Cambios genéticos en la esquizofrenia y la bipolaridad

Epigenetic clue to schizophrenia and bipolar disorder

•  by Andy Coghlan
• Magazine issue 2832. 
• For similar stories, visit the Mental Health , The Human Brain and Genetics Topic Guides

El presente artículo, dedicado a una especialidad apasionante, la psiquiatría molecular, pretende desentrañar las bases genéticas de la esquizofrenia y el trastorno bipolar. Los investigadores han utilizado comparaciones entre gemelos, es decir, personas cuyo ADN es idéntico. Dichos estudios han puesto de manifiesto la importancia de la estructura genética, y sobre todo de la actividad del ADN. Se tienen en cuenta los cambios en su medio (en el entorno del ADN o genes). Algunos genes y las variaciones en su medio parecen ser determinantes en el desarrollo de dichas patologías psiquiátricas. Aquí se utiliza el término "cambios epigenéticos" que son aquellos que, sin alterar la secuencia del ADN, (ATCTG) dejan señales químicas en los genes y el resultado es que modifican su grado de  actividad. Los cambios epigenéticos se observaron en genes ya vinculados al trastorno bipolar y la esquizofrenia. No hay que entender que  se sabe todo sobre el origen molecular de dichas enfermedades. Pero al menos se han identificado el papel de las modificaciones en el funcionamiento del genoma (cambios epigenéticos) relacionables con el desarrollo de dichas condiciones patológicas. 

El presente trabajo apareció reportado en "New Scientist" pero los originales son de "Human Molecular Genetics".

"TWIN studies have shown that people with schizophrenia and bipolar disorder have changes in gene activity caused by their environment. The finding provides the strongest evidence yet that such gene changes might cause the conditions.

Jonathan Mill at the Institute of Psychiatry, King's College London, and colleagues scanned the genome of 22 pairs of identical twins - chosen because one twin in each pair was diagnosed with schizophrenia or bipolar disorder.

As expected, the twins had identical DNA. However, they showed significant differences in chemical "epigenetic" markings - changes that do not alter the sequence of DNA but leave chemical marks on genes that dictate how active they are. These changes were on genes that have been linked with bipolar disorder and schizophrenia.

Mill's team scanned for differences in the attachment of chemical methyl groups at 27,000 sites in the genome. Methylation normally switches genes off, and de-methylation turns them on.

Regardless of which condition the twin had, the most significant differences, with variations of up to 20 per cent in the amount of methylation, were in the promoter "switch" for a gene called ST6GALNAC1, which has been linked with schizophrenia. Although the function of the gene isn't fully established, it is thought to add sugars to proteins, which could alter the speed or specificity of their usual function.

The findings tallied with another study which involved screening post-mortem brain tissue from people who had had some form of psychosis. The researchers found differences of up to 25 per cent in methylation of the same gene compared with controls.

The twin scans also revealed methylation differences in GPR24, a gene previously linked to bipolar disorder. One gene, called ZNF659, showed over-methylation in people with schizophrenia and under-methylation in those who were bipolar, suggesting that the conditions might result from opposing gene activity (Human Molecular Genetics, DOI: 10.1093/hmg/ddr416).

"We know these disorders are related, and there are clinical features shared by both," says Mill. "But our scan suggests there are some genes that might be overactive in one disease and underactive in the other."

Mill says twins would need to be scanned regularly throughout life to find out whether epigenetic changes precede the onset of the disorders. It might be possible then to link the alterations to environmental changes such as stressful events or diet, which have been shown to cause inheritable epigenetic changes in mice. 

"I feel this is the best evidence yet, from human studies, supporting the hypothesis that epigenetic mechanisms may drive psychiatric disorders," says David Sweatt, who studies epigenetics at the University of Alabama and was not involved in the study.