<p>Background: Previous research suggests that early life socioeconomic stress and certain genetic polymorphisms may be partly associated with increased adiposity; however, research on both genetic and environmental predictors fail to account for the dramatic increase in obesity over that last several decades. Hypothesis: It was hypothesized that a GxE interaction between DRD2-related SNPs and parental education would predict trunk and total fat mass. This same interaction would also predict total calories from a 24-hour diet recall, which would mediate its effect on trunk and total fat mass. Sample: The current study analyzed genetic and psychosocial data from 697 participants collected for the Family Heart Study, an investigation examining the relationship between psychosocial behaviors and cardiovascular risk factors. Methods: Interactions were assessed between four single nucleotide polymorphisms (SNPs) in the D2 receptor and ANKK1 genes and tertiles of parental education predicting DXA-scan-measured trunk and total body fat mass. A measure of total calories, as assessed by a 24-hour diet recall, was tested as a mediator of this effect. Results: An interaction between mother's education and RS1116313 SNP predicted trunk fat (F(4,191)=2.94, p=0.022) and total body fat (F(4, 191)=3.94, p=0.004). The effects were driven by a reduction in trunk and total fat mass among C/C or T/T homozygotes with a high mother's education, which was not observed among C/T heterozygotes. Father's education was neither an interactive nor a main effect predictor in any models. Interactions predicting total calories were also non-significant, and no support for mediation was found. Post-hoc analyses revealed that leisure activity was also not a mediator. Alternatively, certain dietary components were predicted by the interactions between mother's education and RS1124492 and between mother's education and RS1800498. Conclusions: Trunk and total body fat composition are predicted by an interaction between mother's education and the RS1116313 SNP. This effect does not appear to be mediated by total calories or leisure activity. Other SNPs associated with the D2 receptor interact with mother's education to predict dietary components.</p> / Dissertation

