Compositionality, stochasticity and cooperativity in dynamic models of gene regulation

We present an approach for constructing dynamic models for the simulation of gene regulatory networks from simple computational elements. Each element is called a ``gene gate'' and defines an input/output-relationship corresponding to the binding and production of transcription factors. The proposed reaction kinetics of the gene gates can be mapped onto stochastic processes and the standard ode-description. While the ode-approach requires fixing the system's topology before its correct implementation, expressing them in stochastic pi-calculus leads to a fully compositional scheme: network elements become autonomous and only the input/output relationships fix their wiring. The modularity of our approach allows to pass easily from a basic first-level description to refined models which capture more details of the biological system. As an illustrative application we present the stochastic repressilator, an artificial cellular clock, which oscillates readily without any cooperative effects.Comment: 15 pages, 8 figures. Accepted by the HFSP journal (13/09/07

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; second, to identify genetic markers that predict depressive reactivity to victimization

The interactive effect of neighborhood peer cigarette use and 5HTTLPR genotype on individual cigarette use

Previous cross-sectional research has shown that adolescents’ cigarette use is interactively associated with that of their school peers and their 5HTTLPR genotype, such that the cigarette use of persons with more copies of the 5HTTLPR*S’ allele is more dependent on school peers’ cigarette use behaviors than their counterparts. This analysis seeks to extend this novel finding by examining whether the same conclusion can be reached when substituting neighborhood peers for school peers and examining the timing of the initiation of any and regular smoking in adolescence. A similar conclusion is reached using an independent sample with longitudinal measures of cigarette use among 6th through 8th graders clustered in 82 neighborhoods, of whom 1,098 contributed genetic data. The proportion of respondents who had ever smoked cigarettes by the first wave was calculated for each Census block group in the study. 5HTTLPR genotype was assayed using the method of Whisman and colleagues (2011). The timing of any or regular smoking initiation and over four years were modeled as dependent variables using Cox proportional hazards models. The interaction of neighborhood peer smoking behavior in the first wave and 5HTTLPR genotype statistically significantly predicted any smoking initiation (hazard ratio: 3.532; p-value=0.002) and regular smoking initiation (hazard ratio: 5.686; p-value=0.000), net of controls for sex, race/ethnicity, grade in the first wave of data, and parental educational attainment. These findings reach the same conclusions as previous cross-sectional research. The findings for any smoking initiation are consistent with the diathesis-stress model of gene-environment interaction; the findings for regular smoking initiation are consistent with the differential susceptibility model

Genotype, Childhood Maltreatment, and Their Interaction in the Etiology of Adult Antisocial Behaviors

BACKGROUND: Maltreatment by an adult or caregiver during childhood is a prevalent and important predictor of antisocial behaviors in adulthood. A functional promoter polymorphism in the monoamine oxidase A (MAOA) gene has been implicated as a moderating factor in the relationship between childhood maltreatment and antisocial behaviors. Although there have been numerous attempts at replicating this observation, results remain inconclusive. METHODS: We examined this gene-environment interaction hypothesis in a sample of 3356 white and 960 black men (aged 24-34) participating in the National Longitudinal Study of Adolescent Health. RESULTS: Primary analysis indicated that childhood maltreatment was a significant risk factor for later behaviors that violate rules and the rights of others (p .05). Power analyses indicated that these results were not due to insufficient statistical power. CONCLUSIONS: We could not confirm the hypothesis that MAOA genotype moderates the relationship between childhood maltreatment and adult antisocial behaviors

Add Health Wave IV Documentation: Candidate Genes

During Wave IV, Add Health collected biological specimens from a large, nationally representative sample of young adults. Given the size of the Wave IV sample, its geographic distribution, and in-home setting of the respondent interviews, biological specimen collection involved practical, relatively non-invasive, cost-efficient and innovative methods. These methods included collection of saliva by trained and certified field interviewers, salivary buccal cell lysis and DNA stabilization in the field, then shipment to a central lab for DNA extraction, genotyping, and archiving. The collection of saliva followed the interview and collection of cardiovascular and anthropometric measures (Entzel et al. 2009). It preceded the collection of capillary whole blood (Whitsel et al. 2012) and data on respondent use of prescription and select over-the-counter medications (Tabor et al. 2010). Further details on the design of Add Health Waves I-IV are available elsewhere (Harris 2012; Harris et al. in press)

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)

BackgroundThe 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.MethodsWe 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.ResultsLinear 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.DiscussionOur 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

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

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 (Add 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 (5HTT), and monoamine oxidase A (MAOA). 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

Biomarkers in Wave III of the Add Health Study

One of the many unique features of Wave III of the Add Health Study was the collection of biological samples. These biological samples permitted the identification of individuals with sexually transmitted infections [STI] (including HIV), and genotype ascertainment for pairs of full-siblings or twins who resided in the same households. The STI testing allows for analyses of individual, household, family, and environmental risk factors for laboratory-confirmed sexually transmitted infections (versus self-report), and the genetic sample facilitates analyses that differentiate between parental, social, and genetic influence, as well as the extent to which genetic differences in neurotransmitter function are associated with a wide range of behaviors. The inclusion of these biomarker data requires special considerations in the analysis of Wave III Add Health data. Thus, the purpose of this monograph is to outline relevant procedures, design, and sampling schemes used in the collection of biomarker data, and to serve as a user’s guide for its analysis and interpretation. The monograph is intended to supplement existing descriptions of the Add Health study, rather than to replace them. Therefore, please refer to the web pages describing the Add Health Study design for more extensive detail on the study (www.cpc.unc.edu/addhealth) and the sampling weights necessary to work with the data (www.cpc.unc.edu/addhealth/codebooks/wave3). Issues that require special consideration include sample design (e.g., who was selected for each type of biomarker test), specimen collection, laboratory methods, and laboratory test performance. Each of these themes is described in separate chapters to this monograph, but should be viewed as complementary to each other

Population Frequencies of the Triallelic 5HTTLPR in Six Ethnicially Diverse Samples from North America, Southeast Asia, and Africa

Genetic differences between populations are a 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