Gene-environment Interaction Effects Research Articles

Role of Rare and Low-Frequency Variants in Gene-Alcohol Interactions on Plasma Lipid Levels.

Alcohol intake influences plasma lipid levels, and such effects may be moderated by genetic variants. We aimed to characterize the role of aggregated rare and low-frequency protein-coding variants in gene by alcohol consumption interactions associated with fasting plasma lipid levels. In the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, fasting plasma triglycerides and high- and low-density lipoprotein cholesterol were measured in 34 153 individuals with European ancestry from 5 discovery studies and 32 277 individuals from 6 replication studies. Rare and low-frequency functional protein-coding variants (minor allele frequency, ≤5%) measured by an exome array were aggregated by genes and evaluated by a gene-environment interaction test and a joint test of genetic main and gene-environment interaction effects. Two dichotomous self-reported alcohol consumption variables, current drinker, defined as any recurrent drinking behavior, and regular drinker, defined as the subset of current drinkers who consume at least 2 drinks per week, were considered. We discovered and replicated 21 gene-lipid associations at 13 known lipid loci through the joint test. Eight loci (PCSK9, LPA, LPL, LIPG, ANGPTL4, APOB, APOC3, and CD300LG) remained significant after conditioning on the common index single-nucleotide polymorphism identified by previous genome-wide association studies, suggesting an independent role for rare and low-frequency variants at these loci. One significant gene-alcohol interaction on triglycerides in a novel locus was significantly discovered (P=6.65×10-6 for the interaction test) and replicated at nominal significance level (P=0.013) in SMC5. In conclusion, this study applied new gene-based statistical approaches and suggested that rare and low-frequency genetic variants interacted with alcohol consumption on lipid levels.

Gene-Environment Interaction of FOXO and Residential Greenness on Mortality Among Older Adults.

Residential greenness is an important environmental factor that is strongly associated with mortality. To our knowledge, there was no previous study on the gene-environment interaction analysis between residential greenness and forkhead box O (FOXO) gene, a candidate longevity gene. Our sample consisted of 3179 participants aged 65 and older from the Chinese Longitudinal Healthy Longevity Survey. Residential greenness was measured by satellite-derived normalized difference vegetation index (NDVI) using a 500-m radius around each residential location. Contemporaneous NDVI, cumulative NDVI, and changes in NDVI over time were calculated. We used Cox-proportional hazard regression models to assess the main effect and gene-environment interaction effect of FOXO single nucleotide polymorphism (SNP) and residential greenness on mortality. We found that participants carrying two minor alleles of the three studied FOXO3A SNPs had lower mortality risk than those without minor allele (hazard ratio [HR]: 0.803 95% confidence interval [CI]: 0.654-0.987 for rs4946936, HR: 0.807 95% CI: 0.669-0.974 for rs2802292, HR: 0.803 95% CI: 0.666-0.968 for rs2253310). We found no difference in mortality among the genotypes of the other three FOXO1A SNPs (rs17630266, rs2755213, or rs2755209). Higher contemporaneous NDVI was associated with lower mortality risk (HR: 0.887 95% CI: 0.863-0.911 for 0.1-U of NDVI). The protective effect of both contemporaneous NDVI and cumulative NDVI was stronger for two minor allele carriers compared with zero minor allele carriers of the three FOXO3A SNPs. Compared with the zero minor allele genotype of the three FOXO3A SNPs, the protective effect on the mortality risk of minor allele homozygotes also increased with the increasing NDVI level at percentile 25, 50, and 75 (interaction term coefficient p < 0.05). We found gene-environment interaction between FOXO and residential greenness on mortality in this population study. A higher level of greenness may interact with FOXO pathways.

The intergenerational transmission of mathematics achievement in middle childhood: A prospective adoption design.

