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.

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.

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.

The National Longitudinal Study of Adolescent to Adult Health (Add Health) sibling pairs genome-wide data.

Here we provide a detailed description of the genome-wide information available on the National Longitudinal Study of Adolescent to Adult Health (Add Health) sibling pair subsample (Harris et al. in Twin Res Hum Genet 16:391-398, 2013). A total of 2,020 samples were genotyped (including duplicates) arising from 1946 Add Health individuals from the sibling pairs subsample. After various steps for quality control (QC) and quality assurance (QA), we have high quality genome-wide data available on 1,888 individuals. In this report, we first highlight the QC and QA steps that were taken to prune the data of poorly performing samples and genetic markers. We further estimate the pairwise biological relationships using genome-wide data and compare those estimates to the assumed relationships in Add Health. Additionally, using genome-wide data from known regional reference populations from Europe, West Africa, North and South America, Japan and China, we estimate the relative genetic ancestry of the respondents. Finally, rather than conducting a traditional cross-sectional genome-wide association study (GWAS) of body mass index (BMI), we opted to utilize the extensive publicly available genome-wide information to conduct a weighted GWAS of longitudinal BMI while accounting for both family and ethnic variation.

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.

Relation of the multilocus genetic composite reflecting high dopamine signaling capacity to future increases in BMI.

Because food intake exerts its rewarding effect by increasing dopamine (DA) signaling in reward circuitry, it theoretically follows that individuals with a greater number of genotypes putatively associated with high DA signaling capacity are at increased risk for overeating and subsequent weight gain. We tested the association between the multilocus genetic composite risk score, defined by the total number of genotypes putatively associated with greater DA signaling capacity (i.e. TaqIA A2 allele, DRD2-141C Ins/Del and Del/Del genotypes, DRD4-S allele, DAT1-S allele, and COMT Val/Val genotype), and future increases in Body Mass Index (BMI) in three prospective studies. Participants in Study 1 (N = 30; M age = 15.2; M baseline BMI = 26.9), Study 2 (N = 34; M age = 20.9; M baseline BMI = 28.2), and Study 3 (N = 162; M age = 15.3, M baseline BMI = 20.8) provided saliva samples from which epithelial cells were collected, permitting DNA extraction. The multilocus genetic composite risk score was associated with future increases in BMI in all three studies (Study 1, r = 0.37; Study 2, r = 0.22; Study 3, r = 0.14) and the overall sample (r = 0.19). DRD4-S was associated with increases in BMI in Study 1 (r = 0.42), Study 2 (r = 0.27), and in the overall sample (r = 0.17). DAT1-S was associated with increases in BMI in Study 3 (r = 0.17) and in the overall sample (r = 0.12). There were no associations between the other genotypes (TaqIA, COMT, and DRD2-141C) and change in BMI over 2-year follow-up. Data suggest that individuals with a genetic propensity for greater DA signaling capacity are at risk for future weight gain and that combining alleles that theoretically have a similar function may provide a more reliable method of modeling genetic risk associated with future weight gain than individual genotypes.

Genetic Heterogeneity in Adolescents' Depressive Symptoms in Response to Victimization.

This study had two objectives: first, to determine the degree to which experiences of victimization by peers during adolescence led to a subsequent rise in depressive symptoms, and second, to identify genetic markers that predict depressive reactivity to victimization. We used a cohort sequential design to obtain a longitudinal sample of 1,475 adolescents (3,263 observations) in Grades 8 to 12 (56% female; 47% Black, 46% White). Multilevel growth curve models were used to assess whether victimization predicted depressive symptoms 6 months later, beyond baseline trajectories for depressive symptoms. We modeled the interactive effects of peer victimization with three genetic polymorphisms (on 5-HTTLPR, DRD2 TaqIA, and BDNF Val66Met) on depressive symptoms. Although victimization predicted subsequent depressive symptoms, there was substantial heterogeneity in the magnitude of the effect of victimization. Val alleles, associated with higher brain-derived neurotrophic factor (BDNF) functioning, predicted more sensitivity to victimization. Neither DRD2 TaqIA, a marker associated with dopaminergic functioning, nor 5-HTTLPR, a marker associated with serotonin activity, was associated with sensitivity to victimization. The social stress of peer victimization triggers depressive symptoms most strongly in individuals who are homozygous for the Val allele on the BDNF Val/Met polymorphism. This polymorphism has been linked with sensitivity to social defeat in animal models. Future research should explore behavioral, cognitive, and emotional explanations of the effects of BDNF Val/Met on responsivity to victimization.

Self-regulatory failure and the perpetration of adolescent dating violence: Examining an alcohol use by gene explanation.

