Gene-environment Interaction Studies Research Articles

Pregnancy does not modify the risk of MS in genetically susceptible women.

ObjectiveTo use the case-only gene-environment (G E) interaction study design to estimate interaction between pregnancy before onset of MS symptoms and established genetic risk factors for MS among White adult females.MethodsWe studied 2,497 female MS cases from 4 cohorts in the United States, Sweden, and Norway with clinical, reproductive, and genetic data. Pregnancy exposure was defined in 2 ways: (1) live birth pregnancy before onset of MS symptoms and (2) parity before onset of MS symptoms. We estimated interaction between pregnancy exposure and established genetic risk variants, including a weighted genetic risk score and both HLA and non-HLA variants, using logistic regression and proportional odds regression within each cohort. Within-cohort associations were combined using inverse variance meta-analyses with random effects. The case-only G × E independence assumption was tested in 7,067 individuals without MS.ResultsEvidence for interaction between pregnancy exposure and established genetic risk variants, including the strongly associated HLA-DRB1*15:01 allele and a weighted genetic risk score, was not observed. Results from sensitivity analyses were consistent with observed results.ConclusionOur findings indicate that pregnancy before symptom onset does not modify the risk of MS in genetically susceptible White females.

The incidence of psychotic disorders among migrants and minority ethnic groups in Europe: findings from the multinational EU-GEI study.

In Europe, the incidence of psychotic disorder is high in certain migrant and minority ethnic groups (hence: 'minorities'). However, it is unknown how the incidence pattern for these groups varies within this continent. Our objective was to compare, across sites in France, Italy, Spain, the UK and the Netherlands, the incidence rates for minorities and the incidence rate ratios (IRRs, minorities v. the local reference population). The European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) study was conducted between 2010 and 2015. We analyzed data on incident cases of non-organic psychosis (International Classification of Diseases, 10th edition, codes F20-F33) from 13 sites. The standardized incidence rates for minorities, combined into one category, varied from 12.2 in Valencia to 82.5 per 100 000 in Paris. These rates were generally high at sites with high rates for the reference population, and low at sites with low rates for the reference population. IRRs for minorities (combined into one category) varied from 0.70 (95% CI 0.32-1.53) in Valencia to 2.47 (95% CI 1.66-3.69) in Paris (test for interaction: p = 0.031). At most sites, IRRs were higher for persons from non-Western countries than for those from Western countries, with the highest IRRs for individuals from sub-Saharan Africa (adjusted IRR = 3.23, 95% CI 2.66-3.93). Incidence rates vary by region of origin, region of destination and their combination. This suggests that they are strongly influenced by the social context.

Interaction between physical activity and polygenic risk score for type-2 diabetes in older Americans

Abstract Background Genetics plays an important role in the development of type-2 diabetes (T2D). Polygenic risk scores (PRS) are increasingly used to quantify genetic risk of T2D in epidemiological studies. These scores, when integrated into analyses of modifiable lifestyle factors, may improve understanding of T2D etiology, as the strength of association with T2D and some lifestyle or demographic factors may vary according to genetic predisposition. Methods We examined PRS-lifestyle factor interactions on T2D with data from the United States Health and Retirement Study (HRS), a prospective longitudinal cohort of older adults (≥50 at baseline). HRS contains nationally representative samples of Black and White Americans with pre-calculated PRS for T2D (N = 14,001). Covariates included sex, education, BMI, smoking, alcohol, and physical activity. Predicted prevalence and incidence of T2D were calculated with logistic regression models. Nonparametric bootstrap method was performed to calculate differences in T2D prevalence and incidence by PRS percentiles and interaction variables. Results Significant interaction (p_interaction=0.0096) was detected between PRS and physical activity among Whites only. In those with the lowest decile of PRS, T2D prevalence was similar (∼10%) for those reporting no physical activity compared to low or moderate activity. In those with the top decile of PRS, lower T2D prevalence (17%, 95%CI:14.8,19.6) was observed among those with moderate compared to no activity (24%, 95%CI:20.4,27.5). Incident T2D in Whites followed a similar pattern (p_interaction=0.0194). Among Black participants, no significant interaction with any lifestyle variables was detected. Conclusions Interaction of different genetic risk profiles with lifestyle factors may inform understanding of why certain inventions are more or less effective in different groups of people, potentially improving clinical and prevention interventions. Key messages Protection conferred by physical activity on T2D varied by underlying genetic risk. Gene-environment interaction studies provide insights on why lifestyle factors vary in their associations with T2D.