The present study uses a parent-offspring adoption design to examine the dual roles of heritable and environmental influences on children's mathematics achievement. Linked sets (N=195) of adopted children, adoptive parents, and birth parents each completed a measure of mathematics fluency (i.e., simple computational operations). Birth parent mathematics achievement and adoptive father mathematics achievement positively correlated with child achievement scores at age 7, whereas adoptive mother and adopted child mathematics achievement scores were not significantly associated with one another. Additionally, findings demonstrated no significant effects of gene-environment interactions on child mathematics achievement at age 7. These results indicate that both heritable and rearing environmental factors contribute to children's mathematics achievement and identify unique influences of the paternal rearing environment on mathematics achievement in middle childhood.

Testing gene-environment interactions for rare and/or common variants in sequencing association studies.

The risk of many complex diseases is determined by a complex interplay of genetic and environmental factors. Advanced next generation sequencing technology makes identification of gene-environment (GE) interactions for both common and rare variants possible. However, most existing methods focus on testing the main effects of common and/or rare genetic variants. There are limited methods developed to test the effects of GE interactions for rare variants only or rare and common variants simultaneously. In this study, we develop novel approaches to test the effects of GE interactions of rare and/or common risk, and/or protective variants in sequencing association studies. We propose two approaches: 1) testing the effects of an optimally weighted combination of GE interactions for rare variants (TOW-GE); 2) testing the effects of a weighted combination of GE interactions for both rare and common variants (variable weight TOW-GE, VW-TOW-GE). Extensive simulation studies based on the Genetic Analysis Workshop 17 data show that the type I error rates of the proposed methods are well controlled. Compared to the existing interaction sequence kernel association test (ISKAT), TOW-GE is more powerful when there are GE interactions' effects for rare risk and/or protective variants; VW-TOW-GE is more powerful when there are GE interactions' effects for both rare and common risk and protective variants. Both TOW-GE and VW-TOW-GE are robust to the directions of effects of causal GE interactions. We demonstrate the applications of TOW-GE and VW-TOW-GE using an imputed data from the COPDGene Study.

A unified method for rare variant analysis of gene-environment interactions.

Advanced technology in whole-genome sequencing has offered the opportunity to comprehensively investigate the genetic contribution, particularly rare variants, to complex traits. Several region-based tests have been developed to jointly model the marginal effect of rare variants, but methods to detect gene-environment (GE) interactions are underdeveloped. Identifying the modification effects of environmental factors on genetic risk poses a considerable challenge. To tackle this challenge, we develop a method to detect GE interactions for rare variants using generalized linear mixed effect model. The proposed method can accommodate either binary or continuous traits in related or unrelated samples. Under this model, genetic main effects, GE interactions, and sample relatedness are modeled as random effects. We adopt a kernel-based method to leverage the joint information across rare variants and implement variance component score tests to reduce the computational burden. Our simulation studies of continuous and binary traits show that the proposed method maintains correct type I error rates and appropriate power under various scenarios, such as genotype main effects and GE interaction effects in opposite directions and varying the proportion of causal variants in the model. We apply our method in the Framingham Heart Study to test GE interaction of smoking on body mass index or overweight status and replicate the Cholinergic Receptor Nicotinic Beta 4 gene association reported in previous large consortium meta-analysis of single nucleotide polymorphism-smoking interaction. Our proposed set-based GE test is computationally efficient and is applicable to both binary and continuous phenotypes, while appropriately accounting for familial or cryptic relatedness.

A Fast and Accurate Method for Genome-wide Scale Phenome-wide G × E Analysis and Its Application to UK Biobank

The etiology of most complex diseases involves genetic variants, environmental factors, and gene-environment interaction (G × E) effects. Compared with marginal genetic association studies, G × E analysis requires more samples and detailed measure of environmental exposures, and this limits the possible discoveries. Large-scale population-based biobanks with detailed phenotypic and environmental information, such as UK-Biobank, can be ideal resources for identifying G × E effects. However, due to the large computation cost and the presence of case-control imbalance, existing methods often fail. Here we propose a scalable and accurate method, SPAGE (SaddlePoint Approximation implementation of G × E analysis), that is applicable for genome-wide scale phenome-wide G × E studies. SPAGE fits a genotype-independent logistic model only once across the genome-wide analysis in order to reduce computation cost, and SPAGE uses a saddlepoint approximation (SPA) to calibrate the test statistics for analysis of phenotypes with unbalanced case-control ratios. Simulation studies show that SPAGE is 33-79 times faster than the Wald test and 72-439 times faster than the Firth's test, and SPAGE can control type I error rates at the genome-wide significance level even when case-control ratios are extremely unbalanced. Through the analysis of UK-Biobank data of 344,341 white British European-ancestry samples, we show that SPAGE can efficiently analyze large samples while controlling for unbalanced case-control ratios.