Studies report that alcohol use is related to partner violence, but for many, alcohol use does not culminate in violence against partners. Guided by a self-regulatory failure framework, we predicted that alcohol use would be more strongly associated with dating violence perpetration among adolescents with genotypes linked to impulsivity and emotional reactivity. The hypothesis was tested using random coefficient modeling of data from a multi-wave longitudinal study spanning grades 8-12 (ages 13-18) (n = 1,475). Analyses adjusted for multiple testing and race, and the potential for gene by environment correlation was examined. As predicted, alcohol use was more strongly associated with dating violence among adolescents who had a high rather than a low multilocus genetic profile composed of five genetic markers that influence dopamine signaling. Alcohol use was more strongly related to dating violence among boys with long rather than short 5-HTTLPR alleles, the opposite of the prediction. MAOA-uVNTR did not interact with alcohol, but it had a main effect on dating violence by boys in later grades in the expected direction: boys with more low activity alleles perpetrated more dating violence. Exploratory analyses found variation in findings by race. Our findings demonstrate the importance of incorporating genes into etiological studies of adolescent dating violence, which to date has not been done. Aggr. Behav. Aggr. Behav. 42:189-203, 2015. © 2014 Wiley Periodicals, Inc.

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.

Simple sequence repeats in the national longitudinal study of adolescent health: an ethnically diverse resource for genetic analysis of health and behavior.

Simple sequence repeats (SSRs) are one of the earliest available forms of genetic variation available for analysis and have been utilized in studies of neurological, behavioral, and health phenotypes. Although findings from these studies have been suggestive, their interpretation has been complicated by a variety of factors including, among others, limited power due to small sample sizes. The current report details the availability, diversity, and allele and genotype frequencies of six commonly examined SSRs in the ethnically diverse, population-based National Longitudinal Study of Adolescent Health. A total of 106,743 genotypes were generated across 15,140 participants that included four microsatellites and two di-nucleotide repeats in three dopamine genes (DAT1, DRD4, DRD5), the serotonin transporter, and monoamine oxidase A. Allele and genotype frequencies showed a complex pattern and differed significantly between populations. For both di-nucleotide repeats we observed a greater allelic diversity than previously reported. The availability of these six SSRs in a large, ethnically diverse sample with extensive environmental measures assessed longitudinally offers a unique resource for researchers interested in health and behavior.

Genes in the dopaminergic system and delinquent behaviors across the life course: the role of social controls and risks.

This paper examines the interaction between social control and social risk mechanisms and genes within the dopaminergic system (DAT1 and DRD2) as related to serious and violent forms of delinquent behavior among adolescents and young adults. We use nine waves of data from the National Youth Survey Family Study to examine the relevance of protective or risky social factors at four social levels including school, neighborhood, friends, and family within the gene-environment interaction framework. We extend previous work in this area by providing a testable typology of gene-environment interactions derived from current theories in this area. We find consistent evidence that the associations between putatively risky genotypes and delinquent behavior are suppressed within protective social environments. We also provide some evidence that supports the differential susceptibility hypothesis for these outcomes. Our findings largely confirm the conclusions of previous work and continue to highlight the critical role of the social environment within candidate gene studies of complex behaviors.

Social, behavioral, and genetic linkages from adolescence into adulthood.

The influence of genetic factors on health and behavior is conditioned by social, cultural, institutional, and physical environments in which individuals live, work, and play. We encourage studies supporting multilevel integrative approaches to understanding these contributions to health, and describe the Add Health study as an exemplar. Add Health is a large sample of US adolescents in grades 7 to 12 in 1994-1995 followed into adulthood with 4 in-home interviews and biomarker collections, including DNA. In addition to sampling multiple environments and measuring diverse social and health behavior, Add Health features a fully articulated behavioral genetic sample (3000 pairs) and ongoing genotyping of 12,000 archived samples. We illustrate approaches to understanding health through investigation of the interplay among biological, psychosocial, and physical, contextual, or cultural experiences.

Youth genetic vulnerability to maternal depressive symptoms: 5-HTTLPR as moderator of intergenerational transmission effects in a multiwave prospective study.

BACKGROUND: Maternal depressive symptoms are a strong predictor of increases in depressive symptoms in offspring, yet knowledge of individual differences that may moderate the association between youth and maternal symptoms is still relatively scant. Youth genetic susceptibility to maternal depressive symptoms in particular is a nearly unexplored area of research. METHODS: This study used a multiwave prospective design and lagged hierarchical linear modeling analyses to examine whether youth 5-HTTLPR genotype moderated the longitudinal association between mother and youth depressive symptoms in a community sample (N = 241 youth). Maternal and youth symptoms were assessed every 3 months over 1 year (five waves of data). RESULTS: Youth 5-HTTLPR interacted with idiographic elevations in maternal depressive symptoms (elevations relative to mothers' average level of symptoms) to predict prospective increases in youth symptoms 3 months later. Youth with the SS genotype experienced greatest increases in depressive symptoms when exposed to elevations in maternal symptoms. Youth 5-HTTLPR did not interact with maternal nomothetic elevations in depressive symptoms (severity of symptoms compared to the sample as a whole). CONCLUSION: These findings advance knowledge on genetic susceptibility for intergenerational transmission of depression between mothers and their children.

