Allelic functional variation of serotonin transporter expression is a susceptibility factor for late onset Alzheimerʼs disease

Li, T.; Holmes, C H; Sham, Pak-Chung; Vallada, Homero; Birkett, Joseph; Kirov, George; Lesch, Klaus‐Peter; Powell, John; Lovestone, Simon; Collier, D.

doi:10.1097/00001756-199702100-00021

Cited by 102 publications

(73 citation statements)

References 6 publications

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“…In summary, the present study supports the data of Li et al 24 and suggests that in addition to the ⑀4 apoE polymorphism, the low-activity 5-HTTLPR allele s is also a risk factor for AD, in accordance with the hypothesis of a multifactorial ethiology for the late onset form of this disorder. However, it is still unknown whether the association of 5-HTTLPR and AD is due to linkage desequilibrium or if this polymorphism acts directly on AD.…”

supporting

confidence: 92%

“…23 However, no association between this polymorphism and bipolar disorders or schizophrenia was observed by us in Brazilian patients 21 or by other authors in schizophrenia, 22 panic disorder, 29 autism 23 and obsessive compulsive disorder. 30 For AD, results from the present study confirmed in a different population that the low activity allele of the serotonin transporter is a risk factor for AD, as recently reported by Li et al 24 Interestingly, however, the genotype distributions differed in the two studies which could be explained by the different genetic background of our population. In addition, we also observed that the genotype and gene frequencies for the 5-HTTLPR do not vary with age in normal subjects.…”

supporting

confidence: 89%

“…However, discordant results were found by us and other investigators for affective disorders and other psychiatric conditions. [21][22][23] Subsequently, Li et al 24 also reported an excess of the low activity allele (s) in patients with late onset AD as compared to normal controls.…”

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confidence: 98%

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The short variant of the polymorphism within the promoter region of the serotonin transporter gene is a risk factor for late onset Alzheimer's disease

et al. 1998

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We analyzed a deletion/insertion polymorphism within the promoter region of the serotonin transporter gene (5-HTTPLR) in 81 patients with late onset Alzheimer's (AD) disease (mean age 70.02 ± 8.13 years). Control groups included 81 normal subjects with comparable age (mean age 75.6 ± 10.2) and 82 younger normal subjects (mean age 37.4 ± 9.1). Statistical analysis showed a significant difference in the genotype and gene frequencies between the AD group and normal controls ( 2 = 9.021; 2 d.f. and 2 = 5.59, 1 d.f., respectively, PϽ0.05) due to the higher frequency of the L allele and the lower frequency of the s allele in controls than among AD patients. However, no differences were found in the genotype frequencies in older as compared to younger normal control groups ( 2 = 0.337, 2 d.f. and PϾ0.05). The present study confirms, in a different population, that the short variant of the 5-HTTPLR polymorphism may be a risk factor for late onset AD.

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confidence: 92%

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confidence: 89%

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The short variant of the polymorphism within the promoter region of the serotonin transporter gene is a risk factor for late onset Alzheimer's disease

et al. 1998

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“…[37][38][39] The larger reduction in GMVs in patients homozygous for the L-allele may then be explained by a larger susceptibility to neurodegenerative changes. However, this seems to be unlikely, although not exclusive, because our patients were young.…”

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confidence: 99%

Reduced gray matter brain volumes are associated with variants of the serotonin transporter gene in major depression

et al. 2008

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The serotonergic system is involved in the pathophysiology of major depression as well as in the early central nervous system development and adult neuroplasticity. The aim of the study was to examine in 77 patients with major depression and 77 healthy controls the association between the triallelic polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) and gray matter (GM) brain volumes measured with 1.5 T magnetic resonance imaging. Voxel-based morphometry were estimated on magnetic resonance images and genotyping was performed. We found that healthy controls have a strong association between the 5-HTTLPR and GM volumes of the dorsolateral prefrontal cortex, left anterior gyrus cinguli, left amygdala as well as right hippocampus, whereas there is no such association in patients with major depression. Healthy subjects carrying the S-or L G -allele have smaller GM volumes than those with the L A -allele, indicating that 5-HTTLPR contributes to the development of brain structures. Patients with depression show reduced GM volumes, particularly when they are homozygous for the L A -allele, suggesting that these patients are more vulnerable for morphological changes during depressive episodes.

