Dan T. A. Eisenberg

Examining impulsivity as an endophenotype using a behavioral approach: a DRD2 TaqI A and DRD4 48-bp VNTR association study

BackgroundResearch on the genetic basis for impulsivity has revealed an array of ambiguous findings. This may be a result of limitations to self-report assessments of impulsivity. Behavioral measures that assess more narrowly defined aspects of impulsivity may clarify genetic influences. This study examined the relationship between possession of the DRD2 TaqI A and DRD4 48 bp VNTR genetic polymorphisms and performance on a behavioral measure of impulsivity, the delay discounting task (DDT), and three traditional self-report measures.Methods195 individuals (42% male) were recruited from a university campus and were assessed in small group sessions using personal computers. Genotyping was conducted using previously established protocols. For the DRD2 TaqI A locus, individuals were designated as possessing at least one copy of the A1 allele (A1+) or not (A1-), and for the DRD4 48-bp VNTR locus, individuals were designated as having at least one long allele (7 repeats or longer, L+) or not (L-). Principal analyses used multiple univariate factorial 2 (A1+/A1-) × 2 (L+/L-) analyses of variance.ResultsA significant main effect of A1+ status on DDT performance was evident (p = .006) as well as a significant interaction effect (p = .006) between both genes. No other significant effects were evident on the self-report measures, with the exception of a trend toward an interaction effect on the Sensation Seeking Scale. Exploratory analyses suggested that the significant effects were not a function of population stratification or gender.DiscussionThese data suggest that the DRD2 TaqI A and DRD4 VNTR polymorphisms influence impulsivity as measured with a delay discounting task. Specifically, these findings suggest that an interaction between the functional effects of the two unlinked genotypes results in significant difference in the balance of mesolimbic dopaminergic activation relative to frontal-parietal activation. However, these findings are also the first in this area and must be replicated.ConclusionThese findings suggest a meaningful interaction between the DRD2 TaqI A and DRD4 VNTR polymorphisms in the expression of impulsivity and provide initial support for the utility of using behavioral measures for clarifying genetic influences on impulsivity.

Further validation of a cigarette purchase task for assessing the relative reinforcing efficacy of nicotine in college smokers.

The authors sought to further validate a cigarette purchase task (CPT), a self-report analogue of a progressive-ratio operant schedule, for the assessment of the relative reinforcing efficacy (RRE) of nicotine in smokers. The measure was assessed in terms of its correspondence to typically observed operant behavior, convergent validity, and divergent validity. Participants were 33 individuals (58% male, age M = 19.30 years) who smoked at least weekly (M = 5.31 cigarettes/day) and underwent a single assessment session. Data from the CPT exhibited the predicted inverse relationship between consumption and price, the predicted relationship between consumption and expenditure, and a heterogeneous pattern of interrelationships among the indices of reinforcement. In addition, 2 indices from the measure, intensity of demand and maximum expenditure for cigarettes, exhibited robust convergent and divergent validity. Although this is an incipient research area and the current study used a relatively small sample, these findings support the validity of a CPT as a time- and cost-efficient method for assessing nicotine reinforcement. Theoretical implications of the findings, limitations, and future directions are also discussed.

An evolutionary review of human telomere biology: The thrifty telomere hypothesis and notes on potential adaptive paternal effects

Telomeres, repetitive DNA sequences found at the ends of linear chromosomes, play a role in regulating cellular proliferation, and shorten with increasing age in proliferating human tissues. The rate of age‐related shortening of telomeres is highest early in life and decreases with age. Shortened telomeres are thought to limit the proliferation of cells and are associated with increased morbidity and mortality. Although natural selection is widely assumed to operate against long telomeres because they entail increased cancer risk, the evidence for this is mixed. Instead, here it is proposed that telomere length is primarily limited by energetic constraints. Cell proliferation is energetically expensive, so shorter telomeres should lead to a thrifty phenotype. Shorter telomeres are proposed to restrain adaptive immunity as an energy saving mechanism. Such a limited immune system, however, might also result in chronic infections, inflammatory stress, premature aging, and death—a more “disposable soma.” With an increased reproductive lifespan, the fitness costs of premature aging are higher and longer telomeres will be favored by selection. Telomeres exhibit a paternal effect whereby the offspring of older fathers have longer telomeres due to increased telomere lengths of sperm with age. This paternal effect is proposed to be an adaptive signal of the expected age of male reproduction in the environment offspring are born into. The offspring of lineages of older fathers will tend to have longer, and thereby less thrifty, telomeres, better preparing them for an environment with higher expected ages at reproduction. Am. J. Hum. Biol., 2011.