Gene-environment interaction promotes Alzheimer's risk as revealed by synergy of repeated mild traumatic brain injury and mouse App knock-in

There is a strong unmet need for translational progress towards Alzheimer's disease (AD) modifying therapy. Unfortunately, preclinical modeling of the disease has been disappointing, relying primarily on transgenic mouse overexpression of rare dominant mutations. Clinical manifestation of AD symptoms is known to reflect interaction between environmental and genetic risks. Mild traumatic brain injury (mTBI) is an environmental risk for dementia, including Alzheimer's, but there has been limited mechanistic analysis of mTBI contribution to AD. Here, we investigate the interplay between mTBI and Aβ precursor protein gene mutation in AD pathogenesis. We employed a knock-in (KI) model of AD that expresses the Aß-containing exons from human APP bearing the Swedish and Iberian mutations, namely AppNL-F/NL-F mice. Without environmental risk, this genetic variation yields minimal mouse symptomatology. Anesthetized 4-month-old KI mice and their age-matched wild type (WT) controls were subjected to repeated mild closed head injury (rmCHI), once daily for 14 days. Anesthetized, uninjured genotype- and age-matched mice were used as sham controls. At 3- and 8-months post-injury, amyloid-β, phospho-tau and Iba1 expression in the injured KI cortices were assessed. Our data reveal that rmCHI enhances accumulation of amyloid-β and hyperphosphorylated tau inclusions, as well as neuroinflammation in AppNL-F/NL-F mice. Furthermore, novel object recognition and Morris water maze tests demonstrated that rmCHI greatly exacerbates persistent cognitive deficits in APPNL-F/NL-F mice. Therefore, study of gene-environment interaction demonstrates that combining risk factors provides a more robust model for AD, and that repeated mTBI substantially accelerates AD pathology in a genetically susceptible situation.

S126. THE RELATION OF THE PSYCHOSIS CONTINUUM WITH SCHIZOPHRENIA POLYGENIC RISK SCORE AND CANNABIS USE

BackgroundThere has been much debate about whether research into psychosis should be conducted using symptom dimensions as opposed to diagnostic categories. Indeed, dimensions, like categories, may be practical but arbitrary tools for research and clinical practice; hence, they should not be based on psychometric data only. The aim of this study was to externally validate empirically derived symptom dimensions using combined genetic and environmental data. Specifically, we examined the hypothesis that the continuous multivariate distribution of psychosis is a function of cannabis use and genetic liability to schizophrenia, as summarised by polygenic risk score (SZ-PRS).MethodsAs part of the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) study, we analysed a large multinational sample of First Episode Psychosis patients (FEP) and population controls, with available genotype and psychopathology information. Using item response modelling in Mplus, we estimated a bifactor model of psychotic symptoms in FEP, and of psychotic experiences in controls. Using PRSice, we built SZ-PRS by weighting individuals’ risk variants by the log(odds ratio), where the odds ratio was extracted from the latest summary statistics of Psychiatric Genomic Consortium mega-analyses on schizophrenia. Finally, we used linear regression to test the combined associations of the positive symptom/experience dimensions with SZ-PRS and daily/current cannabis use, separately in FEP and controls, after covarying for 10 ancestry principal components, sex, age, and primary diagnosis.ResultsThe continuous distribution of psychosis was represented by two bi-factor models composed of 1) in FEP, one general psychosis factor and five specific dimensions; 2) in controls, one general psychosis factor and three specific dimensions.Linear regression modelling showed that in 617 FEP, both daily cannabis use (B=0.31; 95%CI 0.11 to 0.52; p=0.002) and SZ-PRS (B=0.22; 95%CI 0.04 to 0.39; p=0.014) were independently associated with the dimension of positive symptoms. Similar results were found in 979 population controls, with a positive association of both current use of cannabis (B=0.26, 95%CI 0.06 to 0.46; p=0.011) and SZ-PRS (B=0.13, 95%CI 0.02 to 0.25; p=0.022) with the dimension of psychotic experiences.DiscussionWe found two factors associated with the latent dimensional structure of psychosis. SZ risk variants and cannabis use independently map onto specific dimensions of positive symptoms, contributing to variation across the psychosis continuum. Our study supports the theory that psychotic experiences in the general population are biologically similar to clinical psychotic symptoms.