Observed positive parenting behaviors and youth genotype: evidence for gene-environment correlations and moderation by parent personality traits.

Gene-environment correlations (rGE) have been demonstrated in behavioral genetic studies, but rGE have proven elusive in molecular genetic research. Significant gene-environment correlations may be difficult to detect because potential moderators could reduce correlations between measured genetic variants and the environment. Molecular genetic studies investigating moderated rGE are lacking. This study examined associations between child catechol-O-methyltransferase genotype and aspects of positive parenting (responsiveness and warmth), and whether these associations were moderated by parental personality traits (neuroticism and extraversion) among a general community sample of third, sixth, and ninth graders (N = 263) and their parents. Results showed that parent personality traits moderated the rGE association between youths' genotype and coded observations of positive parenting. Parents with low levels of neuroticism and high levels of extraversion exhibited greater sensitive responsiveness and warmth, respectively, to youth with the valine/valine genotype. Moreover, youth with this genotype exhibited lower levels of observed anger. There was no association between the catechol-O-methyltransferase genotype and parenting behaviors for parents high on neuroticism and low on extraversion. Findings highlight the importance of considering moderating variables that may influence child genetic effects on the rearing environment. Implications for developmental models of maladaptive and adaptive child outcomes, and interventions for psychopathology, are discussed within a developmental psychopathology framework.

The National Longitudinal Study of Adolescent Health (Add Health) sibling pairs data.

This article describes the design and phenotype and genotype data available for sibling pairs with varying genetic relatedness in the National Longitudinal Study of Adolescent Health (Add Health). Add Health is a nationally representative longitudinal study of over 20,000 adolescents in the United States in 1994-1995 who have been followed for 15 years into adulthood. The Add Health design included oversamples of more than 3,000 pairs of individuals with varying genetic resemblance, ranging from monozygotic twins, dizygotic twins, full siblings, half siblings, and unrelated siblings who were raised in the same household. Add Health sibling pairs are therefore nationally representative and followed longitudinally from early adolescence into adulthood with four in-home interviews during the period 1994-2009. Add Health has collected rich longitudinal social, behavioral, environmental, and biological data, as well as buccal cell DNA from all sample members, including sibling pairs. Add Health has an enlightened dissemination policy and to date has released phenotype and genotype data to more than 10,000 researchers in the scientific community.

Examining associations between disordered eating and serotonin transporter gene polymorphisms.

OBJECTIVE: The serotonin system has been implicated in mood and appetite regulation, and the serotonin transporter gene (SLC6A4) is a commonly studied candidate gene for eating pathology. However, most studies have focused on a single polymorphism (5-HTTLPR) in SLC6A4; little research has utilized multiple single nucleotide polymorphisms (SNPs) to investigate associations between SLC6A4 and eating pathology more comprehensively. METHOD: Family-based association tests were conducted for seven polymorphisms in or near SLC6A4, using families from the Colorado Center for Antisocial Drug Dependence. Data were available for 135 families, with phenotypic data available for female twins and female nontwin siblings. Seven items assessed two disordered eating characteristics: weight and shape concerns and behaviors (WSCB) and binge eating (BE). RESULTS: No significant associations were found between any genetic variant and the two disordered eating characteristics. DISCUSSION: This study suggests that utilizing polymorphisms in and near SLC6A4, including 5-HTTLPR, may not be useful in identifying genetic risk factors for disordered eating.

Chronic family stress interacts with 5-HTTLPR to predict prospective depressive symptoms among youth.

BACKGROUND: Previous research, predominantly with adults, has shown that the serotonin transporter gene (5-HTTLPR) interacts with stress (G × E) to predict depressive symptoms; however, few G × E studies have been conducted with youth using rigorous methods, particularly a prospective design and contextual interview to assess stress. This study examined the interaction between 5-HTTLPR and stress, both chronic and episodic, to predict longitudinal change in depressive symptoms among children and adolescents. METHODS: A general community sample of youth (N = 200; 57% girls; mean age: 12.09 years old) was genotyped for 5-HTTLPR (rs 25531) at baseline. They were interviewed via contextual stress procedures to ascertain chronic family stress and episodic stressors and completed depressive symptoms questionnaires at baseline and 6 months later. RESULTS: A significant G × E showed that chronic family stress predicted prospective increases in depressive symptoms over 6 months among youth possessing the high-risk S allele. This G × E was not found for episodic stressors occurring in the last 6 months. There was no moderation by sex or pubertal status. CONCLUSIONS: These findings advance knowledge on G × E effects in depression among youth. This is the first study to show that chronic family stress, but not episodic stressors, when ascertained by rigorous stress interview, interacts with 5-HTTLPR to prospectively predict depressive symptoms among children and adolescents.