APOE effects on cognition from childhood to adolescence.

The ε4 allele of APOE is a well-established genetic risk factor for cognitive aging and dementia, but its influence on early life cognition is unknown. Consequently, we assessed associations of APOE genotypes with cognitive performance during 7, 12, and 16 year-assessments in our ongoing Colorado Adoption/Twin Study of Lifespan behavioral development (CATSLife). In general, APOE ε4 was associated with lower Verbal, Performance, and Full Scale IQ scores during childhood and adolescence (e.g., Full Scale IQ was lower by 1.91 points per ε4 allele, d = -0.13), with larger effects in females (e.g., average Full Scale IQ scores were 3.41 points lower in females per each ε4 allele vs. 0.33 points lower in males). Thus, these results suggest that deleterious effects of the APOE ε4 allele are manifested before adulthood, especially in females, and support both early origin theories and differential life-course vulnerabilities for later cognitive impairment.

No Support for Historical Candidate Gene or Candidate Gene-by-Interaction Hypotheses for Major Depression Across Multiple Large Samples.

OBJECTIVE: Interest in candidate gene and candidate gene-by-environment interaction hypotheses regarding major depressive disorder remains strong despite controversy surrounding the validity of previous findings. In response to this controversy, the present investigation empirically identified 18 candidate genes for depression that have been studied 10 or more times and examined evidence for their relevance to depression phenotypes. METHODS: Utilizing data from large population-based and case-control samples (Ns ranging from 62,138 to 443,264 across subsamples), the authors conducted a series of preregistered analyses examining candidate gene polymorphism main effects, polymorphism-by-environment interactions, and gene-level effects across a number of operational definitions of depression (e.g., lifetime diagnosis, current severity, episode recurrence) and environmental moderators (e.g., sexual or physical abuse during childhood, socioeconomic adversity). RESULTS: No clear evidence was found for any candidate gene polymorphism associations with depression phenotypes or any polymorphism-by-environment moderator effects. As a set, depression candidate genes were no more associated with depression phenotypes than noncandidate genes. The authors demonstrate that phenotypic measurement error is unlikely to account for these null findings. CONCLUSIONS: The study results do not support previous depression candidate gene findings, in which large genetic effects are frequently reported in samples orders of magnitude smaller than those examined here. Instead, the results suggest that early hypotheses about depression candidate genes were incorrect and that the large number of associations reported in the depression candidate gene literature are likely to be false positives.

Imputation of behavioral candidate gene repeat variants in 486,551 publicly-available UK Biobank individuals.

Some of the most widely studied variants in psychiatric genetics include variable number tandem repeat variants (VNTRs) in SLC6A3, DRD4, SLC6A4, and MAOA. While initial findings suggested large effects, their importance with respect to psychiatric phenotypes is the subject of much debate with broadly conflicting results. Despite broad interest, these loci remain absent from the largest available samples, such as the UK Biobank, limiting researchers' ability to test these contentious hypotheses rigorously in large samples. Here, using two independent reference datasets, we report out-of-sample imputation accuracy estimates of >0.96 for all four VNTR variants and one modifying SNP, depending on the reference and target dataset. We describe the imputation procedures of these candidate variants in 486,551 UK Biobank individuals, and have made the imputed variant data available to UK Biobank researchers. This resource, provided to the scientific community, will allow the most rigorous tests to-date of the roles of these variants in behavioral and psychiatric phenotypes.

The role of genetic and environmental influences on the association between childhood ADHD symptoms and BMI.

BACKGROUND/OBJECTIVES: Although childhood attention deficit hyperactivity disorder (ADHD) has been previously associated with concurrent and later obesity in adulthood, the etiology of this association remains unclear. The objective of this study is to determine the shared genetic effects of ADHD symptoms and BMI in a large sample of sibling pairs, consider how these shared effects may vary over time, and examine potential sex differences. SUBJECT/METHODS: Sibling pair data were obtained from the National Longitudinal Study of Adolescent to Adult Health (Add Health); childhood ADHD symptoms were reported retrospectively during young adulthood, while three prospective measurements of BMI were available from young adulthood to later adulthood. Cholesky decomposition models were fit to this data using Mx and maximum-likelihood estimation. The twin and sibling sample for these analyses included: 221 monozygotic (MZ) pairs (92 male-male, 139 female-female), 228 dizygotic (DZ) pairs (123 male-male, 105 female-female), 471 full-sibling (FS) pairs (289 male-male, 182 female-female), 106 male-female DZ twin pairs, and 234 male-female FS pairs. RESULTS: The magnitude of the association between childhood ADHD symptoms and BMI changed over time and by sex. The etiological relationship between childhood ADHD symptoms and the three prospective measurements of BMI differed for males and females, such that unique or non-shared environmental influences contributed to the relationship within males and genetic factors contributed to the relationship within females. Specifically, among females, genetic influences on childhood ADHD symptoms were partially shared with those effecting BMI and increased from adolescence to later adulthood (genetic correlation = 0.20 (95% CI: 0.07-0.36) in adolescence and 0.24 (95% CI: 0.10, 0.41) in adulthood). CONCLUSION: Genetic influences on ADHD symptoms in childhood are partially shared with those effecting obesity. However, future research is needed to determine why this association is limited to females.

