Xiaoyun Tan

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

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.

Association of smoking and personality with a polymorphism of the dopamine transporter gene: Results from a community survey

In studies that used mixed volunteer samples, Lerman et al. [1999: Health Psychol 18:14-20] and Sabol et al. [1999: Health Psychol 18:7-13] reported on an association of smoking with a polymorphism of the dopamine transporter gene. We attempted to replicate this association in a nonvolunteer community sample of 861 Caucasians. No associations were found with either smoking initiation or smoking cessation. Sabol et al. [1999] also reported on an association of the dopamine transporter polymorphism with the personality trait of novelty seeking. However, we failed to find any associations with a range of personality traits, including a scale of fun seeking that correlates with novelty seeking. These negative findings suggest that either the original associations are not replicable or that any association is very small.

COMT and DRD3 polymorphisms, environmental exposures, and personality traits related to common mental disorders.

In a community sample of 2,327 Caucasians, we tested the hypotheses that polymorphisms in the COMT and DRD3 genes are associated with personality traits conferring vulnerability to anxiety, depression, or alcohol misuse, or with current symptoms of these; and that the association is stronger in persons who also have been exposed to stressor experiences. To conserve resources and to allow replication, the genetic analysis was undertaken in two stages. For the COMT polymorphism, no statistically significant associations were found in the first sample of 862 persons. The remainder of the sample was therefore not analysed for that gene. For the DRD3 polymorphism, those in the first sample with at least one of the Ser(9) alleles had significantly higher scores in neuroticism (p=0.006) and behavioral inhibition (p=0.003). There was a trend, failing to meet the 1% significance criterion, for those with this genotype also to have higher depression and anxiety. The groups did not differ in alcohol use. In persons with the Ser(9) allele who were also exposed to stressors, there was a higher level of depression at the 5% level; and the depression level was higher in homozygotes. But when the remainder of the sample (1,465) was analysed, none of the associations reached statistical significance. We conclude that neither the COMT nor DRD3 polymorphisms are associated with anxiety, depression, or alcohol abuse. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:102-107, 2000

No interaction between the serotonin transporter polymorphism (5-HTTLPR) and childhood adversity or recent stressful life events on symptoms of depression: results from two community surveys.

In this study we investigated interactions between the 5‐HTTLPR genotype and environmental risk factors (G × E) on symptoms of depression in two large Australian community samples of adolescents and young adults. We postulated that a significant interaction between the 5‐HTTLPR genotype and environmental risk factors of childhood adversity or stressful life events on symptoms of depression would be observed in subjects with at least one short allele (s/l or s/s) compared with subjects with no short alleles (l/l). We did not find significant G × E interactions between the 5‐HTTLPR genotype and recent stressful life events or childhood adversity on symptoms of depression in our sample populations. However, we did find adolescents aged 17–18 years homozygous for the long allele (l/l) and exposed to persistently high levels of family adversity over a 6‐year period were at a greater risk of depression than subjects with the same genotype exposed to no or persistently low levels of family adversity. This interaction should be interpreted cautiously due to the small number of depressed subjects in the sample with persistently high levels of family adversity.

Association of a functional polymorphism of the monoamine oxidase A gene promoter with personality and psychiatric symptoms.

A functional polymorphism in the promoter of the monoamine oxidase gene has recently been described by Sabol et al. This polymorphism is a strong candidate for associations with personality traits and psychiatric symptoms. We report relevant data from a general population sample of 850 Caucasian Australians. We found no associations with anxiety and depression symptoms, with personality traits that predispose to anxiety (neuroticism, behavioral inhibition, negative affect) or to a personality trait related to antisocial behavior (psychoticism).

No Associations Between Telomere Length and Age-Sensitive Indicators of Physical Function in Mid and Later Life

Telomere length, which declines with age, has been hypothesized to act as an indicator of biological aging. If it fulfills this purpose, shorter telomere length should correlate with age-related loss of physical function, independent of age. In this cross-sectional Australian population study, the associations between peripheral blood leukocyte telomere length and age-sensitive indicators of physical function (lung function, blood pressure, and grip strength) were examined in two narrow age range cohorts aged 44-49 years (n = 351) and 64-70 years (n = 295). Telomere length was correlated with systolic blood pressure but only for women of the younger cohort and in the opposite direction to that expected (partial r = .181, p = .017). This evidence does not provide support for the hypothesis that telomere length is related to age-associated changes in physical function.

DRD4-exonIII-VNTR moderates the effect of childhood adversities on emotional resilience in young-adults

Most individuals successfully maintain psychological well-being even when exposed to trauma or adversity. Emotional resilience or the ability to thrive in the face of adversity is determined by complex interactions between genetic makeup, previous exposure to stress, personality, coping style, availability of social support, etc. Recent studies have demonstrated that childhood trauma diminishes resilience in adults and affects mental health. The Dopamine receptor D4 (DRD4) exon III variable number tandem repeat (VNTR) polymorphism was reported to moderate the impact of adverse childhood environment on behaviour, mood and other health-related outcomes. In this study we investigated whether DRD4-exIII-VNTR genotype moderates the effect of childhood adversities (CA) on resilience. In a representative population sample (n = 1148) aged 30–34 years, we observed an interactive effect of DRD4 genotype and CA (β = 0.132; p = 0.003) on resilience despite no main effect of the genotype when effects of age, gender and education were controlled for. The 7-repeat allele appears to protect against the adverse effect of CA since the decline in resilience associated with increased adversity was evident only in individuals without the 7-repeat allele. Resilience was also significantly associated with approach-/avoidance-related personality measures (behavioural inhibition/activation system; BIS/BAS) measures and an interactive effect of DRD4-exIII-VNTR genotype and CA on BAS was observed. Hence it is possible that approach-related personality traits could be mediating the effect of the DRD4 gene and childhood environment interaction on resilience such that when stressors are present, the 7-repeat allele influences the development of personality in a way that provides protection against adverse outcomes.