Worldwide allele frequencies of the human apolipoprotein E gene: Climate, local adaptations, and evolutionary history

The epsilon4 allele of the apolipoprotein E (APOE) gene is associated with increased cholesterol levels and heart disease. Population allele frequencies of APOE have previously been shown to vary, with epsilon4 frequencies generally increasing with latitude. We hypothesize that this trend resulted from natural selection protecting against low-cholesterol levels. In high-latitude cold environments and low-latitude hot environments, metabolic rate is elevated, which could require higher cholesterol levels. To explore this hypothesis, we compiled APOE allele frequencies, latitude, temperature, and elevation from populations around the world. epsilon4 allele frequencies show a curvilinear relationship with absolute latitude, with lowest frequencies found in the mid-latitudes where temperatures generally require less expenditure on cooling/thermogenesis. Controlling for population structure in a subset of populations did not appreciably change this pattern of association, consistent with selection pressures that vary by latitude shaping epsilon4 allele frequencies. Temperature records also predict APOE frequency in a curvilinear fashion, with lowest epsilon4 frequencies at moderate temperatures. The model fit between historical temperatures and epsilon4 is less than between latitude and epsilon4, but strengthened after correcting for estimated temperature differences during the Paleolithic. Contrary to our hypothesis, we find that elevation did not improve predictive power, and an integrated measure of the cholesterol effect of multiple APOE alleles was less related to latitude than was epsilon4 alone. Our results lend mixed support for a link between past temperature and human APOE allele distribution and point to the need to develop better models of past climate in future analyses.

Delayed paternal age of reproduction in humans is associated with longer telomeres across two generations of descendants

Telomeres are repeating DNA sequences at the ends of chromosomes that protect and buffer genes from nucleotide loss as cells divide. Telomere length (TL) shortens with age in most proliferating tissues, limiting cell division and thereby contributing to senescence. However, TL increases with age in sperm, and, correspondingly, offspring of older fathers inherit longer telomeres. Using data and samples from a longitudinal study from the Philippines, we first replicate the finding that paternal age at birth is associated with longer TL in offspring (n = 2,023, P = 1.84 × 10−6). We then show that this association of paternal age with offspring TL is cumulative across multiple generations: in this sample, grandchildren of older paternal grandfathers at the birth of fathers have longer telomeres (n = 234, P = 0.038), independent of, and additive to, the association of their father’s age at birth with TL. The lengthening of telomeres predicted by each year that the father’s or grandfather’s reproduction are delayed is equal to the yearly shortening of TL seen in middle-age to elderly women in this sample, pointing to potentially important impacts on health and the pace of senescent decline in tissues and systems that are cell-replication dependent. This finding suggests a mechanism by which humans could extend late-life function as average age at reproduction is delayed within a lineage.

Testosterone exposure, dopaminergic reward, and sensation-seeking in young men

To test the relationship between androgen exposure, dopaminergic reward and sensation-seeking, we compared variation in salivary testosterone (T), 2D:4D digit ratio, facial masculinity, Zuckermans sensation-seeking scale (SSS) and the D4 dopamine receptor (DRD4) genes from 98 young men, between the ages of 18 and 23 years. In univariate analyses, both salivary T and facial masculinity were significantly correlated with the SSS boredom susceptibility subscale, while the presence of the 7-repeat allele (7R+) in the dopamine receptor D4 gene was associated with the SSS thrill and adventure-seeking and overall sensation-seeking. Neither left nor right 2D:4D digit ratio was associated with any sensation-seeking scale. In multivariate models, salivary T and facial masculinity were significant predictors of SSS boredom susceptibility, while 7R+ was a significant predictor of SSS thrill and adventure-seeking. For overall SSS, both 7R+ and salivary T were significant predictors. There was no significant interaction of 7R+ and androgen exposure for SSS or any of the SSS subscales. These results add to earlier reports of an association between T and sensation-seeking. In addition, our results also indicate that genetic variation in DRD4 is independently associated with SSS sensation-seeking.