Relations between early maternal sensitivity and toddler self-regulation: Exploring variation by oxytocin and dopamine D2 receptor genes.

Gene-by-environment interactions between maternal sensitivity during infancy and child oxytocin receptor gene (OXTR rs53576) and D2 dopamine receptor gene (DRD2 TaqIA, rs1822497) genotypes were explored as predictors of toddlers' well-regulated behavioral and physiological responses to maternal compliance demands. Maternal sensitivity was assessed across a range of mother-child interactions when children were 6 months and 1 year of age (N = 186), and toddler self-regulatory responses were assessed through compliance and vagal withdrawal during a toy clean-up task when children were 2 years of age. Sensitivity-by-OXTR interactions suggested two diathesis-stress patterns, predicting compliance for the GG genotype group, and predicting physiological regulation for the AA/AG genotype group. A main effect for DRD2 genotype indicated that children with an A1 allele displayed less-compliant behavior in toddlerhood. These results suggest that genetic differences may contribute to variation both in risk for self-regulatory difficulties, and in relations between maternal sensitivity and children's responses to compliance demands at different levels of analysis.

Dopamine D2 -141C Ins/Del and Taq1A polymorphisms, body mass index, and prediction error brain response.

The prediction error model is a widely used paradigm that is conceptually based on neuronal dopamine function. However, whether dopamine receptor gene alleles contribute to human neuroimaging prediction error results is uncertain. Recent research implicated the dopamine D2 receptor in behavior response during a prediction error paradigm and we expected that polymorphisms of that receptor would contribute to prediction error brain response. In this study, healthy female participants in the early follicular phase of the menstrual cycle underwent a taste prediction error paradigm during functional magnetic resonance imaging. Participants were also genotyped for dopamine receptor polymorphisms. Our data suggest that the dopamine D2 receptor -141C Ins/Del and Taq1A polymorphisms together with body mass index selectively explain putamen prediction error response. This was true using a region of interest analysis as well as for a whole-brain analysis (FWE corrected). Polymorphisms for dopamine D1 or D4 receptors, dopamine transporter, or COMT did not significantly contribute to prediction error activation. The prediction error model is a computational reward-learning paradigm that is important in psychiatric research and has been associated with dopamine. The results from this study indicate that dopamine D2 receptor polymorphisms together with body mass index are important determinants to include in research that tests prediction error response of the brain. Psychiatric disorders are frequently associated with elevated or reduced body weight. Adding BMI to genetic information in brain-imaging studies that use reward and the prediction error paradigm may be important to increase validity and reliability of results.

MAO-A Phenotype Effects Response Sensitivity and the Parietal Old/New Effect during Recognition Memory.

A critical problem for developing personalized treatment plans for cognitive disruptions is the lack of understanding how individual differences influence cognition. Recognition memory is one cognitive ability that varies from person to person and that variation may be related to different genetic phenotypes. One gene that may impact recognition memory is the monoamine oxidase A gene (MAO-A), which influences the transcription rate of MAO-A. Examination of how MAO-A phenotypes impact behavioral and event-related potentials (ERPs) correlates of recognition memory may help explain individual differences in recognition memory performance. Therefore, the current study uses electroencephalography (EEG) in combination with genetic phenotyping of the MAO-A gene to determine how well-characterized ERP components of recognition memory, the early frontal old/new effect, left parietal old/new effect, late frontal old/new effect, and the late posterior negativity (LPN) are impacted by MAO-A phenotype during item and source memory. Our results show that individuals with the MAO-A phenotype leading to increased transcription have lower response sensitivity during both item and source memory. Additionally, during item memory the left parietal old/new effect is not present due to increased ERP amplitude for correct rejections. The results suggest that MAO-A phenotype changes EEG correlates of recognition memory and influences how well individuals differentiate between old and new items.

