Depression Gene Risk Doubted

A new study concludes that a highly touted gene previously thought to put stressed individuals at risk for depression might not be associated with this most common form of mental illness after all. However, the link between stressful life events and depression risk still appears to be valid.

Neil Risch

In the June 17 edition of the Journal of the American Medical Association (JAMA) , researchers led by Neil Risch, PhD, director of the Institute for Human Genetics at UCSF, along with collaborators from the National Institute of Mental Health (NIMH), highlight the need for careful validation of initial studies, including studies based on the most updated approaches to studying human genetic variations and disease risk. Interpreting these studies becomes more complex as researchers seek to consider how life events or environmental exposures interact with genes to affect risk.

Nature and Nurture

Few would argue that nature and nurture — both genes and environment — are not important influences on disease risk. Depression is a prime research focus for scientists who explore the roles of genes and the environment and their interplay. But the search for the biological underpinnings of mental illnesses such as schizophrenia and depression has led to several false alarms about genetic risks. Genetic links to disease risk have been heralded in scientific journals and the news media, only to be questioned later. Now there is another to add to the list. The original study appeared in the leading journal Science in 2003. The scientists, in research spearheaded by Avshalom Caspi of King’s College, London, were in the vanguard of those exploring the environmental context for genetic risk factors in behavioral disorders. Given the time and expense of conducting genetic analysis even five years ago, researchers commonly limited their studies to “candidate” genes. Caspi and collaborators were specifically interested in a possible role for different inheritable forms of the gene that encodes a protein called the serotonin transporter. There are two common forms of the gene — a long form and a short form. Inheriting one or two copies of either form had not previously been clearly associated with risk for depression. But Caspi and collaborators decided to tally life stresses — romantic rejection, job loss, bereavement — to see whether a role for either form of the gene emerged as a risk among the most stressed. Serotonin is a signaling molecule, or neurotransmitter, that relays signals from one nerve cell to the next. The serotonin transporter pulls neurotransmitter molecules out of the gap, or synapse, between nerve cells, putting them into storage for release into the synapse again as needed. A popular class of antidepressants acts to dampen the activity of the serotonin transporter. This allows more serotonin to remain in the synapse longer, boosting the signaling in serotonin-driven nerve pathways in a manner thought to alleviate depression. Caspi’s team found that inheriting the short form of the gene was associated with increased risk for developing depression among those who were stressed.

Association Between Gene and Depression Trumpeted

“The original finding was given so much acclaim that it has become fixed in many people’s minds as true,” says Risch. “It was named by Science as runner-up breakthrough of the year, and has been accepted in many quarters, including among psychiatrists, sociologists and psychologists.” This finding also spurred a large number of studies that attempted to identify genetic associations for mental disorders by including environmental factors in the study design. However, there was disagreement in the field about whether the original study findings had been confirmed in subsequent studies. Many scientists grew concerned that clinical practice and research direction based on acceptance of the genetic link were beginning to speed ahead. The director of the Genomics Research Branch at the NIMH, Thomas Lehner, PhD, along with other NIMH program staff, convened a workshop to review the status of this research. They aimed to provide input on future directions for research into the roles of genetic and environmental factors in mental disorders. Lehner and NIMH colleague Kathleen Merikangas, PhD, of the NIMH Genetic Epidemiology Research Branch subsequently gathered together a team of experts in biostatistics, epidemiology, genetics and psychiatry to develop an objective review of the issue and to reexamine available data. Risch, a genetic epidemiologist, was recruited to play a leading role. In a meta-analysis of data from more than 14,000 patients in 14 prior studies, Risch and his collaborators re-analyzed and combined data according to criteria used in the original study by Caspi and collaborators. In their re-analysis of the data, the researchers found that there was no statistically significant association between the gene variants and depression, regardless of whether stress was factored in.

Different Paths to Depression

Similarly designed studies are more likely to reveal valid, positive associations when the focus is on a single gene or environmental influence with a strong effect, according to Risch and Merikangas. “To say someone is depressed is almost like saying someone has a fever,” Merikangas says. “It is a very nonspecific disorder. Individuals with depression become depressed via many different pathways. Until we understand more about subgroups of depression, along with their biological underpinnings, it’s going to be very hard to identify genetic variants that play a role.” Nonetheless, Merikangas would not rule out the possibility that genome-wide association studies (GWASs) would lead to valid discoveries. These studies survey upward of a million markers to examine the whole human genome for important variations associated with health or disease. No candidate genes are singled out for scrutiny. Such a study might lead to discovery of biological mechanisms or genes that are important in depression, if it were possible to identify and focus on specific subcategories of depression, Merikangas said. Risch notes the any GWAS also requires careful validation of positive findings. “Compared to the days of candidate gene studies, I do think that GWAS produces more reliable findings,” he says. “But for anything as complicated as behavior, the more inputs there are that contribute to the behavior, the less likely it is that any one of them will stand out.”

Interaction Between the Serotonin Transporter Gene (5-HTTLPR), Stressful Life Events, and Risk of Depression: A Meta-analysis

Neil Risch, Richard Herrell, Thomas Lehner, Kung-Yee Liang, Lindon Eaves, Josephine Hoh, Andrea Griem, Maria Kovacs, Jurg Ott, Kathleen Ries Merikangas

JAMA 301(23):2462-2470 (June 17, 2009)

Abstract | Full Text

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