Fran Lowry

June 17, 2013

MIAMI — People with certain genetic profiles may have an increased risk of developing bipolar disorder after experiencing stressful life events such as death of a loved one, divorce, or job loss, according to new research.

In a case-control study, individuals who had at least 1 copy of the valine to methionine substitution at codon 158 (Val158Met) polymorphism in the catechol-O-methyltransferase (COMT) gene had a 2 times' greater risk of developing bipolar disorder in response to stress than did individuals with a different genetic profile.

"It seems to be that your genetic makeup in the presence of stress may increase your susceptibility for developing bipolar disorder," lead author Georgina Hosang, PhD, from the Institute of Psychiatry, King's College London and Middlesex University, in London, United Kingdom, told Medscape Medical News.

"If this finding is replicated, perhaps we can identify individuals who are more sensitive to their environment and target them in terms of equipping them with skills to better manage stress," Dr. Hosang said here at the 10th International Conference on Bipolar Disorders (ICBD).

Why Are Some Resilient to Stress?

Research suggests that gene-environment interactions play an important role in the development of bipolar disorder, but actual research in this area is scant, she said in a poster session.

The research that has been done shows that the Val158Met polymorphism of the COMT gene significantly moderates the impact of military stress and childhood trauma on psychosis and schizotypy, and also that it influences stress vulnerability in psychopathology.

Dr. Georgina Hosang

"I began to wonder why some people become unwell, or if they have a mood disorder they relapse, and others seem to be fairly resilient to stress. That led me to think about genetic vulnerability to stress," Dr. Hosang said.

In the current study, she and her team recruited 482 bipolar individuals and 200 psychiatrically healthy control participants. Their ages were similar, with a mean of 37 years for the bipolar patients and 34 years for control participants.

All participants completed the List of Threatening Experiences Questionnaire, which measures things such as bereavement, job loss, interpersonal problems, marital difficulties, and having problems with the law. "We know these events are generally quite stressful," she said.

The bipolar patients reported the stressful life events they experienced 6 months before their worst depressive and worst manic episode, and the healthy control participants reported events they experienced 6 months before their interview.

The genotypic information for the COMT Val158Met variant (rs4680) was extracted from genome-wide association study (GWAS) analysis of participants' DNA samples.

The researchers found that the impact of stressful life events was significantly moderated by the COMT genotype for both the worst depressive and worst manic episodes.

The variant was associated with significantly more episodes of severe depression (odds ratio [OR], 2.57; 95% confidence interval [CI], 1.19 - 5.55; P = .016) and severe mania (OR, 2.27; 95% CI, 1.05 - 4.90; P = 0.037), and individuals with the variant had twice the risk for bipolar disorder.

"Bipolar disorder is one of those illnesses that tends to run in families, and so people think of it as just a genetic disorder, but I interviewed more than 200 people with bipolar disorder, and one of the things that became apparent was the importance of lifestyle and stress," Dr. Hosang said.

A Useful Study

Commenting on this study for Medscape Medical News, Clement Zai, MD, from the Center for Addiction and Mental Health, Toronto, Canada, agreed on the importance of the genetic and environmental interaction.

Dr. Clement Zai

"To my knowledge, this is the first study to look at the relationship between stressful life events and the COMT Val158Met polymorphism focusing solely on bipolar disorder. The results from this study are useful and definitely merit further research," Dr. Zai added.

"As Dr. Hosang says, the study shows the importance of environment and gene interactions. It needs replication, of course, using a larger sample, but it contributes to the growing awareness of the importance of genetics as well as the search for genetic and other biomarkers to hopefully aid in the treatment and even prophylaxis of bipolar disorder," he said.

Dr. Hosang and Dr. Zai report no relevant financial relationships.

10th International Conference on Bipolar Disorders (ICBD). Abstract 85. Presented June 14, 2013.


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