Population differences in associations of serotonin transporter promoter polymorphism (5HTTLPR) di- and triallelic genotypes with blood pressure and hypertension prevalence.

Based on prior research finding the 5HTTLPR L allele associated with increased cardiovascular reactivity to laboratory stressors and increased risk of myocardial infarction, we hypothesized that the 5HTTLPR L allele will be associated with increased blood pressure (BP) and increased hypertension prevalence in 2 large nationally representative samples in the United States and Singapore. METHODS: Logistic regression and linear models tested associations between triallelic (L'S', based on rs25531) 5HTTLPR genotypes and hypertension severity and mean systolic and diastolic blood pressure (SBP and DBP) collected during the Wave IV survey of the National Longitudinal Study of Adolescent to Adult Health (Add Health, N=11,815) in 2008-09 and during 2004-07 in 4196 Singaporeans. RESULTS: In US Whites, L' allele carriers had higher SBP (0.9 mm Hg, 95% CI=0.26-1.56) and greater odds (OR=1.23, 95% CI=1.10-1.38) of more severe hypertension than those with S'S' genotypes. In African Americans, L' carriers had lower mean SBP (-1.27mm Hg, 95% CI=-2.53 to -0.01) and lower odds (OR = 0.78, 95% CI=0.65-0.94) of more severe hypertension than those with the S'S' genotype. In African Americans, those with L'L' genotypes had lower DBP (-1.13mm Hg, 95% CI=-2.09 to -0.16) than S' carriers. In Native Americans, L' carriers had lower SBP (-6.05mm Hg, 95% CI=-9.59 to -2.51) and lower odds of hypertension (OR = 0.34, 95% CI=0.13-0.89) than those with the S'S' genotype. In Asian/Pacific Islanders those carrying the L' allele had lower DBP (-1.77mm Hg, 95% CI=-3.16 to -0.38) and lower odds of hypertension (OR = 0.68, 95% CI=0.48-0.96) than those with S'S'. In the Singapore sample S' carriers had higher SBP (3.02mm Hg, 95% CI=0.54-5.51) and DBP (1.90mm Hg, 95% CI=0.49-3.31) than those with the L'L' genotype. CONCLUSIONS: These findings suggest that Whites carrying the L' allele, African Americans and Native Americans with the S'S' genotype, and Asians carrying the S' allele will be found to be at higher risk of developing cardiovascular disease and may benefit from preventive measures.

Individual differences in EEG correlates of recognition memory due to DAT polymorphisms.

Introduction: Although previous research suggests that genetic variation in dopaminergic genes may affect recognition memory, the role dopamine transporter expression may have on the behavioral and EEG correlates of recognition memory has not been well established. Objectives: The study aims to reveal how individual differences in dopaminergic functioning due to genetic variations in the dopamine transporter gene influences behavioral and EEG correlates of recognition memory. Methods: Fifty-eight participants performed an item recognition task. Participants were asked to retrieve 200 previously presented words while brain activity was recorded with EEG. Regions of interest were established in scalp locations associated with recognition memory. Mean ERP amplitudes and event-related spectral perturbations when correctly remembering old items (hits) and recognizing new items (correct rejections) were compared as a function of dopamine transporter group. Results: Participants in the dopamine transporter group that codes for increased dopamine transporter expression (10/10 homozygotes) display slower reaction times compared to participants in the dopamine transporter group associated with the expression of fewer dopamine transporters (9R-carriers). 10/10 homozygotes further displayed differences in ERP and oscillatory activity compared to 9R-carriers. 10/10 homozygotes fail to display the left parietal old/new effect, an ERP signature of recognition memory associated with the amount of information retrieved. 10/10 homozygotes also displayed greater decreases of alpha and beta oscillatory activity during item memory retrieval compared to 9R-carriers. Conclusion: Compared to 9R-carriers, 10/10 homozygotes display slower hit and correct rejection reaction times, an absence of the left parietal old/new effect, and greater decreases in alpha and beta oscillatory activity during recognition memory. These results suggest that dopamine transporter polymorphisms influence recognition memory.

Parenting and adolescents' psychological adjustment: Longitudinal moderation by adolescents' genetic sensitivity.