The aetiology of Parkinson's disease (PD) is still unclear. Research findings suggest that both environmental and genetic factors may contribute to its development. The interactions between genes and the environment might exist and play a key role. Cigarette smoking was found to be one of the few factors exhibiting a protective effect. If chemical compounds found in cigarette smoke influence PD risk, the difference in the ability of certain individuals in metabolising these substances might alter their susceptibility to the risk of developing PD. Many metabolic enzyme genes exhibit polymorphic traits with alteration of gene function. These might be associated with an altered susceptibility of individuals to PD. Few studies have examined the hypothesis that metabolic enzyme gene polymorphisms might modulate the effect of smoking on PD risk. However, it is crucial to consider these potential interactions when we try to elucidate the aetiology of PD. Even if each factor only contributes a slight variation and influences a small portion of the whole population, non-linear and unpredictable interactions may account for a high proportion of the aetiological fraction. Previous studies have not been strictly designed to examine the interactions between smoking and metabolic enzyme genetic polymorphisms. These studies have not been able to elucidate the extent of the interaction. Therefore, this PhD project attempted to examine whether genetic factors, operating in the phase one and phase two metabolic pathways, interact with smoking to influence the development of PD. This is the first genetic epidemiological study of PD specifically addressing this issue. The research aids in further understanding the aetiology of PD and may be useful for identifying people at higher risk. A case-only design was chosen for this project for two reasons: first, PD is a relatively rare disease and the case-only design is much more efficient at detecting gene-environment interactions; second, the PD cases for the project were recruited over the past few years and represent a prevalence series, for which an appropriate comparison group for the cases is difficult to identify and recruit. In a case-only study, only cases are used to investigate the multiplicative effects of the exposures and susceptible genotypes of interest, while non-case subjects (traditionally controls) are solely used to test the independence between the exposure and the susceptible genotype. Therefore, this approach avoids the challenges of control selection, a major limitation inherent in the case-control approach. This thesis comprised of three independent studies: the first study investigated the interactions between genetic polymorphisms of GSTM1, P1, T1 and Z1 and smoking in PD; the second study examined the interactions between genetic polymorphisms of CYP2E1 and smoking in PD; and the third study examined the interactions between genetic polymorphisms of CYP2D6 and smoking in PD. The first two studies recruited 400 white Caucasian PD cases from both hospital wards and private neurology clinics (230 men and 170 women). The third study further included 142 white Caucasian PD cases newly recruited from the same sources (542 in total, 321 men, and 221 women). The mean age of cases was 67 years with the average onset age at 60 years. GSTM1, GSTP1, GSTT1, GSTZ1 AND CYP2E1 genotyping processes were performed using protocols previously published with minor modification, whereas CYP2D6 genotyping methods were mainly developed by me with assistance from associate supervisor Dr. George Mellick. Reliability and validity of the PCR and RFLP methods were assessed through re-conducting the genotype assays using at least a 10% sample of our DNA samples. The results for all re-assessments were 100% concordant. Crude bivariate analyses were adjusted for potential confounding effects of the variables, including age at onset, gender, family history of PD and pesticide exposures. Among our unaffected, aged subjects (mean age: 63.9 years, sd: 11.4 years), the genotype frequencies at each locus were similar to those reported in other Caucasian populations. The first study showed that the proportion of carriers of the GSTP1-114Val allele (mutant) increased with increasing smoking dose from 0 to > 30 pack-years. Homozygotes of the 114Ala allele (wild-type) decreased with increasing smoking dose (trend test: p=0.02). This trend existed both in male and female cases. This dose-effect relationship was most significant in the group of cases with late-onset PD (i.e., age at onset > 55 years) with the ORicase-only values of 1.88 (95%CI: 0.65-5.48) and 2.63 (95%CI: 1.07-6.49) for > 0-10 and > 10 pack-years, respectively. No similar trend was found among our unaffected, aged subjects (p=0.42). Haplotype analyses revealed significant differences for GSTP1 haplotypes between smoking and non-smoking PD cases (ORicase-only for *C haplotype=2.00 (95%CI: 1.11-3.60), p=0.03). In this case, smoking-exposed PD cases were more likely to posses the *C haplotype defined by A to G base-pair transition at nucleotide +313 and C to T base-pair transition at nucleotide +341 (at amino acid level, valine at both positions 105 and 114). The second study found no difference in CYP2E1 genotype frequencies between PD cases who ever smoked compared to those who never smoked (odds ratio for interaction (ORi) = 1.00 (95% CI: 0.39-2.51, p=0.99)). No CYP2E1 gene-smoking interactions were detected in relation to age at onset of PD. The third study found that among cases without regular pesticide exposures, CYP2D6 PMs who smoked more than 5 pack-years had a later mean age at disease onset (68.6 years) than those with extensive metaboliser phenotypes (EMs) (61.1 years, p=0.02) and non-smokers (60.5 years, p=0.01). Analysis of aged subjects without PD confirmed that neither smoking status nor CYP2D6 PM status was associated with age itself. Our data suggest: 1. smoking exposure is independent of GSTM1, P1, T1, Z1 and CYP2E1 genotypes; 2. smoking may be, to some extent, associated with CYP2D6 genotypes; 3. there are no multiplicative interactive effects linking smoking and GSTM1, T1, Z1 or CYP2E1 genotypes with the risk for PD; 4. there is a multiplicative interactive effect between smoking and GSTP1 haplotype - particularly for genotypes carrying the 114Val allele; and 5. there is a multiplicative interactive effect between smoking and CYP2D6 PMs - particularly for people who ever smoked cigarettes more than 5 pack-years. In general, this thesis provides a model for exploring the gene-smoking interactions in PD. Further studies need to consider the recruitment of a large number of population-based and randomly-selected samples and to pay more attention to measurement of environmental exposures. Further studies also need to examine simultaneously the impact of smoking, pesticide exposures and other potential risk factors on PD. These studies will build evidence for interactions contributing to this common neurological movement disorder.