Gene-environment Interaction on the Risk of Type 2 Diabetes Among Ethnic Minority Populations Living in Europe and North America: A Systematic Review.

The body of evidence on gene-environment interaction (GEI) related to type 2 diabetes (T2D) has grown in the recent years. However, most studies on GEI have sought to explain variation within individuals of European ancestry and results among ethnic minority groups are inconclusive. To investigate any interaction between a gene and an environmental factor in relation to T2D among ethnic minority groups living in Europe and North America. We systematically searched Medline and EMBASE databases for the published literature in English up to 25th March 2019. The screening, data extraction and quality assessment were performed by reviewers independently. 1068 studies identified through our search, of which nine cohorts of six studies evaluating several different GEIs were included. The mean follow-up time in the included studies ranged from 5 to 25.7 years. Most studies were relatively small scale and few provided replication data. All studies included in the review included ethnic minorities from North America (Native-Americans, African- Americans, and Aboriginal Canadian), none of the studies in Europe assessed GEI in relation to T2D incident in ethnic minorities. The only significant GEI among ethnic minorities was HNF1A rs137853240 and smoking on T2D incident among Native-Canadians (Pinteraction = 0.006). There is a need for more studies on GEI among ethnicities, broadening the spectrum of ethnic minority groups being investigated, performing more discovery using genome-wide approaches, larger sample sizes for these studies by collaborating efforts such as the InterConnect approach, and developing a more standardized method of reporting GEI studies are discussed.

Clinical Integration of Genome Diagnostics for Congenital Anomalies of the Kidney and Urinary Tract.

Revolutions in genetics, epigenetics, and bioinformatics are currently changing the outline of diagnostics and clinical medicine. From a nephrologist's perspective, individuals with congenital anomalies of the kidney and urinary tract (CAKUT) are an important patient category: not only is CAKUT the predominant cause of kidney failure in children and young adults, but the strong phenotypic and genotypic heterogeneity of kidney and urinary tract malformations has hampered standardization of clinical decision making until now. However, patients with CAKUT may benefit from precision medicine, including an integrated diagnostics trajectory, genetic counseling, and personalized management to improve clinical outcomes of developmental kidney and urinary tract defects. In this review, we discuss the present understanding of the molecular etiology of CAKUT and the currently available genome diagnostic modalities in the clinical care of patients with CAKUT. Finally, we discuss how clinical integration of findings from large-scale genetic, epigenetic, and gene-environment interaction studies may improve the prognosis of all individuals with CAKUT.

Low serum 25-hydroxyvitamin D status in the pathogenesis of stress fractures in military personnel: An evidenced link to support injury risk management.

Stress fractures are common amongst healthy military recruits and athletes. Reduced vitamin D availability, measured by serum 25-hydroxyvitamin D (25OHD) status, has been associated with stress fracture risk during the 32-week Royal Marines (RM) training programme. A gene-environment interaction study was undertaken to explore this relationship to inform specific injury risk mitigation strategies. Fifty-one males who developed a stress fracture during RM training (n = 9 in weeks 1-15; n = 42 in weeks 16-32) and 141 uninjured controls were genotyped for the vitamin D receptor (VDR) FokI polymorphism. Serum 25OHD was measured at the start, middle and end (weeks 1, 15 and 32) of training. Serum 25OHD concentration increased in controls between weeks 1-15 (61.8±29.1 to 72.6±28.8 nmol/L, p = 0.01). Recruits who fractured did not show this rise and had lower week-15 25OHD concentration (p = 0.01). Higher week-15 25OHD concentration was associated with reduced stress fracture risk (adjusted OR 0.55[0.32-0.96] per 1SD increase, p = 0.04): the greater the increase in 25OHD, the greater the protective effect (p = 0.01). The f-allele was over-represented in fracture cases compared with controls (p<0.05). Baseline 25OHD status interacted with VDR genotype: a higher level was associated with reduced fracture risk in f-allele carriers (adjusted OR 0.39[0.17-0.91], p = 0.01). Improved 25OHD status between weeks 1-15 had a greater protective effect in FF genotype individuals (adjusted OR 0.31[0.12-0.81] vs. 1.78[0.90-3.49], p<0.01). Stress fracture risk in RM recruits is impacted by the interaction of VDR genotype with vitamin D status. This further supports the role of low serum vitamin D concentrations in causing stress fractures, and hence prophylactic vitamin D supplementation as an injury risk mitigation strategy.

