J. Koji Lum

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.

Mitochondrial and Nuclear Genetic Relationships among Pacific Island and Asian Populations

Mitochondrial and autosomal short tandem-repeat (STR) genetic distances among 28 Pacific Island and Asian populations are significantly correlated (r=.25, P<.01) but describe distinct patterns of relationships. Maternally inherited-mtDNA data suggest that Remote Oceanic Islanders originated in island Southeast Asia. In contrast, biparental STR data reveal substantial genetic affinities between Remote Oceanic Islanders and Near Oceanic populations from highland Papua New Guinea and Australia. The low correlation between maternal and biparental genetic markers from the same individuals may reflect differences in genome-effective population sizes or in sex-biased gene flow. To explore these possibilities, we have examined genetic diversity, gene flow, and correlations among genetic, linguistic, and geographic distances within four sets of populations representing potential geographic and cultural spheres of interaction. GST estimates (a measure of genetic differentiation inversely proportional to gene flow) from mtDNA sequences vary between 0.13 and 0.39 and are typically five times greater than GST estimates from STR loci (0.05-0.08). Significant correlations (r>.5, P<.05) between maternal genetic and linguistic distances are coincident with high mtDNA GST estimates (>0.38). Thus, genetic and linguistic distances may coevolve, and their correspondence may be preserved under conditions of genetic isolation. A significant correlation (r=.65, P<.01) between biparental genetic and geographic distances is coincident with a low STR GST estimate (0.05), indicating that isolation by distance is observed under conditions of high nuclear-gene flow. These results are consistent with an initial settlement of Remote Oceania from island Southeast Asia and with extensive postcolonization male-biased gene flow with Near Oceania.

mtDNA lineage analyses: origins and migrations of Micronesians and Polynesians.

The islands of Micronesia and Polynesia collectively comprise the last major region of the globe to be settled by humans. Both of these groups of islands were colonized within the last 4,000 years by Austronesian-speaking agriculturists. Based on biogeographic and linguistic patterns, central-eastern Micronesia and Polynesia are included by many in a single category called Remote Oceania. Similarities of biologic, linguistic, and cultural traits within Remote Oceania highlight a question central to Oceanic studies: Are similarities among islands due to a common origin of isolated communities, to ongoing interactions among islands, or both? Analyses of mitochondrial DNA (mtDNA) sequences reveal that most remote Oceanic populations are polyphyletic. These polyphyletic populations violate the assumptions of many genetic distance and population demography models and so are problematic to interpret. The majority of mtDNA sequences from Micronesian and Polynesian populations are derived from Asia, whereas others are inferred to have originated in New Guinea. These data support an Island Southeast Asian origin and a colonization route along the north coast of New Guinea. The Marianas and Yap proper (main island) appear to have been independently settled directly from Island Southeast Asia, and both have received migrants from Central-Eastern Micronesia since then. Palau clearly demonstrates a complex prehistory including a significant influx of lineages from New Guinea. Thus genetic similarities among Micronesian and Polynesian populations result, in some cases, from a common origin, and in others, from extensive gene flow.

High and variable frequencies of CYP2C19 mutations: medical consequences of poor drug metabolism in Vanuatu and other Pacific islands.

Cytochrome P450 (CYP) 2C19 is polymorphic with poor metabolizers representing 3-6% of Europeans and Africans, and 13-23% of Asians. Greater than 99% of the poor metabolizer alleles in Asian populations are defined by two single base pair mutations (CYP2C19*2 and CYP2C19*3). We have recently reported an unprecedentedly high prevalence (71%) of CYP2C19-related poor metabolizer genotype individuals and poor metabolism of proguanil on two malarious islands of Vanuatu in eastern Melanesia. To elucidate this further, a total of 5538 individuals from 24 populations on 16 different islands of Vanuatu were genotyped. Of these, 61% had a poor metabolizer genotype (*2/*2, *2/*3 or *3/*3) with substantial variation among the populations (38-79%). The overall frequencies of CYP2C19*1 (wild-type), CYP2C19*2, and CYP2C19*3 were 0.223, 0.633, and 0.144, respectively. A significant linear correlation was observed between heterozygosity and South latitude (r = 0.552, P < 0.05). The genotype frequencies of 21 of the 24 populations were consistent with Hardy-Weinberg expectations (P > 0.05). Comparisons of genetic, linguistic and geographical patterns among populations suggest that short range gene flow is largely responsible for the current distribution of CYP2C19 alleles in Vanuatu. Taken together with previous studies of nuclear genetic loci of Pacific island populations, these data predict that the poor metabolizer genotype is common throughout Polynesia and Micronesia and may be even more prevalent in western Melanesia than in Vanuatu. This suggests that the majority of Pacific Islanders metabolize a wide variety of clinically important drugs to a significantly lower degree than the average European.