This study examined possible interactions between DRD4 genotype and parenting on children’s externalizing, internalizing, and prosocial behaviors, and explored both parent and child perceptions of all variables. Both diathesis-stress and differential susceptibility hypotheses were assessed for examining possible interactions for children with the DRD4 7-repeat allele. Data were collected from 58 families within the Southern Illinois Twins/Triplets and Siblings Study (SITSS). Results indicated that although no gene-environment interactions were found when examining child perceptions, a significant interaction emerged between DRD4 and parenting in predicting externalizing behaviors when using parent reports. Children without the 7-repeat allele appeared to be malleable to both positive and negative parenting, supporting differential susceptibility. Also, child and parent reports of parenting were both predictive of child behavior. Lastly, MZ twins perceived more similar parenting environments than DZ twins, and there appeared to be a stronger environmental effect of parenting on externalizing after controlling for the effects of genes. This study adds to the differential susceptibility literature and points to the importance of considering perceptions of both children and parents when examining the effects of parenting on child behaviors.

abstract: Several decades of research have concluded that child social functioning is a critical predictor of wellbeing across various developmental domains. Most scientists agree that both genetic and environmental influences play defining roles in social behavior; the processes by which they concurrently affect child development, however, has been the subject of less research. This work examines distinct mechanisms that shape child prosociality by examining genetic and environmental influences on development, via two empirical studies. The first study analyzed the evocative-reactive and the evocative-socially-mediated hypotheses as gene-environment correlation (rGE) mechanisms connecting the arginine vasopressin receptor 1a (AVPR1a) and dopamine receptor D2 (DRD2) genes, child prosocial behavior, and parent differential treatment (PDT). Findings present modest evidence for the evocative-reactive rGE hypothesis; specifically, AVPR1a marginally influenced child prosociality, which subsequently predicted mother preference in adolescence. The second study examined several gene-environment interactions (GxEs) in exploring how social environmental variables- positive and negative parenting- predicted child prosociality, as moderated by socially-implicated child genes, DRD2 and dopamine receptor D4 (DRD4). Findings indicated that while positive parenting was predictive of child prosociality regardless of genetic variants, the effects of negative parenting on child prosociality were dependent on child genetic variants. Together, findings from these studies suggest modest genetic and environmental influences on child behavior in middle childhood and adolescence, consistent with previous research and theory. Directions for future research are offered, and intervention and policy implications are discussed. / Dissertation/Thesis / Ph.D. Family and Human Development 2013

Anxiety is the most commonly reported mental health problem among adolescents. Still, many adolescents in need of treatment are not detected and the clinical characteristics and etiological pathways of adolescent anxiety are under-researched topics. This thesis examined the clinical utility of the Swedish versions of the Spence Children’s Anxiety Scale (SCAS) and the clinical characteristics of multiple anxiety disorders among psychiatrically referred adolescents, and the influence of parenting and oxytocin gene (OXT) variants on anxiety among adolescents in the general population.  Studies employed cross-sectional and longitudinal designs and were based on questionnaire, interview, and genotype data. Support for the reliability and validity of both SCAS and SCAS-P was obtained. The overall ability to predict anxiety among referred adolescents ranged from fair to excellent for both scales.  Among adolescents psychiatrically referred for any reason, the prevalence of any anxiety disorder was 46%. Homotypic comorbidity was observed in 43%, and heterotypic comorbidity in 91%. Early adolescent anxiety influenced homotypic anxiety in late adolescence independent of parental rejection and control. The mediating role of parenting was small with indirect effect sizes no larger than one-tenth the size of direct effects, irrespective of the informant on parenting behavior. Significant interaction effects with positive and negative parenting were observed for OXT variants rs4813625 and rs2770378 in relation to social anxiety. The nature of the interactions was in line with the differential susceptibility framework for rs4813625, whereas for rs2770378, results indicated a diathesis–stress type of interaction. The findings suggest that psychiatrically referred adolescents with anxiety disorders are best characterized as a highly complex patient group and call attention to the necessity of structured assessment. For this purpose, this thesis provides evidence for the clinical utility of the SCAS; routine utilization of this questionnaire can improve detection of adolescents in need of anxiety treatment. Findings of this theses further suggest that the influence of positive and negative parenting behaviors on anxiety may be of greater importance among some adolescents than others, depending on individual differences in sensitivity to parenting. The etiology of anxiety among adolescents may therefore involve differential susceptibility effects of the interplay between genes and parenting behaviors.

