5-HTTLPR: the genetics of the serotonin reuptake tranporter
The activity of the serotonin system is modulated by the serotonin reuptake transporter, a protein which serves to recycle serotonin by bringing it back into the presynaptic axon, ready for re-use. This mechanism is vital in all serotonergic response, as the activity of the serotonin reuptake transporter will influence free serotonin levels. This is the putative mechanism by which SSRIs operate: they block the presynaptic serotonin reuptake transporters, so preventing the reuptake of serotonin and increasing the level of free serotonin in the synaptic cleft, relieving depressive symptoms.
Studies into the operation and variation in the reuptake transporter are many and research papers on the subject number into the hundreds, doubtless because of its overarching importance in the role of serotonin in the brain. Indeed, variations in the expression of the serotonin reuptake transporter are implicated in a number of diseases including anxiety, depression, alcoholism and obsessive-compulsive disorder (OCD), and the reuptake transporter is even thought to be anomalous (and similar to that of patients with OCD) in individuals involved in the early, obsessive stages of romantic love (Marazziti et al., 1999).
Of particular interest is a polymorphism in the promoter region—the region controlling transcriptional control—of the gene coding for the serotonin reuptake transporter referred to as 5-HTTLPR (serotonin-linked polymorphic region). The region comprises GC repeat units, and an insertion/deletion in this region creates two alleles: L (long, 16 GC repeats, greater-expressing) and S (short, 14 repeats, lesser-expressing). The S allele leads to a lower transcription of the gene and hence lower expression of the serotonin reuptake transporter.
For years, clinicians had known that different people seemed to vary wildly in their predisposition to mental illness—some were depression-prone, others apparently not. Similarly, of those suffering from the disease (a sizeable proportion of Western populations) and being treated with SSRI antidepressants, the drugs were a magic bullet for some but had intolerable side-effects in others. What genetic idiosyncrasies could underlie this variability?
Animal studies initially showed a connection between the 5-HTTLPR polymorphism and behaviour. The work of Bennett et al. (2002) examined a polymorphism in rhesus monkeys referred to as rh5-HTTLPR, analogous to the human 5-HTTLPR polymorphism. These animals (and primates in general) are particularly well-suited to such research because of their neurological and genetic similarity to humans. The researchers, after genotyping each monkey, examined the levels of a serotonin metabolite in the monkeys’ cerebrospinal fluid, which acts as a proxy for the free level of serotonin. What they discovered was intriguing: presence of the S (short) allele was linked with markedly lowered levels of the metabolite, suggesting lowered serotonin activity. More interesting still was the discovery that this relationship only held true in monkeys that had been ‘peer-reared’; that is, separated from their mothers at birth and allowed to grow up in the presence of other monkeys. No such relationship was found in monkeys that were parent-reared, suggesting that the animals’ early environment affected their ultimate genetic life prospects.
This research paved the way for other animal studies as well as ones in humans: the former have shown that even slightly stressful environments such as changes in the behaviour of the mothers of the monkeys causes marked physiological changes in the offspring (Mathew, 2002). Depressed serotonin levels and mental illness are known to be linked in humans: subjects fed a tryptophan-deficient diet (tryptophan being a precursor of serotonin and so essential for its biosynthesis) quickly develop depressive symptoms, and recovered depressive patients relapse on such a regimen (Kramer, 1993). Given this, the hypothesis that 5-HTTLPR’s allelic variants could be associated with mental illness was quickly put forward.
Sure enough, a body of research has confirmed this and a meta-analysis by Brown et al. (2008) of several studies reviews the currently-available evidence on childhood maltreatment, allelic variations in 5-HTTLPR and the incidence of depression in these individuals and found similar responses in humans to those in the rhesus monkeys: those with a history of neglect and either an SS or SL genotype were much more likely to become depressed in later life than if either of those factors were present alone. Psychologists had long known that childhood abuse seemed to predispose individuals to later mental illness, but this suggests that a traumatic childhood appears to combine with certain genotypes—nature and nurture playing off each other—to cause later problems. Why exactly this synergy should occur is still the subject of ongoing research.
While mental illnesses are hugely complex and impossible to generalise, it is apparent that SS and SL individuals are more depression-prone and indeed more prone to mental illness generally. 5-HTTLPR also seems to affect the efficacy of SSRI antidepressants: in European populations at least, individuals with an SS genotype showed lower responses to common SSRIs than either LS or LL individuals (Lesch & Gutknecht, 2005). SS individuals also suffer worse side-effects from these drugs. This suggests that research into SSRI efficacy is not complete unless it controls for subjects’ genotype, as some individuals should be expected to fare less well on the treatment. Indeed, though SSRIs are the most-prescribed class of antidepressant there is little consensus about the mode of operation of SSRIs with the efficacy and safety of these drugs being highly contested (Kirsch et al., 2008) and the literature in this field mired in controversy (Turner E. et al., 2008).
More recent research has shown that within the 5-HTTLPR insertion is a further polymorphism referred to as A/G, giving four effective 5-HTTLPR alleles: LA, LG, SA and SG. Yet newer research, however, reveals that even this current understanding may be limited: Nakamura et al. (2000) report a total of fourteen 5-HTTLPR alleles (ten of which had never before been seen), with the suggestion that more such alleles are yet to be discovered. The true complexity and significance of this gene is only beginning to be understood.