NEW APPROACH TO STUDYING COLLECTIVE EFFECTS OF GENETIC FACTORS ON ALZHEIMER’S DISEASE

Despite the wide recognition of the multifactorial nature of Alzheimer’s disease (AD), mechanisms of the collective influence of genetic and environmental factors on AD remain poorly understood. We used the Cardiovascular Health Study (CHS) and Framingham Heart Study (FHS) data to investigate the effects of genetic and gene-environment interactions on AD prevalence in the association analysis using logistic regression. Based on results of this analysis, we developed several new measures of integrated effects of SNPs, including for specific gene or group of genes, by constructing SNP-specific Interaction Polygenic Risk Scores (SIPRSs), Gene-specific Interaction Polygenic Risk Scores (GIPRS), and Trait-specific Interaction Polygenic Risk Scores (TIPRS), and tested them in the above data. We found strong interaction effects on AD among the SNPs in NRG3 gene and smoking, and among the SNPs in ATM and creatinine. In summary, we developed a new approach to measuring the collective impact of SNPs on complex traits, and discovered significant effects of the newly constructed SIPRS, GIPRS, and TIPRS on AD prevalence. The results of this study open a new opportunity of investigating the joint impacts of genetic and environmental factors on AD and other phenotypes of aging and health.

Association of single nucleotide polymorphisms of adiponectin and leptin genes with breast cancer.

Single nucleotide polymorphisms (SNPs) in adiponectin gene [rs1501299 (+276G/T) and rs266729 (-11377C/G)] and one SNP of leptin gene [rs7799039 (-2548G/A)] are known to influence plasma levels of adiponectin and leptin respectively. Literature is scarce on the association of adiponectin gene polymorphism rs266729 with breast cancer. The present study was taken up to study these polymorphisms and their association with breast cancer. Ninety-three patients diagnosed with malignant breast cancer were included as cases along with 186 age matched healthy controls. Adiponectin +276G/T, -11377C/G and leptin -2548G/A polymorphism were studied using polymerase chain reaction (PCR) based restriction fragment length polymorphism (RFLP). Adipokine levels in blood were measured using enzyme linked immunosorbent assay. Adiponectin +276G/T and leptin -2548G/A showed a significant increased risk for breast cancer even after adjusting for confounding variables like present age, age at menarche, age at first child birth and age at menopause. In the subset analysis, based on menopausal state, stronger association was observed between SNP in adiponectin gene +276G/T with the breast cancer in post-menopausal women after adjusting for all other variables. No association was found with adiponectin -11377C/G. No association of the gene polymorphisms with adipokine levels was observed. Also, no significant association was seen for the effect of gene-environment interaction i.e. presence of polymorphism with obesity and menopausal statefor any of the SNPs studied. Adiponectin +276G/T is strongly associated with breast cancer in postmenopausal women while leptin -2548G/A polymorphisms is significantly associated with breast cancer irrespective of the menopausal state in south Indian subjects.

FKBP5 Genotype Linked to Combined PTSD-Depression Symptom in Chinese Earthquake Survivors.