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“…10 Associations have also been reported between the short allele of the 5-HTTLPR and severe alcohol dependence 11 and late-onset Alzheimer's disease. 12 A limitation of the negative studies is that their sample size is smaller than the original study of Lesch et al, 1 which leaves open the possibility of lack of statistical power. Here we report data from a population sample of 759 Caucasians which is larger than any study so far.…”

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An association study of a functional polymorphism of the serotonin transporter gene with personality and psychiatric symptoms

et al. 1998

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A functional polymorphism in the regulatory region of the serotonin transporter gene has been reported to be associated with anxiety-related personality traits. 1 We attempted to replicate this finding in an association study involving 759 Caucasians selected from the general Australian population. We found no associations with personality traits (including neuroticism, negative affect and behavioral inhibition), anxiety and depressive symptoms, or alcohol misuse.The human serotonin transporter (5-HTT) gene has a functional polymorphism in its regulatory region which Lesch et al 1 found to be associated with anxietyrelated personality traits. Individuals with a short allele in the 5-HTT gene-linked polymorphic region (5-HTTLPR) scored higher on neuroticism, anxiety and harm avoidance than those who were homozygous for the long allele. The association was found in both population and sib-pair samples which were predominantly Caucasian. Subsequent studies have not been able to replicate these results. Several studies have failed to find associations of the 5-HTTLPR with neuroticism and harm avoidance. [2][3][4] Association studies with psychiatric disorders have also generally been negative, including studies on panic disorder, 5-7 unipolar and bipolar affective disorder 8 and anorexia. 9 However, a study of unipolar and bipolar affective disorder in three centres did find an association with the short allele in the combined data from the centres, even though the associations were not statistically significant in the individual centres. 10 Associations have also been reported between the short allele of the 5-HTTLPR and severe alcohol dependence 11 and late-onset Alzheimer's disease. 12 A limitation of the negative studies is that their sample size is smaller than the original study of Lesch et al, 1 which leaves open the possibility of lack of statistical power. Here we report data from a population sample of 759 Caucasians which is larger than any study so far. The study includes measures of anxiety-related personality traits (neuroticism, negative affect, behavioral inhibition), anxiety and depressive symptoms, and a measure of alcohol misuse.The allele frequencies were 56.5% for the long allele and 43.5% for the short. The genotype frequencies were: long/long 33.5%, long/short 46.1%, and short/short 20.4%. Table 1 shows the mean scores on the personality and psychiatric symptom measures. For most scales, the numbers of subjects were slightly smaller than indicated in the table because of missing data. There were no significant differences at the P Ͻ 0.05 level on any measure when the data were analyzed by genotype. Similarly, there were no significant differences when short/short and long/short individuals were combined into one group and contrasted with the long/long group. There were also no significant differences between genotypes in age, sex, education or occupational status, so it was not necessary to adjust for these as covariates in the analysis.A check was also made for interaction effects involving t...

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Allelic functional variation of serotonin transporter expression is a susceptibility factor for late onset Alzheimerʼs disease

Cited by 102 publications

References 6 publications

The short variant of the polymorphism within the promoter region of the serotonin transporter gene is a risk factor for late onset Alzheimer's disease

The short variant of the polymorphism within the promoter region of the serotonin transporter gene is a risk factor for late onset Alzheimer's disease

Reduced gray matter brain volumes are associated with variants of the serotonin transporter gene in major depression

An association study of a functional polymorphism of the serotonin transporter gene with personality and psychiatric symptoms

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