Pages: 1 2 3 4
Serotonin, disease and the future
5-HTTLPR: the genetics of the serotonin reuptake tranporter
The activity of the serotonin system is modulated by the serotonin reuptake transporter, a protein which serves to recycle serotonin by bringing it back into the presynaptic axon, ready for re-use. This mechanism is vital in all serotonergic response, as the activity of the serotonin reuptake transporter will influence free serotonin levels. This is the putative mechanism by which SSRIs operate: they block the presynaptic serotonin reuptake transporters, so preventing the reuptake of serotonin and increasing the level of free serotonin in the synaptic cleft, relieving depressive symptoms.
Studies into the operation and variation in the reuptake transporter are many and research papers on the subject number into the hundreds, doubtless because of its overarching importance in the role of serotonin in the brain. Indeed, variations in the expression of the serotonin reuptake transporter are implicated in a number of diseases including anxiety, depression, alcoholism and obsessive-compulsive disorder (OCD), and the reuptake transporter is even thought to be anomalous (and similar to that of patients with OCD) in individuals involved in the early, obsessive stages of romantic love (Marazziti et al., 1999).
Of particular interest is a polymorphism in the promoter region—the region controlling transcriptional control—of the gene coding for the serotonin reuptake transporter referred to as 5-HTTLPR (serotonin-linked polymorphic region). The region comprises GC repeat units, and an insertion/deletion in this region creates two alleles: L (long, 16 GC repeats, greater-expressing) and S (short, 14 repeats, lesser-expressing). The S allele leads to a lower transcription of the gene and hence lower expression of the serotonin reuptake transporter.
For years, clinicians had known that different people seemed to vary wildly in their predisposition to mental illness—some were depression-prone, others apparently not. Similarly, of those suffering from the disease (a sizeable proportion of Western populations) and being treated with SSRI antidepressants, the drugs were a magic bullet for some but had intolerable side-effects in others. What genetic idiosyncrasies could underlie this variability?
Animal studies initially showed a connection between the 5-HTTLPR polymorphism and behaviour. The work of Bennett et al. (2002) examined a polymorphism in rhesus monkeys referred to as rh5-HTTLPR, analogous to the human 5-HTTLPR polymorphism. These animals (and primates in general) are particularly well-suited to such research because of their neurological and genetic similarity to humans. The researchers, after genotyping each monkey, examined the levels of a serotonin metabolite in the monkeys’ cerebrospinal fluid, which acts as a proxy for the free level of serotonin. What they discovered was intriguing: presence of the S (short) allele was linked with markedly lowered levels of the metabolite, suggesting lowered serotonin activity. More interesting still was the discovery that this relationship only held true in monkeys that had been ‘peer-reared’; that is, separated from their mothers at birth and allowed to grow up in the presence of other monkeys. No such relationship was found in monkeys that were parent-reared, suggesting that the animals’ early environment affected their ultimate genetic life prospects.
This research paved the way for other animal studies as well as ones in humans: the former have shown that even slightly stressful environments such as changes in the behaviour of the mothers of the monkeys causes marked physiological changes in the offspring (Mathew, 2002). Depressed serotonin levels and mental illness are known to be linked in humans: subjects fed a tryptophan-deficient diet (tryptophan being a precursor of serotonin and so essential for its biosynthesis) quickly develop depressive symptoms, and recovered depressive patients relapse on such a regimen (Kramer, 1993). Given this, the hypothesis that 5-HTTLPR’s allelic variants could be associated with mental illness was quickly put forward.
Sure enough, a body of research has confirmed this and a meta-analysis by Brown et al. (2008) of several studies reviews the currently-available evidence on childhood maltreatment, allelic variations in 5-HTTLPR and the incidence of depression in these individuals and found similar responses in humans to those in the rhesus monkeys: those with a history of neglect and either an SS or SL genotype were much more likely to become depressed in later life than if either of those factors were present alone. Psychologists had long known that childhood abuse seemed to predispose individuals to later mental illness, but this suggests that a traumatic childhood appears to combine with certain genotypes—nature and nurture playing off each other—to cause later problems. Why exactly this synergy should occur is still the subject of ongoing research.
While mental illnesses are hugely complex and impossible to generalise, it is apparent that SS and SL individuals are more depression-prone and indeed more prone to mental illness generally. 5-HTTLPR also seems to affect the efficacy of SSRI antidepressants: in European populations at least, individuals with an SS genotype showed lower responses to common SSRIs than either LS or LL individuals (Lesch & Gutknecht, 2005). SS individuals also suffer worse side-effects from these drugs. This suggests that research into SSRI efficacy is not complete unless it controls for subjects’ genotype, as some individuals should be expected to fare less well on the treatment. Indeed, though SSRIs are the most-prescribed class of antidepressant there is little consensus about the mode of operation of SSRIs with the efficacy and safety of these drugs being highly contested (Kirsch et al., 2008) and the literature in this field mired in controversy (Turner E. et al., 2008).
More recent research has shown that within the 5-HTTLPR insertion is a further polymorphism referred to as A/G, giving four effective 5-HTTLPR alleles: LA, LG, SA and SG. Yet newer research, however, reveals that even this current understanding may be limited: Nakamura et al. (2000) report a total of fourteen 5-HTTLPR alleles (ten of which had never before been seen), with the suggestion that more such alleles are yet to be discovered. The true complexity and significance of this gene is only beginning to be understood.
Pages: 1 2 3 4