Cooking with Nature And NurtureWas It a Dash or a Pinch?
Article appears by special arrangement with Alzheimer Research Forum. See original article with additional links/commentary.
21 July 2003. Some foods only reveal their flavor after you add a dash of salt. Similarly, say the authors of an article in the July 18 issue of Science, some genes only show an association with disease when environmental factors are taken into account.
Terrie Moffitt and colleagues in England, the U.S., and New Zealand asked why stressful experiences lead to depression in some people and not others. They found that a functional polymorphism in a serotonin-related gene will only show an association with depression in response to adverse life events. Apropos the venerable question of nature vs. nurture, genes vs. environment, these results suggest that psychiatric geneticists need to think more about how the "salt" of environmental factors brings out the "flavor" of certain genes.
A common polymorphism in the promoter region of the serotonin transporter (5-HTT) would seem to be an obvious bet for modulating depression, given the powerful effects of serotonergic therapeutics in the disorder. Yet, previous research had failed to detect such an effect. In the current study, Moffitt and colleagues studied this polymorphism in the light of events such as unemployment, homelessness, relationship problems, or physical or sexual abuse, which do influence depression. The researchers found that people with one or two copies of the short version of the 5-HTT promoter-which results in less total 5-HTT-were significantly more likely to experience depression in the aftermath of stressful life events, compared to people with two long alleles. This correlation held true for various measures of depression symptoms, diagnosable depression, and suicide.
Beyond the possible diagnostic implications for depression, the study addresses the question of why it has been so difficult to find or confirm genes that cause complex psychiatric or neurodegenerative diseases. This is a problem that besets AD genetics, in particular. That there is a genetic contribution to these diseases is quite clear, and a common assumption has been that, most likely, many genes, each with very small contributions, make up the sum genetic contribution. But the authors suggest that variations in fewer genes-"whose effects are conditional on exposure to environmental risks"-may be the nature side of the nature/nurture equation.
For example, the authors note, "incomplete gene penetrance, a major source of error in linkage pedigrees, can be explained if a gene's effects are expressed only among family members exposed to environmental risk. If risk exposure differs between samples, candidate genes may fail replication."-Hakon Heimer (Alzheimer Research Forum).
Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, McClay J, Mill J, Martin J, Braithwaite A, Poulton R. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science. 2003 Jul 18;301:386-9. Abstract
Comments on Related News
Related News: Forty-Year Study Reveals Patterns of Cognitive Decline in SchizophreniaComment by: Angus MacDonald, SRF Advisor
Submitted 23 September 2013
Posted 23 September 2013
The Dunedin study is not only a rich and rare resource for testing developmental hypotheses, but it has also been mined with ingenuity and resourcefulness over the years by Avshalom Caspi, Terrie Moffitt, and their colleagues to provide a number of provocative findings. In this case, they use the continuity of the sample and its multiple-informant design to test a number of useful hypotheses about the development of cognitive impairments in schizophrenia. Their population-based cohort of over 1,000 children yielded 31 cases of tightly defined schizophrenia by age 38. (The fact that this is over 3 percent of the sample, the authors argue, is explained by the comprehensiveness of their methods, suggesting that lower epidemiological estimates may underrepresent lifetime population risks.)
Their findings provide a particularly clear example of a moderate, generalized deficit in cognitive ability well before the onset of illness that, after onset, leads to further declines in fluid, but not crystalized intelligence. The example is clear because it addresses the diagnostic specificity of the deficit—the pattern was different for children later diagnosed with depression or mild cognitive impairments—and it is corroborated by the reports from others’ throughout their lives. The findings reinforce efforts by the U.S. NIH and FDA to target cognitive impairments as a symptom of interest for patients with schizophrenia.
The findings hold important methodological lessons for schizophrenia researchers, too. As pointed out by Paul Meehl in 1971, psychopathologists who co-vary or control for factors influenced by the illness may make a systematic mistake. This kind of control variable sets up false equivalences by comparing the most able patients to the least able controls.
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Related News: Forty-Year Study Reveals Patterns of Cognitive Decline in Schizophrenia
Comment by: James Gold, SRF Advisor
Submitted 25 September 2013
Posted 25 September 2013
The recent paper by Meier et al. is a powerful confirmation of several observations that have been in the literature for many years. First, cognitive impairment is evident from early in development in people who go on to develop schizophrenia. Second, there is a loss of intellectual function that occurs in those people at risk who later become ill. Third, this "illness-associated" impairment appears to maximally impact more "fluid" intellectual functions and largely spares "crystallized" forms of verbal knowledge (however, those functions are not fully spared, as there is evidence of subnormal performance levels from early in development).
Thus, what Meier et al. have shown is not new, but it is the first time that these key findings have all been demonstrated in the same subjects followed over time in a population-based sample. The inclusion of a group of depressed patients as well as a mild cognitive impairment control group are innovations that enhance confidence that this is an effect related to schizophrenia in particular rather than psychopathology or cognitive limitations in general. Unexpectedly, this study also found a very sizeable number of people meeting diagnostic criteria for schizophrenia who appear to have been untreated with antipsychotics for extended time periods but did receive treatment for other mental health problems. It will be interesting to learn more about the life course and treatment history of this unusual group of people.
View all comments by James Gold