NEWS AND COMMENTARY Major leads in the search for susceptibility genes for depression PB Mitchell 1 , PR Schofield 2 and JA Donald 3 1 School of Psychiatry, University of New South Wales, and Mood Disorders Unit, Prince of Wales Hospital, Randwick, Australia; 2 Garvan Institute of Medical Research, Black Dog Institute, Sydney, Australia; 3 Department of Biological Sciences, Macquarie University, Sydney, Australia The Pharmacogenomics Journal (2003) 3, 305–307. doi:10.1038/sj.tpj.6500212 Published online 11 November 2003 The importance of genetic factors in the causation of depression has been known since at least the early twen- tieth century. Genes contribute 30– 40% of the etiological variance for this condition. 1 Despite such recognition, the role of inherited factors has tended to be discounted over the last century, with the major research and clinical emphases being upon social, interper- sonal, personality, cognitive and psy- chodynamic contributants. Two recent and significant studies 2,3 have once again drawn attention to the role of genetics in the origins of this common and disabling condition. The first, that of Caspi et al 2 —pub- lished in ‘Science’—takes a major con- ceptual advance in examining for susceptibility genes that increase the likelihood of depression in the face of an environmental insult—in the form of stressful life events. The second, that of Zubenko et al, 3 exploits the greater role of genetics in early-onset and recurrent depressive illness, by investigating for linkage in families recruited via probands fulfilling such criteria. GENE–ENVIRONMENT INTERACTIONS IN THE ONSET OF DEPRESSION Historically, the respective roles of genes and environment in the causa- tion of depression have tended to be considered in isolation from one other. Studies such as that of Kendler et al, 4 therefore, have been critical in highlighting the important interac- tion between these factors. Kendler studied a large sample of 2164 MZ and DZ twins, ascertaining whether the co-twin had previously experi- enced depression. They then followed the subjects prospectively over an average of 17 months, examining for the relationship between stressful life events and genetic predisposition to depression. Firstly, Kendler found that few individuals experienced depres- sion in the absence of any such stressful life events. However, secondly and more significantly, he reported that those with the highest genetic risk for depression (MZ twins with a depressed co-twin) experienced the highest rate of depression in response to life events (15%), while those at lowest risk (MZ twins with a well co- twin) experienced the lowest rates after a life event (6%). DZ twins were intermediate; those with a depressed co-twin experienced higher rates than those with a well co-twin. Using such evidence for a gene–en- vironment interplay in the origins of depression, Caspi et al examined for such an interaction in the large Dune- din longitudinal study. The Dunedin cohort comprises 847 members who have been assessed prospectively from the age of 3. The particular focus of this report was on the factors asso- ciated with the likelihood of depres- sion at the age of 26. Stressful life events in the prior 5 years had been recorded in detail. The investigators examined for an association between such life stressors and a polymorphism of the promoter region of the gene for the serotonin transporter (5-HTT), the site of action of the serotonin selective reuptake inhibitor antidepressants such as fluoxetine. This functional polymorphism (SLC6A4) was chosen in view of a number of previous studies suggesting a potential clinical significance. The short allele in the promoter region (‘s’) is associated with lower transcriptional efficiency than the long (‘l’) allele. Animal studies had shown that im- pairment of this gene was associated with anxious and fearful behavior, 5 while, in a large human general popu- lation sample, the short variant ac- counted for 7–9% of inherited variance in anxiety-related personality traits. 6 In 2002, Hariri et al 7 reported that individuals with one or two copies of the short allele exhibited greater amygdala activity in response to fearful stimuli in an fMRI study. Caspi et al 2 found that this poly- morphism moderated the influence of stressful life events on depression. Those subjects with at least one copy of the short allele were more likely than those homozygous for the long allele to experience major depression, depressive symptoms or suicidal thoughts after exposure to life events. For example, homozygotes for the ‘s’ allele who had experienced at least four life events in the 5-year period had a 43% chance of becoming de- pressed, compared to 17% of the ‘l/l’ homozygotes. Heterozygotes were at intermediate risk, indicating a gene– dose effect. This is the first report of a specific gene-by-environment interaction for depression. The same research group had previously reported a gene–envir- onment interaction for violence. 8 In that study, they reported that mal- treated children with a genotype con- ferring high levels of activity of the enzyme monoamine oxidase A were The Pharmacogenomics Journal (2003)3, 305–307 & 2003 Nature Publishing Group All rights reserved 1470-269X/03 $25.00 www.nature.com/tpj