Post-traumatic stress disorder (PTSD) and depression are common mental disorders in individuals experiencing traumatic events. To date, few studies have studied the relationship between genetic basis and phenotypic heterogeneity of traumatized individuals. The present study examined the effects of four FKBP5 SNPs (rs1360780, rs3800373, rs9296158, and rs9470080) in four postdisaster groups (low symptom, predominantly depressive, predominantly PTSD, and combined PTSD-depression symptom groups) as identified by latent profile analysis. A total of 1,140 adults who experienced the 2008 Wenchuan earthquake participated in our study. Earthquake-related trauma, PTSD, and depressive symptoms were measured using standard psychometric instruments. The four FKBP5 SNPs were genotyped using a custom-by-design 2 × 48-Plex SNP scan™ Kit. After adjusting for covariates, the main and gene-environment interaction effects of rs9470080 were all significant when the combined PTSD-depression group was compared with the low symptoms, predominantly depression and predominantly PTSD groups. rs9470080 TT genotype carriers had a higher risk of developing high co-occurring PTSD and depression symptoms than the C allele carriers. However, when trauma exposure was severe, the TT genotype carriers and C allele carriers did not differ in the risk of developing high co-occurring PTSD and depressive symptoms. The other three SNPs demonstrated no significant effects. Moreover, the rs3800373-rs9296158-rs1360780-rs9470080 haplotype A-G-C-T was found significantly associated with combined PTSD-depression symptoms. Our findings support the genetic basis of phenotypic heterogeneity in people exposed to trauma. Furthermore, the results reveal the possibility that the variants of FKBP5 gene may be associated with depression-PTSD comorbidity.

Rs1360780 of the FKBP5 gene modulates the association between maternal acceptance and regional gray matter volume in the thalamus in children and adolescents.

Investigating the effects of gene–environment interactions (G × E) with regard to brain structure may help to elucidate the putative mechanisms associated with psychiatric risk. rs1360780 (C/T) is a functional single-nucleotide polymorphism (SNP) in the gene encoding FK506–binding protein 5 (FKBP5), which is involved in the regulation of the hypothalamic–pituitary–adrenal (HPA) axis stress responses. The minor (T) allele of FKBP5 is considered a risk allele for stress-related disorders, due to the overproduction of FKBP5, which results in impaired communication of stress signals with the HPA axis. Previous studies have reported that interactions between childhood maltreatment and the rs1360780 genotype affect structures in subcortical areas of the brain. However, it is unclear how this SNP modulates the association between non-adverse environments and brain structure. In this study, we examined the interactive effect of the rs1360780 genotype and maternal acceptance on the regional gray matter volume (rGMV) in 202 Japanese children. Maternal acceptance was assessed using a Japanese psychological questionnaire for mothers. Whole-brain multiple regression analysis using voxel-based morphometry showed a significant positive association between maternal acceptance and rGMV in the left thalamus of T-allele carriers, while a significant negative association was found in C/C homozygotes. Post-hoc analysis revealed that at or below the 70th percentiles of maternal acceptance, the T-allele carriers had a reduced thalamic rGMV compared with that of C/C homozygotes. Thus, our investigation indicated that the effect of the maternal acceptance level on brain development was different, depending on the rs1360780 genotype. Importantly, we found that the differences in brain structure between the T-allele carriers and C/C homozygotes at low to moderate levels of maternal acceptance, which is not equivalent to maltreatment. The present study contributes to the G × E research by highlighting the necessity to investigate the role of non-adverse environmental factors.

Post‐traumatic stress symptoms of children and adolescents exposed to the 2008 Wenchuan Earthquake: A longitudinal study of 5‐HTTLPR genotype main effects and gene–environment interactions

Experiencing disasters causes severe mental disorders, among which post-traumatic stress disorder (PTSD) is the most common. We conducted a longitudinal study to examine the effect of 5-hydroxyl tryptamine transporter gene-linked polymorphic region (5-HTTLPR) genotype on child and adolescent PTSD symptom course after the 2008 Wenchuan Earthquake. We genotyped 963 participants who personally experienced the earthquake. PTSD symptoms were measured by University of California, Los Angeles PTSD reaction index at 2.5, 3.5, 4.5 and 5.5 years after the earthquake, respectively. Latent growth model was utilised to examine the main effect and gene-environment interaction effect of 5-HTTLPR on PTSD's symptom course. 5-HTTLPR genotype predicted initial PTSD symptom severity (β=0.108, p=.019) and rates of symptom recovery (β=-0.120, p=.031) between 2.5 and 5.5 years. Compared with L' allele carriers, those with S'S' genotype showed higher initial symptom severity but also faster recovery rate. 5-HTTLPR genotype only predicted symptom severity at 2.5 years after the earthquake, after controlling for sex, age, ethnicity and trauma severity (β=0.108, p=.019). This is the first evidence of the effect of 5-HTTLPR genotype on child and adolescent PTSD symptoms longitudinally, offering a novel perspective on the effect of 5-HTTLPR on PTSD symptom development following trauma exposure.

