Presented by: Caitlin Cleary

Depression Depression is among the top five leading causes of disability and disease burden throughout the world Stressful events involve threat, loss, humiliation, or defeat –Influence the onset and course of depression

Predisposition Stress theories of depression predict that an individual’s sensitivity to stressful events depends on their genetic makeup Gene x environment (GxE) interaction –Do specific genes exacerbate or buffer the effect of stressful life events on depression?

5-HTT Gene Polymorphism The serotonin system is a logical source of candidate genes for depression (SSRI) Serotonin transporter gene (SLC6A4) has a functional polymorphism in the 5’ promoter region The short “s” allele is associated with lower transcriptional efficiency of the promoter compared with the long “l” allele

Previous studies Have shown inconclusive evidence for an association between the short promoter variant and depression The 5-HTT gene may not be directly associated with depression, but could be the result of a GxE interaction Referenced three supporting studies

First Study- D.L. Murphy et al., 2001 Homozygous and heterozygous (5-HTT -/- and +/-) mice exhibited more fearful behavior, and had higher levels of stress hormones as compared to control homozygous (5-HTT +/+) mice No observed differences between strains in the absence of stress

Second Study- A.J. Bennett et al., 2002 The short allele variation of the 5-HTTLPR (gene-linked polymorphic region) in rhesus macaques is associated with decreased serotonergic function in monkeys reared in stressful conditions but not among normally reared monkeys

Third Study- A.R. Hariri et al., 2002 Human neuroimaging research suggests that the stress response is mediated by 5- HTTLPR Humans with 1 or 2 copies of the “s” allele exhibit greater amygdala neuronal activity to fearful stimuli than individuals homozygous for the “l” allele

Purpose To test whether 5-HTT gene variation moderates the influence of life stress on depression To characterize genetic vulnerability to depression (why do stressful experiences lead to depression in some people, but not others?)

Methods Prospective-longitudinal study of a representative birth cohort 847 Caucasian members (M/F), followed from age 21 to 26, divided into groups: 1) s/s homozygotes n=147, 17% 2) s/l heterozygotes n=435, 51% 3) l/l homozygotes n=265, 31%

Methods cont. Stressful life events occurring after the 21 st birthday and before the 26 th birthday were assessed with a life-history calendar These events included employment, financial, housing, health and relationship stressors There was no significant difference between the genotype groups in the number of life events they experienced (suggesting that 5-HTT doesn’t influence exposure to stress)

Methods cont. Study members were assessed for depression using a quantitative measure of depressive symptoms and a categorical diagnosis according to the DSM-IV criteria Also collected informant reports about symptoms of depression at age 26 from “someone who knows you well” Data was analyzed with regression and statistical analysis

Figure 1A. The interaction between genotype and life events showed that the effect of life events on self reports of depression symptoms at age 26 was significantly stronger (P=0.02) among individuals carrying an “s” allele than among l/l homozygotes

Figure 1B. Stressful life events predicted a diagnosis of major depression among carriers of an s allele, but not among l/l homozygotes (P=0.056 )

Figure 1C. Stressful life events predicted suicide ideation or attempt among individuals carrying an s allele but not among l/l homozygotes (P=0.05)

Figure 1D. GxE interaction shows that the effect of life events on informant reports of depression was stronger among individuals carrying an s allele than among l/l homozygotes

GxE If 5-HTT genotype moderates the depressogenic influence of stressful life events, it should moderate the effect of life events that occurred not just in adulthood, but also in earlier developmental stages

Figure 2 The interaction between GxE shows that childhood maltreatment (that occurred during the first decade of life) predicted adult depression only among individuals with an s allele and not among l/l homozygotes (P=0.05)

MAOA involvement? They have previously shown that monoamine oxidase A moderates children’s sensitivity to maltreatment MAOA has a high affinity for 5-HTT, but does not have a protective effect on l/l because the moderation of life stress on depression was observed regardless of MAOA gene status (S4/S5)

Figure 3. The percentage of individuals meeting diagnostic criteria for depression at age 26, as a function of 5- HTT genotype and the number of stressful events between ages Among cohort members suffering 4 or more stressful life events, 33% of individuals with an s allele became depressed, whereas only 17% of l/l homozygotes developed depression

Conclusions GxE interaction extends to the natural development of depression in a representative sample of humans Individuals with 1 or 2 copies of an short allele polymorphism in the promoter region of 5-HTT exhibited more depressive symptoms, diagnosable depression, and suicidality in relation to stressful life events than individuals homozygous for the long allele GxE attributable risk and protective sensitivity indicate that more knowledge of the 5-HTT gene may lead to better pharmacology and prophylaxis for depression resulting from life’s stressful events

Critique Lack of consistency between evidence for a direct relation between 5-HTTLPR and depression – this study doesn’t disprove anything and can’t be taken any farther until their results are replicated The absence of clearly labeled axes on graphs and asterisks indicating significance Missing methods on how to determine the genotype Doesn’t show the linkage maps for candidate genes –does another gene demonstrate similar results?