Daily use of high-potency cannabis is associated with more positive symptoms in first-episode psychosis patients: the EU-GEI case-control study.

Daily use of high-potency cannabis has been reported to carry a high risk for developing a psychotic disorder. However, the evidence is mixed on whether any pattern of cannabis use is associated with a particular symptomatology in first-episode psychosis (FEP) patients. We analysed data from 901 FEP patients and 1235 controls recruited across six countries, as part of the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) study. We used item response modelling to estimate two bifactor models, which included general and specific dimensions of psychotic symptoms in patients and psychotic experiences in controls. The associations between these dimensions and cannabis use were evaluated using linear mixed-effects models analyses. In patients, there was a linear relationship between the positive symptom dimension and the extent of lifetime exposure to cannabis, with daily users of high-potency cannabis having the highest score (B = 0.35; 95% CI 0.14-0.56). Moreover, negative symptoms were more common among patients who never used cannabis compared with those with any pattern of use (B = -0.22; 95% CI -0.37 to -0.07). In controls, psychotic experiences were associated with current use of cannabis but not with the extent of lifetime use. Neither patients nor controls presented differences in depressive dimension related to cannabis use. Our findings provide the first large-scale evidence that FEP patients with a history of daily use of high-potency cannabis present with more positive and less negative symptoms, compared with those who never used cannabis or used low-potency types.

Social disadvantage, linguistic distance, ethnic minority status and first-episode psychosis: results from the EU-GEI case–control study

Ethnic minority groups in Western countries face an increased risk of psychotic disorders. Causes of this long-standing public health inequality remain poorly understood. We investigated whether social disadvantage, linguistic distance and discrimination contributed to these patterns. We used case-control data from the EUropean network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI) study, carried out in 16 centres in six countries. We recruited 1130 cases and 1497 population-based controls. Our main outcome measure was first-episode ICD-10 psychotic disorder (F20-F33), and exposures were ethnicity (white majority, black, mixed, Asian, North-African, white minority and other), generational status, social disadvantage, linguistic distance and discrimination. Age, sex, paternal age, cannabis use, childhood trauma and parental history of psychosis were included as a priori confounders. Exposures and confounders were added sequentially to multivariable logistic models, following multiple imputation for missing data. Participants from any ethnic minority background had crude excess odds of psychosis [odds ratio (OR) 2.03, 95% confidence interval (CI) 1.69-2.43], which remained after adjustment for confounders (OR 1.61, 95% CI 1.31-1.98). This was progressively attenuated following further adjustment for social disadvantage (OR 1.52, 95% CI 1.22-1.89) and linguistic distance (OR 1.22, 95% CI 0.95-1.57), a pattern mirrored in several specific ethnic groups. Linguistic distance and social disadvantage had stronger effects for first- and later-generation groups, respectively. Social disadvantage and linguistic distance, two potential markers of sociocultural exclusion, were associated with increased odds of psychotic disorder, and adjusting for these led to equivocal risk between several ethnic minority groups and the white majority.

Psychotic Experiences Are Associated With Paternal Age But Not With Delayed Fatherhood in a Large, Multinational, Community Sample.

Advanced paternal age has been consistently associated with an increased risk of schizophrenia. It is less known if such an association also exists with subclinical/attenuated forms of psychosis. Additionally, it has been suggested that it is not paternal age per se, but rather delayed fatherhood, as a marker of a genetic liability of psychosis, that is the cause of the association. The aim of the current study was to examine whether paternal age and/or delayed fatherhood (paternity age) predict self-reported positive, negative, and/or depressive dimensions of psychosis in a large sample from the general population. The sample (N = 1465) was composed of control subjects from the 6 countries participating in the European Union Gene-Environment Interaction study. The CAPE, a self-report questionnaire, was used to measure dimensions of subclinical psychosis. Paternal age at the time of respondents' birth and age of paternity were assessed by self-report. We assessed the influence of the variables of interest (paternal age or paternity age) on CAPE scores after adjusting for potential confounders (age, gender, and ethnicity). Paternal age was positively associated with the positive dimension of the CAPE. By contrast, paternity age was not associated with any of the psychosis dimensions assessed by the CAPE. Thus, our results do not support the idea that delayed fatherhood explains the association between age of paternity and psychosis risk. Furthermore, our results provide arguments for the hypothesis of an etiologic continuum of psychosis.

