorder. What proteins and neurotransmitters are responsible for these physiological alterations? Is the under or overproduction of any of these crucial chemicals responsible for some of the symptoms experienced by SZ sufferers?
Neurochemical imbalances are the alleged culprits, but possessing the SZ correlated alleles thus far gives one no “more than twice the risk in susceptibility for schizophrenia [observed] in [the] general population [nota bene: doubling 1% does yield an inordinately high probability].” Glutamate decarboxylase 1 (GAB1) is a gene that encodes for an enzyme necessary for the production of glutamate. Reelin, a glycoprotein associated with neuroplasticity, is another molecule of interest. More than once it has been found that levels of reelin and glutamate decarboxylase 7 are lower in the cortical and hippocampal tissue of schizophrenics. Inhibiting Brain-Derived Neurotrophic Factor (BDNF) induces symptoms similar to schizophrenia. It is known to modulate learning, memory and susceptibility to trauma. Rats in which prenatal stress was used to induce schizophrenic behavioral patterns displayed a significant increase in DNA methyltransferase 1 in their cortex and the hippocampus, but not their cerebellum. Epigenetic alterations in GABAergic and glutamergic systems were also noted. The BDNF gene had been hypomethylated.
In the same study scientists found no substantial differences in histone deacetylases (HDAC) in their postmortem examinations of the rat’s brains. Yet a Korean group found a link between schizophrenia and HDAC4 in living human patients. Another team researched valproate as a means of reawakening silenced reelin promoter regions in the mice with supplemental methionine. According to their research “valproate enhances acetylated histone 3 content, and prevents MET-induced reelin promoter hypermethylation, reelin mRNA downregulation, and PPI and SI deficits.” Promising? Yes, but the road to a cure is a long one. Let us hope the men and women of science continue to do all they can to treat this terrible disease.
References:
Abdolmaleky, Hamid Mostafavi, et al. “DNA hypermethylation of serotonin transporter gene promoter in drug naïve patients with schizophrenia.” Schizophrenia Research 152.2 (2014): 373-380.
Dempster, Emma L., et al. “Disease-associated epigenetic changes in monozygotic twins discordant for schizophrenia and bipolar disorder.” Human Molecular Genetics (2011): ddr416.
Dong, Erbo, et al. “BDNF Epigenetic Modifications Associated with Schizophrenia-Like Phenotype Induced by Prenatal Stress in Mice.” Biological Psychiatry (2014).
Fraga, Mario F., et al. “Epigenetic differences arise during the lifetime of monozygotic twins.” Proceedings of the National Academy of Sciences of the United States of America 102.30 (2005): 10604-10609.
Gogtay, N. et al. Comparison of progressive cortical gray matter loss in childhood-onset schizophrenia with that in childhood-onset atypical psychoses. Arch. Gen. Psychiatry 61,17–22 (2004).
Guilmatre, A. et al. Recurrent rearrangements in synaptic and neurodevelopmental genes and shared biologic pathways in schizophrenia, autism, and mental retardation. Arch. Gen. Psychiatry 66, 947–956 (2009).
Insel, Thomas R. “Rethinking schizophrenia.” Nature 468.7321 (2010): 187-193. Full article available on the NIMH’s website:
http://www.nimh.nih.gov/about/director/bio/publications/rethinking-schizophrenia.shtml
Kim, Kyong-chol, Simonetta Friso, and Sang-Woon Choi. “DNA methylation, an epigenetic mechanism connecting folate to healthy embryonic development and aging.” The Journal of Nutritional Biochemistry 20.12 (2009): 917-926.
Kim, Tae, et al. “Association of histone deacetylase genes with schizophrenia in Korean population.” Psychiatry Research 178.2 (2010): 266-269. http://www.sciencedirect.com/science/article/pii/S0165178109001929
Labrie, Viviane, Shraddha Pai, and Arturas Petronis. “Epigenetics of major psychosis: progress, problems and perspectives.” Trends in Genetics 28.9 (2012): 427-435.
NIMH. “Schizophrenia.” NIMH RSS. National Institute of Health, n.d. Web. 05 Nov. 2014.
Paus, T., Keshavan, M. & Giedd, J. N. Why do many psychiatric disorders emerge during adolescence? Nature Rev. Neurosci. 9, 947–957 (2008).
Petronis, Arturas, et al. “Monozygotic twins exhibit numerous epigenetic differences: clues to twin discordance?.” Schizophrenia Bulletin 29.1 (2003): 169-178.
Rapoport, J. L. et al. Progressive cortical change during adolescence in childhood-onset schizophrenia. A longitudinal magnetic resonance imaging study. Arch. Gen. Psychiatry 56,649–654 (1999).
Reichenberg, A. et al. Static and dynamic cognitive deficits in childhood preceding adult schizophrenia: a 30-year study. Am. J. Psychiatry 167, 160–169 (2010).
Saradalekshmi, Koramannil Radha, et al. “DNA Methyl Transferase (DNMT) Gene Polymorphisms Could Be a Primary Event in Epigenetic Susceptibility to Schizophrenia.” PloS One 9.5 (2014): e98182.
Tolosa, Amparo, et al. “FOXP2 gene and language impairment in schizophrenia: association and epigenetic studies.” BMC Medical Genetics 11.1 (2010): 114.
Tremolizzo, Lucio, et al. “Valproate corrects the schizophrenia-like epigenetic behavioral modifications induced by methionine in mice.” Biological Psychiatry 57.5 (2005): 500-509.
Xu, Bin, et al. “Strong association of de novo copy number mutations with sporadic schizophrenia.” Nature Genetics 40.7 (2008): 880-885.