A single-nucleotide polymorphism influences brain morphology in drug-naïve patients with major depressive disorder.

ObjectiveRecently, a genome-wide association study successfully identified genetic variants associated with major depressive disorder (MDD). The study identified 17 independent single-nucleotide polymorphisms (SNPs) significantly associated with diagnosis of MDD. These SNPs were predicted to be enriched in genes that are expressed in the central nervous system and function in transcriptional regulation associated with neurodevelopment. The study aimed to investigate associations between 17 SNPs and brain morphometry using magnetic resonance imaging (MRI) in drug-naïve patients with MDD and healthy controls (HCs).MethodsForty-seven patients with MDD and 42 HCs were included. All participants underwent T1-weighted structural MRI and genotyping. The genotype–diagnosis interactions associated with regional cortical thicknesses were evaluated using voxel-based morphometry for the 17 SNPs.ResultsRegarding rs301806, an SNP in the RERE genomic regions, we found a significant difference in a genotype effect in the right-lateral orbitofrontal and postcentral lobes between diagnosis groups. After testing every possible diagnostic comparison, the genotype–diagnosis interaction in these areas revealed that the cortical thickness reductions in the MDD group relative to those in the HC group were significantly larger in T/T individuals than in C-carrier ones. For the other SNPs, no brain area was noted where a genotype effect significantly differed between the two groups.ConclusionsWe found that a RERE gene SNP was associated with cortical thickness reductions in the right-lateral orbitofrontal and postcentral lobes in drug-naïve patients with MDD. The effects of RERE gene polymorphism and gene–environment interactions may exist in brain structures of patients with MDD.

Exome sequencing of family trios from the National Birth Defects Prevention Study: Tapping into a rich resource of genetic and environmental data.

The National Birth Defects Prevention Study (NBDPS) is a multisite, population-based, case-control study of genetic and nongenetic risk factors for major structural birth defects. Eligible women had a pregnancy affected by a birth defect or a liveborn child without a birth defect between 1997 and 2011. They were invited to complete a telephone interview to collect pregnancy exposure data and were mailed buccal cell collection kits to collect specimens from themselves, their child (if living), and their child's father. Over 23,000 families representing more than 30 major structural birth defects provided DNA specimens. To evaluate their utility for exome sequencing (ES), specimens from 20 children with colonic atresia were studied. Evaluations were conducted on specimens collected using cytobrushes stored and transported in open versus closed packaging, on native genomic DNA (gDNA) versus whole genome amplified (WGA) products and on a library preparation protocol adapted to low amounts of DNA. The DNA extracted from brushes in open packaging yielded higher quality sequence data than DNA from brushes in closed packaging. Quality metrics of sequenced gDNA were consistently higher than metrics from corresponding WGA products and were consistently high when using a low input protocol. This proof-of-principle study established conditions under which ES can be applied to NBDPS specimens. Successful sequencing of exomes from well-characterized NBDPS families indicated that this unique collection can be used to investigate the roles of genetic variation and gene-environment interaction effects in birth defect etiologies, providing a valuable resource for birth defect researchers.