Novel and Known Gene-Smoking Interactions With cIMT Identified as Potential Drivers for Atherosclerosis Risk in West-African Populations of the AWI-Gen Study

IntroductionAtherosclerosis is a key contributor to the burden of cardiovascular diseases (CVDs) and many epidemiological studies have reported on the effect of smoking on carotid intima-media thickness (cIMT) and its subsequent effect on CVD risk. Gene-environment interaction studies have contributed towards understanding some of the missing heritability of genome-wide association studies. Gene-smoking interactions on cIMT have been studied in non-African populations (European, Latino-American, and African American) but no comparable African research has been reported. Our aim was to investigate smoking-SNP interactions on cIMT in two West African populations by genome-wide analysis.Materials and methodsOnly male participants from Burkina Faso (Nanoro = 993) and Ghana (Navrongo = 783) were included, as smoking was extremely rare among women. Phenotype and genotype data underwent stringent QC and genotype imputation was performed using the Sanger African Imputation Panel. Smoking prevalence among men was 13.3% in Nanoro and 42.5% in Navrongo. We analyzed gene-smoking interactions with PLINK after adjusting for covariates: age and 6 PCs (Model 1); age, BMI, blood pressure, fasting glucose, cholesterol levels, MVPA, and 6 PCs (Model 2). All analyses were performed at site level and for the combined data set.ResultsIn Nanoro, we identified new gene-smoking interaction variants for cIMT within the previously described RCBTB1 region (rs112017404, rs144170770, and rs4941649) (Model 1: p = 1.35E-07; Model 2: p = 3.08E-08). In the combined sample, two novel intergenic interacting variants were identified, rs1192824 in the regulatory region of TBC1D8 (p = 5.90E-09) and rs77461169 (p = 4.48E-06) located in an upstream region of open chromatin. In silico functional analysis suggests the involvement of genes implicated in biological processes related to cell or biological adhesion and regulatory processes in gene-smoking interactions with cIMT (as evidenced by chromatin interactions and eQTLs).DiscussionThis is the first gene-smoking interaction study for cIMT, as a risk factor for atherosclerosis, in sub-Saharan African populations. In addition to replicating previously known signals for RCBTB1, we identified two novel genomic regions (TBC1D8, near BCHE) involved in this gene-environment interaction.

The EUropean Network of National Schizophrenia Networks Studying Gene\u2013Environment Interactions (EU-GEI): Incidence and First-Episode Case\u2013Control Programme

PurposeThe EUropean Network of National Schizophrenia Networks Studying Gene–Environment Interactions (EU-GEI) study contains an unparalleled wealth of comprehensive data that allows for testing hypotheses about (1) variations in incidence within and between countries, including by urbanicity and minority ethnic groups; and (2) the role of multiple environmental and genetic risk factors, and their interactions, in the development of psychotic disorders.MethodsBetween 2010 and 2015, we identified 2774 incident cases of psychotic disorders during 12.9 million person-years at risk, across 17 sites in 6 countries (UK, The Netherlands, France, Spain, Italy, and Brazil). Of the 2774 incident cases, 1130 cases were assessed in detail and form the case sample for case–control analyses. Across all sites, 1497 controls were recruited and assessed. We collected data on an extensive range of exposures and outcomes, including demographic, clinical (e.g. premorbid adjustment), social (e.g. childhood and adult adversity, cannabis use, migration, discrimination), cognitive (e.g. IQ, facial affect processing, attributional biases), and biological (DNA via blood sample/cheek swab). We describe the methodology of the study and some descriptive results, including representativeness of the cohort.ConclusionsThis resource constitutes the largest and most extensive incidence and case–control study of psychosis ever conducted.