Gene-environment (GE) interactions involving the IGF pathway may affect childhood obesity. Detecting such interactions using longitudinal family studies requires accounting for individual and familial correlations. Simulations were performed to study three methods to test for GE interactions in longitudinal family data using repeated outcomes (linear mixed model) or individual outcome averages as summary statistics (twin model, partition based score I test). Interactions between the IGF pathway genes (IGF-1, IGFALS) and environmental factors (physical activity, daycare attendance and sleep duration) were tested using the Quebec Newborn Twin Study data. The twin model yielded the best performance. Results from the QNTS analysis showed suggestive association for an IGF-1 variant at position 102791894 of chromosome 12 interacting with physical activity. However, this association was not statistically significant after multiple testing correction. More robust methods and studies are needed to better understand the IGF pathway’s role in childhood obesity.

No description available.

Objective: To investigate the association of previously reported single nucleotide polymorphisms (SNPs) in relation to orofacial clefts and assess their interaction with environmental factors. Methods: Genome-wide SNP genotypes were obtained for case-parent triads from the EUROCRAN and ITALCLEFT studies. Candidate SNPs were selected from a previous genome-wide association study (Shi et al., 2012) along with surrounding SNPS for a total of 2142 genotyped and imputed SNPs. A total of 411 case-parent triads and 25 case-parent dyads were analyzed using log-linear models to test for maternal and parent-of-origin effects along with their interaction with maternal smoking and maternal folic acid consumption. Results: A significant association (q = 0.025) was detected for a region in the ATXN3 gene. This significance refers to the interaction between maternal periconceptional smoking and maternal genetic effects. Nominally significant associations in genes relating to the brain were also detected. Conclusion: SNPs in the ATXN3 region warrant further investigation.

Genome-wide association studies(GWAS) are used to find associations betweengenetic markers and diseases. One part of GWAS is to study interactions be-tween markers which can play an important role in the risk for the disease. Thesearch for interactions can be computationally intensive. The aim of this thesiswas to improve the performance of software used for gene-environment interac-tion by using parallel programming techniques on graphical processors. A studyof the new programs performance, speedup and efficiency was made using mul-tiple simulated datasets. The program shows significantly better performancecompared with the older program.

Synthetic xenoestrogens have differential estrogenic properties. Research has shown that exposures to xenoestrogens could promote breast cancer by disrupting normal function of the human epidermal growth factor receptor 2 (Her2) gene. Although animal models demonstrated a connection between xenoestrogen exposure and Her2 activity, no study using human cells has systematically examined their carcinogenic potential influencing the Her2 gene expression. Furthermore, breast cancer cells are phenotypically disparate (ER+, Her2+), with some phenotypes (Her2+), leading to more aggressive disease. This study aimed to dosimetrically assess the carcinogenic potential of commonly used xenoestrogens influencing Her2 gene expression, and delineate cellular phenotypes at greater risk of more aggressive disease. The study assessed whether the composition, concentrations, and exposure duration of BPA, EE, NPH, and DDT significantly altered Her2 copy numbers in estrogen and Her2 receptor positive or negative breast cancer lines. Each line was randomly assigned to cases (exposed) and control (unexposed) groups using a randomized block design. Fluorescent in-situ hybridization measured Her2 gene copies. Mann Whitney, Kruskal Wallis, and Incidence Rate Ratios revealed Her2 copy gains in all 4 xenoestrogens and receptor types with persistent exposures. A 44% increase in Her2 was observed in the normal ER and Her2 line, marking a shift in its Her2 status, and a 30-times greater risk was noted in the Her2+ lines. These findings promote positive social change by revealing all 4 xenoestrogens as risk factors for breast cancer. This information can be used by breast cancer advocacy groups, health educators, and steering committees to educate women and formulating policies.