Dopamine receptor genetic polymorphisms and body composition in undernourished pastoralists: An exploration of nutrition indices among nomadic and recently settled Ariaal men of northern Kenya

BackgroundMinor alleles of the human dopamine receptor polymorphisms, DRD2/TaqI A and DRD4/48 bp, are related to decreased functioning and/or numbers of their respective receptors and have been shown to be correlated with body mass, height and food craving. In addition, the 7R minor allele of the DRD4 gene is at a higher frequency in nomadic compared to sedentary populations. Here we examine polymorphisms in the DRD2 and DRD4 genes with respect to body mass index (BMI) and height among men in two populations of Ariaal pastoralists, one recently settled (n = 87) and the other still nomadic (n = 65). The Ariaal live in northern Kenya, are chronically undernourished and are divided socially among age-sets.ResultsFrequencies of the DRD4/7R and DRD2/A1 alleles were 19.4% and 28.2%, respectively and did not differ between the nomadic and settled populations. BMI was higher in those with one or two DRD4/7R alleles in the nomadic population, but lower among the settled. Post-hoc analysis suggests that the DRD4 differences in BMI were due primarily to differences in fat free body mass. Height was unrelated to either DRD2/TaqI A or DRD4/48 bp genotypes.ConclusionOur results indicate that the DRD4/7R allele may be more advantageous among nomadic than settled Ariaal men. This result suggests that a selective advantage mediated through behaviour may be responsible for the higher frequency of the 7R alleles in nomadic relative to sedentary populations around the world. In contrast to previous work, we did not find an association between DRD2 genotypes and height. Our results support the idea that human phenotypic expression of genotypes should be rigorously evaluated in diverse environments and genetic backgrounds.

Season of Birth and Dopamine Receptor Gene Associations with Impulsivity, Sensation Seeking and Reproductive Behaviors

Background Season of birth (SOB) has been associated with many physiological and psychological traits including novelty seeking and sensation seeking. Similar traits have been associated with genetic polymorphisms in the dopamine system. SOB and dopamine receptor genetic polymorphisms may independently and interactively influence similar behaviors through their common effects on the dopaminergic system. Methodology/Principal Findings Based on a sample of 195 subjects, we examined whether SOB was associated with impulsivity, sensation seeking and reproductive behaviors. Additionally we examined potential interactions of dopamine receptor genes with SOB for the same set of traits. Phenotypes were evaluated using the Sociosexual Orientation Inventory, the Barratt Impulsivity Scale, the Eysenck Impulsivity Questionnaire, the Sensation Seeking Scale, and the Delay Discounting Task. Subjects were also asked about their age at first sex as well as their desired age at the birth of their first child. The dopamine gene polymorphisms examined were Dopamine Receptor D2 (DRD2) TaqI A and D4 (DRD4) 48 bp VNTR. Primary analyses included factorial gender×SOB ANOVAs or binary logistic regression models for each dependent trait. Secondary analysis extended the factorial models by also including DRD2 and DRD4 genotypes as independent variables. Winter-born males were more sensation seeking than non-winter born males. In factorial models including both genotype and season of birth as variables, two previously unobserved effects were discovered: (1) a SOB×DRD4 interaction effect on venturesomeness and (2) a DRD2×DRD4 interaction effect on sensation seeking. Conclusion These results are consistent with past findings that SOB is related to sensation seeking. Additionally, these results provide tentative support for the hypothesis that SOB modifies the behavioral expression of dopaminergic genetic polymorphism. These findings suggest that SOB should be included in future studies of risky behaviors and behavioral genetic studies of the dopamine system.

Testing the null hypothesis: comments on ‘Culture-gene coevolution of individualism–collectivism and the serotonin transporter gene’

Chiao & Blizinskys [[1]][1] recently published study, ‘Culture-gene coevolution of individualism–collectivism and the serotonin transporter gene’, addressed an important and under-studied area. It stands in contrast to the dogma that, despite the dramatic cultural and biological diversity of

Substantial Variation in qPCR Measured Mean Blood Telomere Lengths in Young Men from Eleven European Countries

Objectives: Telomeres, repetitive DNA sequences found at the ends of chromosomes, shorten with age in proliferating human tissues and are implicated in senescence. Previous studies suggest that shorter telomeres impair immune and cardiovascular function and result in increased mortality. Although few, prior studies have documented ethnic/population differences in human telomere lengths. The nature and cause(s) of these population differences remain poorly understood.