Interactions among moderate/severe periodontitis, ADIPOQ-rs1501299, and LEPR-rs1137100 polymorphisms on the risk of type 2 diabetes in a Chinese population

ObjectiveType 2 diabetes mellitus (T2DM) is a complex disease influenced by genes and the environment. Periodontitis a demonstrated risk factor of T2DM. Previous studies related to gene-environment interactions on the risk of T2DM mainly focused on gene-obesity interactions. However, the impact of gene-periodontitis interaction on the risk of T2DM has not yet been investigated. This study aimed to investigate gene-environment interactions among moderate/severe periodontitis, polymorphisms of adiponectin (ADIPOQ)-rs1501299, and leptin receptor (LEPR)-rs1137100 on T2DM risk in Chinese subjects. DesignA case-control study was conducted in 239 Chinese participants from Beijing Hypertension Association Institute (BHAL). After full-mouth periodontal examinations, the participants underwent bilateral buccal swabs for DNA testing. ADIPOQ-rs1501299 and LEPR-rs1137100 were used for genotyping. Generalised multifactor dimensionality reduction (GMDR) and logistic regression were used to examine the interactions among single nucleotide polymorphisms (SNPs) and moderate/severe periodontitis on the risk of T2DM. ResultsThe risk of T2DM was higher in moderate/severe periodontitis [adjusted odds ratio (AOR) = 3.67, 95% confidence interval (95%CI): 1.26–10.71] in ADIPOQ-rs1501299 GG genotype (AOR = 3.42, 95%CI: 1.81–6.46) and LEPR-rs1137100 GG genotype (AOR = 3.16, 95%CI: 1.56–6.39). The GMDR model indicated that there was a significant three-factor model (p = 0.001) involving rs1501299, rs1137100, and moderate/severe periodontitis, demonstrating a potential gene-environment interaction among periodontitis, polymorphisms of rs1501299, and rs1137100 influencing the risk of T2DM. Moderate/severe periodontitis patients with rs1501299-GG and rs1137100-GG have the highest T2DM risk after adjusting for age, gender, BMI, WHR, smoking status, alcohol consumption, economic status, and hypertension (AOR = 20.39, 95%CI: 2.64–157.26). ConclusionsInteractions among moderate/severe periodontitis, rs1501299-GG, and rs1137100-GG were associated with an increased risk of T2DM. This study may provide a new insight into the effect of gene-environment interactions on T2DM.

Predator videos and electric shock function as punishers for zebrafish (Danio rerio).

Zebrafish (Danio rerio) are a promising animal model for studying the effects of gene-environment interactions on behavior. Two experiments were conducted to assess punishment effects of presenting predator videos (Indian leaf fish; Nandus nandus) and electric shock on operant approach responses in zebrafish. In Experiment 1, the predator video and shock stimuli were presented upon a response maintained by a single variable-interval schedule of food reinforcement in different groups of fish. In Experiment 2, the predator video and shock stimuli were presented upon one of two response alternatives maintain by concurrently available variable-interval schedules of food reinforcement in different groups of fish. Responding decreased when the predator video and shock stimuli were presented relative to their absence in both experiments. Moreover, responding on an unpunished alternative did not reliably decrease in Experiment 2. These results indicate that the decrease in responding resulted from the punishment contingency rather than from elicited species-specific defense responses or conditioned avoidance. Thus, the predator video and electric shock functioned as punishers of operant behavior for zebrafish. Identifying punishers for this species could lead to research on how gene-environment interactions influence individual differences in sensitivity to punishment.

What Determines Perceived Income Justice? Evidence from the German TwinLife Study

Whether individuals perceive their income as being fair has far reaching consequences in the labor market and beyond. Yet we know little on the determinants of variation in perceived income justice across individuals. In this paper we ask whether genes can explain parts of the variation. To this end, we analyze data from the German TwinLife study. We find that more than 30% in individuals' perceived income justice can be attributed to genetic variation. The rest is mostly driven by idiosyncratic environmental effects. We, furthermore, do not find evidence for gene-environment interaction effects.

Composite kernel machine regression based on likelihood ratio test for joint testing of genetic and gene-environment interaction effect.

