Childhood adversity, epigenetics, and hippocampal volume

September 26, 2014 · Posted in Genetics, Risk Factors · Comment 

upset boy

At the 2014 meeting of the International College of Neuropsychopharmacology, researcher Booij reported that in humans, there is an interaction between adversity experienced during childhood, and an epigenetic variation in the short form of the serotonin transporter (5HT-T ss, or SLC6A4), which can influence hippocampal volume during depression.

Epigenetics refers to environmental influences on the way genes are transcribed. The impact of life experiences such as stress is not registered in DNA sequences, but can influence the structure of DNA or tightness of its packaging. Early life experiences, particularly psychosocial stress, can lead to the accumulation of methyl groups on DNA (a process called methylation), which generally constricts DNA’s ability to start transcription (turning on) of genes and the synthesis of the proteins the genes encode. DNA is tightly wound around proteins called histones, which can also be methylated or acetylated based on events in the environment.  When histones are acetylated, meaning that acetyl groups are attached to them, DNA is wound around them more loosely, facilitating gene transcription (i.e. the reading out of the DNA code into messenger RNA, which then arranges amino acids in order to construct proteins). Conversely, histone methylation usually tightens the winding of DNA and represses transcription.

Booij followed 33 children who had experienced some form of adversity at a young age until they were 15 or 16, examining methylation of the serotonin transporter in their T cells and monocytes compared to 36 children who had not experienced adversity during childhood. He found that in children who had experienced abuse in childhood, the degree of that abuse was correlated with methylation of the serotonin transporter and was inversely related to the volume of the hippocampus, as measured using magnetic resonance imaging (MRI). Thus, child abuse yields lasting epigenetic effects (methylation of the serotonin transporter) and has anatomical consequences in teenagers, as seen in smaller hippocampi. These data parallel converse findings by Joan Luby et al. published in the journal PNAS in 2012, in which increased maternal warmth directed toward a child aged 4-7 was associated with increased volume of the hippocampus several years later.

Study of Twins Sheds Light on Epigenetic Mechanisms Implicated In Bipolar Disorder

March 26, 2013 · Posted in Risk Factors · Comment 

twins

At the 5th Biennial Conference of the International Society for Bipolar Disorders, H. Sugawara and colleagues reported on a particular example of epigenetics, an emerging field that studies ways that events and substances in the environment affect the structure of DNA. Often methyl or acetyl groups attach to DNA, making it easier or more difficult to transcribe. Sugawara’s group discussed hypermethylation of the serotonin transporter gene in bipolar disorder in an analysis of monozygotic twins discordant for bipolar disorder.

Monozygotic (identical) twins are highly concordant for bipolar disorder, meaning if one has the illness the other is likely to, but this does not occur 100% of the time. Thus, environmental or epigenetic mechanisms could account for the lack of genetic transmission of the illness in the odd cases in which one twin does not develop the illness.

Sugawara’s research group found that DNA hypermethylation of the allele encoding the serotonin transporter occurred in the twins with bipolar illness but not in those without. Once the expression of this particular gene had been identified as a difference between twins with and without bipolar disorder, the researchers examined the gene in non-twin patients with bipolar disorder compared to healthy controls and confirmed that people with bipolar disorder were more likely to have the hypermethylated allele.

The researchers believed that carrying a short form of the serotonin transporter was associated with DNA hypermethylation, and they went on to study the expression of mRNA for the transporter in bipolar patients carrying the short form of the allele. They found that DNA methylation was also higher at the serotonin transporter site in postmortem brains of bipolar patients.

Editor’s Note: This study provides one of the first insights into possible environmental mechanisms that explain why some people at risk for bipolar disorder develop the illness and others do not. Another possible mechanism for differential expression of the illness has been suggested by E.F. Torrey and colleagues, who believe that a viral infection may enter an individual’s genome and directly alter DNA sequences. The current data from Sugawara’s research group suggest the importance of further study of the serotonin transporter site in bipolar disorder and the mechanistic reasons for the DNA hypermethylation that occurs there.