We examined whether adolescents' genetic sensitivity, measured by a polygenic index score, moderated the longitudinal associations between parenting and adolescents' psychological adjustment. The sample included 323 mothers, fathers, and adolescents (177 female, 146 male; Time 1 [T1] average age = 12.61 years, SD = 0.54 years; Time 2 [T2] average age = 13.59 years, SD = 0.59 years). Parents' warmth and hostility were rated by trained, independent observers using videotapes of family discussions. Adolescents reported their symptoms of anxiety, depressed mood, and hostility at T1 and T2. The results from autoregressive linear regression models showed that adolescents' genetic sensitivity moderated associations between observations of both mothers' and fathers' T1 parenting and adolescents' T2 composite maladjustment, depression, anxiety, and hostility. Compared to adolescents with low genetic sensitivity, adolescents with high genetic sensitivity had worse adjustment outcomes when parenting was low on warmth and high on hostility. When parenting was characterized by high warmth and low hostility, adolescents with high genetic sensitivity had better adjustment outcomes than their counterparts with low genetic sensitivity. The results support the differential susceptibility model and highlight the complex ways that genes and environment interact to influence development.

Further evidence of the limited role of candidate genes in relation to infant-mother attachment outcomes.

In this paper, we examine the associations between specific candidate genes (DRD2, DRD4, COMT, biallelic and tri-allelic 5HTTLPR, and OXTR) and infant attachment outcomes as main effects and in conjunction with maternal sensitivity. The sample included 200 infants (97 European American, 94 African-American, and 9 biracial) and their mothers. Maternal sensitivity and overtly negative maternal behavior were observed when infants were 6 months and 1 year old in distress-eliciting contexts, attachment was assessed via the Strange Situation at age 1, and DNA samples were collected when children were 2 years old. Consistent with recent research in large samples, there was little evidence that these genes are associated with attachment security, disorganization, or distress as main effects (in additive, dominant, and homozygous models) or in conjunction with maternal sensitivity or overtly negative behavior (primarily dominance models). Furthermore, there was little evidence that associations vary as a function of race.

A Test-Replicate Approach to Candidate Gene Research on Addiction and Externalizing Disorders: A Collaboration Across Five Longitudinal Studies.

This study presents results from a collaboration across five longitudinal studies seeking to test and replicate models of gene-environment interplay in the development of substance use and externalizing disorders (SUDs, EXT). We describe an overview of our conceptual models, plan for gene-environment interplay analyses, and present main effects results evaluating six candidate genes potentially relevant to SUDs and EXT (MAOA, 5-HTTLPR, COMT, DRD2, DAT1, and DRD4). All samples included rich longitudinal and phenotypic measurements from childhood/adolescence (ages 5-13) through early adulthood (ages 25-33); sample sizes ranged from 3487 in the test sample, to ~600-1000 in the replication samples. Phenotypes included lifetime symptom counts of SUDs (nicotine, alcohol and cannabis), adult antisocial behavior, and an aggregate externalizing disorder composite. Covariates included the first 10 ancestral principal components computed using all autosomal markers in subjects across the data sets, and age at the most recent assessment. Sex, ancestry, and exposure effects were thoroughly evaluated. After correcting for multiple testing, only one significant main effect was found in the test sample, but it was not replicated. Implications for subsequent gene-environment interplay analyses are discussed.

Stressful life events moderate the relationship between genes and biased attention to emotional faces in youth.

Attention bias to emotion may be an intermediate trait for stress-reactive psychopathology associated with biologically plausible candidate genes, yet the precise direction of effects within the youth literature remains unclear. The present study investigated whether stressful life events (SLEs) moderate the link between genetic risk (5-HTTLPR and COMT) and attention bias to emotion among youth (n= 467). Analyses revealed a differential effect of gene. Among youth who had experienced more recent SLEs, those homozygous for the low expressing allele of 5-HTTLPR (S/S) demonstrated preferential attention toward negative emotional expressions, whereas youth homozygous for the high expressing COMT genotype (Val/Val) showed attentional avoidance of positive facial expressions. No interaction between 5-HTTLPR and COMT was found. These findings highlight the importance of investigating stress as a moderator within the intermediate trait literature and suggest that biologically plausible candidate genes may have a differential effect in the pathway to psychological disorders.

Depression, Stressful Life Events, and the Impact of Variation in the Serotonin Transporter: Findings from the National Longitudinal Study of Adolescent to Adult Health (Add Health).