Effect of Model Choice in Genetic Association Studies: DRD4 Exon III VNTR and Cigarette Use in Young Adults

A major concern with the vast literature associating the highly polymorphic 48 bp VNTR in exon III of the human dopamine receptor D4 gene (DRD4) with various behavioral phenotypes is the lack of concordance between studies. Part of the problem arises from the absence of a universally accepted scheme for pooling the large number of low frequency genotypes into appropriate categories. Here, we investigated the effect of different pooling strategies and genetic models on the reported association between DRD4‐exIII‐VNTR polymorphism and cigarette smoking. Genotyping was performed on a large randomly selected community‐based sample of 2,274 individuals aged 20–24 years. Participants were grouped into sub‐samples based on their genotypes to test specific genetic models. Multiple regression analyses were used to assess the relationship between DRD4‐exIII‐VNTR genotype and cigarette smoking measures while controlling for confounders. While smoking status and age at start of smoking were not associated with the genotype, a significantly (P = 0.006) higher rate of cigarette consumption was observed among carriers of the 7‐repeat (7r) allele. Thus, 7r carriers were not more likely to be smokers but if they did smoke they consumed significantly more cigarettes per day than 4r carriers. Unlike previous studies this association was observed only when comparing carriers of the 7r with the 4r but not the other repeat alleles. Our study demonstrates the need for caution when grouping functionally different DRD4‐exIII‐VNTR alleles in association studies. It particularly highlights the requirement for better functional characterization of the DRD4‐exIII‐VNTR alleles for interpreting results from association studies.

Cognitive ability, intraindividual variability, and common genetic variants of catechol-O-methyltransferase and brain-derived neurotrophic factor: a longitudinal study in a population-based sample of older adults.

Genetic differences play a significant role in generating individual differences in cognitive abilities. Studies have linked common polymorphisms (valine to methionine substitution; VAL/MET) in the catechol-O-methyltransferase (COMT) and brain-derived neurotrophic factor (BDNF) to cognitive differences between individuals. However, not all studies support these associations and hence, the impact of these polymorphisms on cognition is unclear. Here, we investigated the effect of COMT VAL158MET and BDNF VAL66MET polymorphisms and their interaction on cognitive performance measured longitudinally over 8 years in a population-based sample of older adults (60-64 years at baseline; n = 400). We used multilevel models to examine differences between individuals with different genotypes in performance on psychometric tests while controlling for age, sex, and education. We observed significant main and interaction effects of COMT and BDNF genotypes on reaction time (RT) and intraindividual variability in RT (IIV-RT). Subjects with at least one copy of the COMT*MET allele (which is associated with higher prefrontal dopamine) had significantly faster RT (both simple and choice RT) and less IIV-RT in both tasks than those without the COMT*MET allele when they also carried one or more BDNF*MET alleles (which is associated with lower activity-dependent BDNF secretion). However, RT and IIV-RT did not differ significantly between the COMT genotypes in the absence of the BDNF*MET allele. These polymorphisms had no significant effect on within person change in RT or IIV-RT. Our findings indicate that the interaction between common variants of COMT and BDNF explain individual differences in RT and IIV-RT but do not explain age-related decline in these abilities.

Renin–Angiotensin System Genetic Polymorphisms and Brain White Matter Lesions in Older Australians

BACKGROUND White matter lesions (WMLs), seen as hyperintensities on T2-weighted magnetic resonance imaging brain scans, are common in the brains of healthy older individuals. They are thought to be related to cerebral small vessel disease and to have a genetic component to their aetiology, and hypertension is thought to be an important risk factor. Genetic polymorphisms in hypertension-related genes may therefore be associated with the formation of WMLs. METHODS In this study, a sample of 445 Australians aged 60-65 years was drawn from a larger longitudinal epidemiological study, the Personality and Total Health Through Life Project. The associations of single nucleotide polymorphisms (SNPs) in the genes encoding angiotensinogen (AGT, rs699), angiotensin-converting enzyme (ACE, rs4362), and angiotensin II receptor type 1 (AGTR1, rs5182) with WMLs were examined. RESULTS No individual SNPs showed a significant association with WMLs for the whole sample. When the cohort was stratified by sex, ACE rs4362 and AGT rs699 showed significant associations with WMLs in men only (P = 0.01 and P = 0.03, respectively), and remained significant after controlling for hypertension. Although the AGTR1 SNP did not show any association with WMLs, the interaction of the AGT rs699 and AGTR1 rs5182 SNPs with WMLs was significant before (P = 0.03) and after adjustment for hypertension (P = 0.045). CONCLUSIONS The results provide evidence for association of polymorphisms in the renin-angiotensin system genes with WMLs, independent of hypertension. Male-only associations with WMLs were found for the AGT rs699 and ACE rs362 polymorphisms. Moreover, for the entire sample an interaction between AGT and AGTR1 rs5182 genotypes on WMLs was observed.