Most common human diseases are a result from the combined effect of genes, the environmental factors, and their interactions such that including gene-environment (GE) interactions can improve power in gene mapping studies. The standard strategy is to test the SNPs, one-by-one, using a regression model that includes both the SNP effect and the GE interaction. However, the SNP-by-SNP approach has serious limitations, such as the inability to model epistatic SNP effects, biased estimation, and reduced power. Thus, in this article, we develop a kernel machine regression framework to model the overall genetic effect of a SNP-set, considering the possible GE interaction. Specifically, we use a composite kernel to specify the overall genetic effect via a nonparametric function andwe model additional covariates parametrically within the regression framework. The composite kernel is constructed as a weighted average of two kernels, one corresponding to the genetic main effect and one corresponding to the GE interaction effect. We propose a likelihood ratio test (LRT) and a restricted likelihood ratio test (RLRT) for statistical significance. We derive a Monte Carlo approach for the finite sample distributions of LRT and RLRT statistics. Extensive simulations and real data analysis show that our proposed method has correct type I error and can have higher power than score-based approaches under many situations.

Methods to evaluate rare variants gene-age interaction for triglycerides

Triglycerides are an important measure of heart health. Although more than 90 genes have been found to be associated to lipids, they only explain 12 to 15% of the variance in lipid levels. Evidence suggests that age may interact with the genetic effect on lipid levels. Existing methods to detect the main effect of rare variants cannot be readily applied for testing the gene environment interaction effect of rare variants, as those methods either have unstable results or inflated Type I error rates when the main effect exists. To overcome these difficulties, we developed two statistical methods: testing of optimally weighted combination of single-nucleotide polymorphism (SNP) environment interaction (TOW-SE) and a variable weight TOW-SE (VW-TOW-SE) to test the gene environment interaction effect of rare variants by grouping SNPs into biologically meaningful SNP-sets (SNPs in a gene or pathway) to improve power and interpretability. The proposed methods can be applied to either continuous or binary environmental variables, and to either continuous or binary outcomes. Simulation studies show that Type I error rates of the proposed methods are under control. Comparing the two methods with the existing interaction sequence kernel association test (iSKAT), the VW-TOW-SE is the most powerful test and the TOW-SE is the second most powerful test when gene environment interaction effect exists for both rare and common variants. The three tests were applied to the GAW20 simulated data, among the five regions in which the main effect of common SNPs was simulated and the gene–age interaction effect was not included. As expected, none of the tests indicated positive results.

Complement System and Age-Related Macular Degeneration: Implications of Gene-Environment Interaction for Preventive and Personalized Medicine.

Age-related macular degeneration (AMD) is the most common cause of visual loss in developed countries, with a significant economic and social burden on public health. Although genome-wide and gene-candidate studies have been enabled to identify genetic variants in the complement system associated with AMD pathogenesis, the effect of gene-environment interaction is still under debate. In this review we provide an overview of the role of complement system and its genetic variants in AMD, summarizing the consequences of the interaction between genetic and environmental risk factors on AMD onset, progression, and therapeutic response. Finally, we discuss the perspectives of current evidence in the field of genomics driven personalized medicine and public health.

Parent depressive symptomatology moderates the etiology of externalizing behavior in childhood: An examination of gene-environment interaction effects.

Parent depressive symptomatology is robust risk factor for externalizing behavior in childhood (Goodman et al., 2011). Although the precise mechanisms underlying this association have yet to be fully illuminated, there is some evidence that parent depression can impact externalizing behavior via both genetic and environmental pathways. In the current study, we investigated the extent to which genetic and environmental influences on externalizing behavior are moderated by parent depressive symptoms (i.e., genotype-environment interaction) in a sample of 2,060, 6- to 11-year-old twins. Results suggest that genetic influences explain more variance in externalizing behavior as maternal depressive symptoms increase, whereas shared environmental effects decrease. These findings were specific to maternal depressive symptoms, however, and did not extend to not paternal depressive symptoms. Findings are critical for understanding the role of parental depression as a risk factor for problematic child behavior, and informing programs that seek to minimize the impact of this risk factor. (PsycINFO Database Record