BACKGROUND: The low transcriptionally efficient short-allele of the 5HTTLPR serotonin transporter polymorphism has been implicated to moderate the relationship between the experience of stressful life events (SLEs) and depression. Despite numerous attempts at replicating this observation, results remain inconclusive. METHODS: We examined this relationship in young-adult Non-Hispanic white males and females between the ages of 22 and 26 (n = 4724) participating in the National Longitudinal Study of Adolescent to Adult Health (Add Health) with follow-up information every six years since 1995. RESULTS: Linear and logistic regression models, corrected for multiple testing, indicated that carriers of one or more of the S-alleles were more sensitive to stress than those with two L-alleles and at a higher risk for depression. This relationship behaved in a dose-response manner such that the risk for depression was greatest among those who reported experiencing higher numbers of SLEs. In post-hoc analyses we were not able to replicate an interaction effect for suicide ideation but did find suggestive evidence that the effects of SLEs and 5HTTLPR on suicide ideation differed for males and females. There were no effects of childhood maltreatment. DISCUSSION: Our results provide partial support for the original hypothesis that 5-HTTLPR genotype interacts with the experience of stressful life events in the etiology of depression during young adulthood. However, even with this large sample, and a carefully constructed a priori analysis plan, the results were still not definitive. For the purposes of replication, characterizing the 5HTTLPR in other large data sets with extensive environmental and depression measures is needed.

Depression from childhood into late adolescence: Influence of gender, development, genetic susceptibility, and peer stress.

Depression is a debilitating mental illness with clear developmental patterns from childhood through late adolescence. Here, we present data from the Gene Environment Mood (GEM) study, which used an accelerated longitudinal cohort design with youth (N = 665) starting in 3rd, 6th, and 9th grades, and a caretaker, who were recruited from the general community, and were then assessed repeatedly through semistructured diagnostic interviews every 6 months over 3 years (7 waves of data) to establish and then predict trajectories of depression from age 8 to 18. First, we demonstrated that overall prevalence rates of depression over time, by age, gender, and pubertal status, in the GEM study closely match those trajectories previously obtained in past developmental epidemiological research. Second, we tested whether a genetic vulnerability-stress model involving 5-HTTLPR and chronic peer stress was moderated by developmental factors. Results showed that older aged adolescents with SS/SL genotype, who experienced higher peer chronic stress over 3 years, were the most likely to be diagnosed with a depressive episode over time. Girls experiencing greater peer chronic stress were the most likely to develop depression. This study used repeated assessments of diagnostic interviewing in a moderately large sample of youth over 3 years to show that depression rates increase in middle to late adolescence, or postpubertally, and that the gender difference in depression emerges earlier in adolescence (age 12.5), or postpubertally. Additionally, genetically susceptible older adolescents who experience chronic peer stress were the most likely to become depressed over time.

Genetic variation in the serotonin transporter gene influences ERP old/new effects during recognition memory.

Recognition memory is defined as the ability to recognize a previously encountered stimulus and has been associated with spatially and temporally distinct event-related potentials (ERPs). Allelic variations of the serotonin transporter gene (SLC6A4) have recently been shown to impact memory performance. Common variants of the serotonin transporter-linked polymorphic region (5HTTLPR) of the SLC6A4 gene result in long (l) and short (s) allelic variants with carriers of the s allele having lowered transcriptional efficiency. Thus, the current study examines the effects polymorphisms of the SLC6A4 gene have on performance and ERP amplitudes commonly associated with recognition memory. Electroencephalogram (EEG), genetic, and behavioral data were collected from sixty participants as they performed an item and source memory recognition task. In both tasks, participants studied and encoded 200 words, which were then mixed with 200 new words during retrieval. Participants were monitored with EEG during the retrieval portion of each memory task. EEG electrodes were grouped into four ROIs, left anterior superior, right anterior superior, left posterior superior, and right posterior superior. ERP mean amplitudes during hits in the item and source memory task were compared to correctly recognizing new items (correct rejections). Results show that s-carriers have decreased mean hit amplitudes in both the right anterior superior ROI 1000-1500ms post stimulus during the source memory task and the left anterior superior ROI 300-500ms post stimulus during the item memory task. These results suggest that individual differences due to genetic variation of the serotonin transporter gene influences recognition memory.

Life events, genetic susceptibility, and smoking among adolescents.