Interactions between Polygenic Scores and Environments: Methodological and Conceptual Challenges.

Interest in the study of gene–environment interaction has recently grown due to the sudden availability of molecular genetic data—in particular, polygenic scores—in many long-running longitudinal studies. Identifying and estimating statistical interactions comes with several analytic and inferential challenges; these challenges are heightened when used to integrate observational genomic and social science data. We articulate some of these key challenges, provide new perspectives on the study of gene–environment interactions, and end by offering some practical guidance for conducting research in this area. Given the sudden availability of well-powered polygenic scores, we anticipate a substantial increase in research testing for interaction between such scores and environments. The issues we discuss, if not properly addressed, may impact the enduring scientific value of gene–environment interaction studies.

A Case Control Study of Gene Environment Interaction in Pre-Eclampsia with Special Reference to Organochlorine Pesticides

Objectives: To study and compare the frequency of GSTM1 & T1 gene polymorphism in cases (Pre-eclampsia) and controls (normal pregnancy), to estimate and compare serum levels of Glutathione-S-Transferase enzyme in cases and controls, to quantify and compare Organochlorine pesticides levels in maternal blood of cases and controls and to evaluate the correlation; if any; amongst GSTM1 & T1 gene polymorphism, GST activity and Organochlorine pesticides levels in cases. Methodology: Maternal blood samples of 66 Pre-eclampsia cases and equal number of matched control were collected. Samples were analyzed for OCPs levels, GST activity and GST M1 and T1 gene polymorphism. Results: β-HCH, Heptachlor, Dieldrin, Endosulphan-I levels were found in higher amounts in cases as compared to controls. GSTT1-/GSTM1- (double null polymorphism) was significantly high in cases as compared to controls. GSTT1-(null) genotype was exclusively associated with severe pre-eclampsia. When GST activity was correlated with genotypic variation of GSTT1/M1 gene, null genotypes significantly downregulated GST activity, lowest being with double null genotype. Conclusions: There is a possible role of gene-environment interaction in the pathogenesis of pre-eclampsia. An interaction of increased levels of pesticides with GST polymorphisms (null type) causes low levels of GST enzyme levels (an anti-oxidant) resulting in increased oxidative stress causing pre-eclampsia.

An Understudied Dimension: Why Age Needs to Be Considered When Studying Epigenetic-Environment Interactions.

We live in a complex chemical environment where there are an estimated 350 000 chemical compounds or mixtures commercially produced. A strong body of literature shows that there are time points during early development when an organism’s epigenome is particularly sensitive to chemicals in its environment. What is less understood is how gene-environment and epigenetic-environment interactions change with age. This question is bidirectional: (1) how do chemicals in the environment affect the aging process and (2) how does aging affect an organism’s response to its chemical environment? The study of gene-environment interactions with age is especially important because, in many parts of the world, older individuals are a large and rapidly growing proportion of the population and because aging is a process universal to most of the animal kingdom. Epigenetics has emerged as a crucial framework for studying aging as epigenetic pathways, often triggered by environmental stimuli, have been shown to be essential regulators of the aging process. In this perspective article, we delineate the connection between aging, epigenetics, and environmental exposures. We discuss why it is essential to consider age when researching how an organism interacts with its environment. We describe recent advances in understanding how the chemical environment affects aging and the gap in research on how age affects an organism’s response to the environment. Finally, we highlight how model organisms and network approaches can help fill this crucial gap. Taken together, systemic changes that occur in the epigenome with age indicate that adult organisms cannot be treated as a homogeneous population and that there are discrete mechanisms modulating the aging epigenome that we do not yet understand.

Gene-environment interaction: New insights into perceived parenting and social anxiety among adolescents.