Associations between Dopamine D4 Receptor Gene Variation with Both Infidelity and Sexual Promiscuity

Background Human sexual behavior is highly variable both within and between populations. While sex-related characteristics and sexual behavior are central to evolutionary theory (sexual selection), little is known about the genetic bases of individual variation in sexual behavior. The variable number tandem repeats (VNTR) polymorphism in exon III of the human dopamine D4 receptor gene (DRD4) has been correlated with an array of behavioral phenotypes and may be predicatively responsible for variation in motivating some sexual behaviors, particularly promiscuity and infidelity. Methodology/Principal Findings We administered an anonymous survey on personal history of sexual behavior and intimate relationships to 181 young adults. We also collected buccal wash samples and genotyped the DRD4 VNTR. Here we show that individuals with at least one 7-repeat allele (7R+) report a greater categorical rate of promiscuous sexual behavior (i.e., having ever had a “one-night stand”) and report a more than 50% increase in instances of sexual infidelity. Conclusions/Significance DRD4 VNTR genotype varies considerably within and among populations and has been subject to relatively recent, local selective pressures. Individual differences in sexual behavior are likely partially mediated by individual genetic variation in genes coding for motivation and reward in the brain. Conceptualizing these findings in terms of r/K selection theory suggests a mechanism for selective pressure for and against the 7R+ genotype that may explain the considerable global allelic variation for this polymorphism.

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.

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.

Polymorphisms in the Dopamine D4 and D2 Receptor Genes and Reproductive and Sexual Behaviors

Human reproductive and sexual behaviors are heritable and may represent integral life history traits that are likely partially subserved by the dopamine system. Two dopamine receptor polymorphisms, DRD4 48bp VNTR and DRD2 TaqI A, were examined in relation to the Sexual-Orientation Inventory (SOI), age at first sexual intercourse, desired age of marriage, and desired age to have children in 195 (45% male) individuals from a general student population. As DRD4 7R alleles have been associated with migratory behavior, we also examined whether those with more 7R alleles had a greater frequency of multi-racial ancestries. Minor alleles of both polymorphisms (7R and A1 respectively) are believed to decrease the function of their respective receptors. Individuals with DRD4 7R alleles were more likely to have had sexual intercourse and to desire children earlier in life. In addition, DRD4 7R+ individuals were more likely to report multi-racial ancestries. Individuals with DRD2 A1 alleles were more likely to not want children and not want to marry. These results suggest that polymorphisms in the DRD4 and DRD2 genes are meaningfully associated with variation in reproductive and sexual behaviors. These results are provisionally interpreted as consistent with other findings suggesting that DRD4 7R and DRD2 A1 alleles are adaptive for lower offspring investment strategies in dynamic social environments.

Origins of the Moken Sea Gypsies inferred from mitochondrial hypervariable region and whole genome sequences.

The origins of the Moken ‘Sea Gypsies,’ a group of traditionally boat-dwelling nomadic foragers, remain speculative despite previous examinations from linguistic, sociocultural and genetic perspectives. We explored Moken origin(s) and affinities by comparing whole mitochondrial genome and hypervariable segment I sequences from 12 Moken individuals, sampled from four islands of the Mergui Archipelago, to other mainland Asian, Island Southeast Asian (ISEA) and Oceanic populations. These analyses revealed a major (11/12) and a minor (1/12) haplotype in the population, indicating low mitochondrial diversity likely resulting from historically low population sizes, isolation and consequent genetic drift. Phylogenetic analyses revealed close relationships between the major lineage (MKN1) and ISEA, mainland Asian and aboriginal Malay populations, and of the minor lineage (MKN2) to populations from ISEA. MKN1 belongs to a recently defined subclade of the ancient yet localized M21 haplogroup. MKN2 is not closely related to any previously sampled lineages, but has been tentatively assigned to the basal M46 haplogroup that possibly originated among the original inhabitants of ISEA. Our analyses suggest that MKN1 originated within coastal mainland SEA and dispersed into ISEA and rapidly into the Mergui Archipelago within the past few thousand years as a result of climate change induced population pressure.