Genetic Sensitivity to the Environment: The Case of the Serotonin Transporter Gene and Its Implications for Studying Complex Diseases and Traits

Abstract

Evidence of marked variability in response among people exposed to the same environmental risk implies that individual differences in genetic susceptibility might be at work. The study of such Gene-by-Environment (GxE) interactions has gained momentum. In this article, the authors review research about one of the most extensive areas of inquiry: variation in the promoter region of the serotonin transporter gene (SLC6A4; also known as 5-HTT) and its contribution to stress sensitivity. Research in this area has both advanced basic science and generated broader lessons for studying complex diseases and traits. The authors evaluate four lines of evidence about the 5-HTT stress-sensitivity hypothesis: 1) observational studies about the serotonin transporter linked polymorphic region (5-HTTLPR), stress sensitivity, and depression in humans; 2) experimental neuroscience studies about the 5-HTTLPR and biological phenotypes relevant to the human stress response; 3) studies of 5-HTT variation and stress sensitivity in nonhuman primates; and 4) studies of stress sensitivity and genetically engineered 5-HTT mutations in rodents. The authors then dispel some misconceptions and offer recommendations for GxE research. The authors discuss how GxE interaction hypotheses can be tested with large and small samples, how GxE research can be carried out before as well as after replicated gene discovery, the uses of GxE research as a tool for gene discovery, the importance of construct validation in evaluating GxE research, and the contribution of GxE research to the public understanding of genetic science.

BDNF Val66Met genotype modulates the effect of childhood adversity on subgenual anterior cingulate cortex volume in healthy subjects

“…The leading explanation for this variability proposes that genetic variance modulates the effect of stress on the brain (9;10). Indeed, numerous studies have shown that persons with a specific genetic make-up are more prone to develop stress-related mental disorders after experiencing major life events like CA (11)(12)(13). Moreover, recent studies suggest that gene by stress interactions may be involved in inter-individual differences in local brain volume (14) and may also play a role in the onset of several psychiatric disorders, like bipolar disorder, schizophrenia, attention deficit hyperactivity disorder and depression (for review see (15)).…”

Plastic and immobile: Unequal intergenerational mobility by genetic sensitivity score within sibling pairs

“…Over the last two decades, research has found evidence of GxE interaction, suggesting genetic effects on a variety of measures (e.g., depression, college attendance) depend on our environment (Caspi et al 2003;Guo et al 2008;Shanahan et al 2008;Thapar et al 2007;Caspi et al 2010). Replication of GxE effects have often proved elusive (see Dick 2011 and Manuck and McCaffery 2014 for reviews).…”

The BDNF Val66Met Polymorphism Interacts with Maternal Parenting Influencing Adolescent Depressive Symptoms: Evidence of Differential Susceptibility Model

“…One important prerequisite for candidate G 9 E is its biological plausibility, that is, genes and environment are convergent to one biological pathway underlying the focused psychopathology (Caspi et al 2010;Moffitt et al 2006;Rutter et al 2009). Biological plausibility for the present research resides in the joint effect of BDNF Val66Met and parenting on abnormal BDNF functioning, which has been shown to be involved in depression (Castrén and Rantamäki 2010).…”