Social anxiety symptoms (SAS) are among the most common mental health problems during adolescence, and it has been shown that parenting influences the adolescent's level of social anxiety. In addition, it is now widely assumed that most mental health problems, including social anxiety, originate from a complex interplay between genes and environment. However, to date, gene-environment (G × E) interactions studies in the field of social anxiety remain limited. In this study, we have examined how 274 genes involved in different neurotransmission pathways interact with five aspects of perceived parenting as environmental exposure (i.e., support, proactive control, psychological control, punitive control, and harsh punitive control) to affect SAS during adolescence. We have applied an analytical technique that allows studying genetic information at the gene level, by aggregating data from multiple single-nucleotide-polymorphisms within the same gene and by taking into account the linkage disequilibrium structure of the gene. All participants were part of the STRATEGIES cohort of 948 Flemish adolescents (mean age = 13.7), a population-based study on the development of problem behaviors in adolescence. Relevant genes were preselected based on prior findings and neurotransmitter-related functional protein networks. The results suggest that genes involved in glutamate (SLC1A1), glutathione neurotransmission (GSTZ1), and oxidative stress (CALCRL), in association with harsh punitive parenting, may contribute to social anxiety in adolescence. Isolated polymorphisms in these genes have been related to anxiety and related disorders in earlier work.Conclusions: Taken together, these findings provide new insights into possible biological pathways and environmental risk factors involved in the etiology of social anxiety symptoms' development. Taken together, these findings provide new insights into possible biological pathways and environmental risk factors involved in the etiology of social anxiety symptoms' development.

Sex differences in cognitive functioning of patients at-risk for psychosis and healthy controls: Results from the European Gene-Environment Interactions study.

Sex differences in cognitive functioning have long been recognized in schizophrenia patients and healthy controls (HC). However, few studies have focused on patients with an at-risk mental state (ARMS) for psychosis. Thus, the aim of the present study was to investigate sex differences in neurocognitive performance in ARMS patients compared with HC. The data analyzed in this study were collected within the multicenter European Gene-Environment Interactions study (11 centers). A total of 343 ARMS patients (158 women) and 67 HC subjects (33 women) were included. All participants completed a comprehensive neurocognitive battery. Linear mixed effects models were used to explore whether sex differences in cognitive functioning were present in the total group (main effect of sex) and whether sex differences were different for HC and ARMS (interaction between sex and group). Women performed better in social cognition, speed of processing, and verbal learning than men regardless of whether they were ARMS or HC. However, only differences in speed of processing and verbal learning remained significant after correction for multiple testing. Additionally, ARMS patients displayed alterations in attention, current IQ, speed of processing, verbal learning, and working memory compared with HC. Findings indicate that sex differences in cognitive functioning in ARMS are similar to those seen between healthy men and women. Thus, it appears that sex differences in cognitive performance may not be specific for ARMS, a finding resembling that in patients with schizophrenic psychoses.

Generalized Markovian Quantity Distribution Systems: Social Science Applications

Interest in the study of gene–environment interaction has recently grown due to the sudden availability of molecular genetic data—in particular, polygenic scores—in many long-running longitudinal studies. Identifying and estimating statistical interactions comes with several analytic and inferential challenges; these challenges are heightened when used to integrate observational genomic and social science data. We articulate some of these key challenges, provide new perspectives on the study of gene–environment interactions, and end by offering some practical guidance for conducting research in this area. Given the sudden availability of well-powered polygenic scores, we anticipate a substantial increase in research testing for interaction between such scores and environments. The issues we discuss, if not properly addressed, may impact the enduring scientific value of gene–environment interaction studies.

Semiparametric Bayesian variable selection for gene-environment interactions.

Many complex diseases are known to be affected by the interactions between genetic variants and environmental exposures beyond the main genetic and environmental effects. Study of gene-environment (G×E) interactions is important for elucidating the disease etiology. Existing Bayesian methods for G×E interaction studies are challenged by the high-dimensional nature of the study and the complexity of environmental influences. Many studies have shown the advantages of penalization methods in detecting G×E interactions in "large p, small n" settings. However, Bayesian variable selection, which can provide fresh insight into G×E study, has not been widely examined. We propose a novel and powerful semiparametric Bayesian variable selection model that can investigate linear and nonlinear G×E interactions simultaneously. Furthermore, the proposed method can conduct structural identification by distinguishing nonlinear interactions from main-effects-only case within the Bayesian framework. Spike-and-slab priors are incorporated on both individual and group levels to identify the sparse main and interaction effects. The proposed method conducts Bayesian variable selection more efficiently than existing methods. Simulation shows that the proposed model outperforms competing alternatives in terms of both identification and prediction. The proposed Bayesian method leads to the identification of main and interaction effects with important implications in a high-throughput profiling study with high-dimensional SNP data.