Although stressful life events during adolescence are associated with the adoption of unhealthy behaviors such as smoking, both social circumstances and physical traits can moderate the relationship. This study builds on the stress paradigm and gene-environment approach to social behavior by examining how a polymorphism in the serotonin transporter gene 5-HTTLPR moderates the effect of life events on adolescent smoking. Tests of interaction hypotheses use data from the Family Transitions Project, a longitudinal study of 7th graders followed for 5years. A sibling-pair design with separate models for the gender composition of pairs (brothers, sisters, or brother/sister) controls for unmeasured family background. The results show that negative life events are significantly and positively associated with smoking. Among brother pairs but not other pairs, the results provide evidence of gene-environment interaction by showing that life events more strongly influence smoking behavior for those with more copies of the 5-HTTLPR S allele.

Molecular Genetic Testing in Reward Deficiency Syndrome (RDS): Facts and Fiction.

BACKGROUND: The Brain Reward Cascade (BRC) is an interaction of neurotransmitters and their respective genes to control the amount of dopamine released within the brain. Any variations within this pathway, whether genetic or environmental (epigenetic), may result in addictive behaviors or RDS, which was coined to define addictive behaviors and their genetic components. METHODS: To carry out this review we searched a number of important databases including: Filtered: Cochrane Systematic reviews; DARE; Pubmed Central Clinical Quaries; National Guideline Clearinghouse and unfiltered resources: PsychINFO; ACP PIER; PsychSage; Pubmed/Medline. The major search terms included: dopamine agonist therapy for Addiction; dopamine agonist therapy for Reward dependence; dopamine antagonistic therapy for addiction; dopamine antagonistic therapy for reward dependence and neurogenetics of RDS. RESULTS: While there are many studies claiming a genetic association with RDS behavior, not all are scientifically accurate. CONCLUSION: Albeit our bias, this Clinical Pearl discusses the facts and fictions behind molecular genetic testing in RDS and the significance behind the development of the Genetic Addiction Risk Score (GARSPREDX™), the first test to accurately predict one's genetic risk for RDS.

Cortisol reactivity to stress among youth: stability over time and genetic variants for stress sensitivity.

Stress sensitivity may be one process that can explain why some genetically at-risk individuals are more susceptible to some types of stress-reactive psychopathologies. Dysregulation of the limbic-hypothalamic-pituitary-adrenal (LHPA) axis, including cortisol reactivity to challenge, represents a key aspect of stress sensitivity. However, the degree of stability over time among youth, especially differential stability as a function of particular genetic variants, has not been investigated. A general community sample of children and adolescents (mean age = 11.4; 56% girls) provided a DNA sample and completed 2 separate laboratory stress challenges, across an 18-month follow-up (N = 224 at Time 1; N = 194 at Time 2), with repeated measures of salivary cortisol. Results showed that test-retest stability for several indices of cortisol reactivity across the laboratory challenge visits were significant and of moderate magnitude for the whole sample. Moreover, gene variants of several biologically plausible systems relevant for stress sensitivity (especially 5-HTTLPR and CRHR1) demonstrated differential stability of cortisol reactivity over 18-months, such that carriers of genotypes conferring enhanced environmental susceptibility exhibited greater stability of cortisol levels over time for some LHPA axis indices. Findings suggest that LHPA axis dysregulation may exhibit some trait-like aspects underlying stress sensitivity in youth, especially for those who carry genes related to greater genetic susceptibility to environmental stress.

Population frequencies of the Triallelic 5HTTLPR in six Ethnicially diverse samples from North America, Southeast Asia, and Africa.

Genetic differences between populations are potentially an important contributor to health disparities around the globe. As differences in gene frequencies influence study design, it is important to have a thorough understanding of the natural variation of the genetic variant(s) of interest. Along these lines, we characterized the variation of the 5HTTLPR and rs25531 polymorphisms in six samples from North America, Southeast Asia, and Africa (Cameroon) that differ in their racial and ethnic composition. Allele and genotype frequencies were determined for 24,066 participants. Results indicated higher frequencies of the rs25531 G-allele among Black and African populations as compared with White, Hispanic and Asian populations. Further, we observed a greater number of 'extra-long' ('XL') 5HTTLPR alleles than have previously been reported. Extra-long alleles occurred almost entirely among Asian, Black and Non-White Hispanic populations as compared with White and Native American populations where they were completely absent. Lastly, when considered jointly, we observed between sample differences in the genotype frequencies within racial and ethnic populations. Taken together, these data underscore the importance of characterizing the L-G allele to avoid misclassification of participants by genotype and for further studies of the impact XL alleles may have on the transcriptional efficiency of SLC6A4.