scholarly journals NAD deficiency due to environmental factors or gene–environment interactions causes congenital malformations and miscarriage in mice

2020 ◽  
Vol 117 (7) ◽  
pp. 3738-3747 ◽  
Author(s):  
Hartmut Cuny ◽  
Melissa Rapadas ◽  
Jessica Gereis ◽  
Ella M. M. A. Martin ◽  
Rosemary B. Kirk ◽  
...  
Keyword(s):  
Environmental Factors ◽  
Congenital Malformation ◽  
Genetic Variants ◽  
Congenital Malformations ◽  
Environment Interaction ◽  
Loss Of Function ◽  
Vitamin B3 ◽  
Gene Environment ◽  
Nad Synthesis ◽  
Embryo Loss

Causes for miscarriages and congenital malformations can be genetic, environmental, or a combination of both. Genetic variants, hypoxia, malnutrition, or other factors individually may not affect embryo development, however, they may do so collectively. Biallelic loss-of-function variants in HAAO or KYNU, two genes of the nicotinamide adenine dinucleotide (NAD) synthesis pathway, are causative of congenital malformation and miscarriage in humans and mice. The variants affect normal embryonic development by disrupting the synthesis of NAD, a key factor in multiple biological processes, from its dietary precursor tryptophan, resulting in NAD deficiency. This study demonstrates that congenital malformations caused by NAD deficiency can occur independent of genetic disruption of NAD biosynthesis. C57BL/6J wild-type mice had offspring exhibiting similar malformations when their supply of the NAD precursors tryptophan and vitamin B3 in the diet was restricted during pregnancy. When the dietary undersupply was combined with a maternal heterozygous variant in Haao, which alone does not cause NAD deficiency or malformations, the incidence of embryo loss and malformations was significantly higher, suggesting a gene–environment interaction. Maternal and embryonic NAD levels were deficient. Mild hypoxia as an additional factor exacerbated the embryo outcome. Our data show that NAD deficiency as a cause of embryo loss and congenital malformation is not restricted to the rare cases of biallelic mutations in NAD synthesis pathway genes. Instead, monoallelic genetic variants and environmental factors can result in similar outcomes. The results expand our understanding of the causes of congenital malformations and the importance of sufficient NAD precursor consumption during pregnancy.

scholarly journals A role for gene-environment interactions in Autism Spectrum Disorder is suggested by variants in genes regulating exposure to environmental factors

2019 ◽  
Author(s):  
João Xavier Santos ◽  
Célia Rasga ◽  
Ana Rita Marques ◽  
Hugo F. M. C. Martiniano ◽  
Muhammad Asif ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Environmental Factors ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Environment Interaction ◽  
Postnatal Exposure ◽  
Loss Of Function ◽  
Single Nucleotide Variants ◽  
Gene Environment

AbstractIntroductionAutism Spectrum Disorder (ASD) is a clinically heterogeneous neurodevelopmental disorder defined by deficits in social communication and interaction and repetitive and stereotyped interests and behaviors. ASD heritability estimates of 50-83% support a strong role of genetics in its onset, with large sequencing studies reporting a high burden of rare potentially pathogenic copy number variants (CNVs) and single nucleotide variants (SNVs) in affected subjects. Recent data strongly suggests that prenatal to postnatal exposure to ubiquitous environmental factors (e.g. environmental toxins, medications and nutritional factors) contribute to ASD risk. Detoxification processes and physiological permeability barriers (i.e. blood-brain barrier, placenta and respiratory cilia) are crucial in regulating exposure and response to external agents during early development. Thus, the objectives of this study were: 1) to find genes involved in detoxification and regulation of barriers permeability with a high load of relevant CNVs and SNVs in ASD subjects; 2) to explore interactions between the identified genes and environmental factors relevant for the disorder.Material and MethodsThrough literature and databases review we searched for genes involved in detoxification and regulation of barriers permeability processes. Genetic data collected from large datasets of subjects with ASD (Autism Genome Project (AGP), Simmons Simplex Collection (SSC), and Autism Sequencing Consortium (ASC)) was used to identify potentially pathogenic variants targeting detoxification and barrier genes. Data from control subjects without neuropsychiatric disorder history was used for comparison purposes. The Comparative Toxicogenomics Database (CTD) was interrogated to identify putatively relevant gene-environment interactions reported in humans throughout the literature.ResultsWe compiled a list of 519 genes involved in detoxification and regulation of permeability barriers. The analysis of AGP and SSC data resulted in the identification of 7 genes more-frequently targeted by CNVs in ASD-subjects from both datasets, after Bonferroni correction for multiple testing (AGP: P<3.5211×10−4; SSC: P< 4.587×10−4). Moreover, 8 genes were exclusively targeted by CNVs from ASD subjects. Regarding SNVs analyses using the ASC dataset, we found 40 genes targeted by potentially pathogenic loss-of-function and/or missense SNVs exclusive to 6 or more cases. The CTD was interrogated for interactions between 55 identified genes and 54 terms for unique chemicals associated with the disorder. A total of 212 gene-environment interaction pairs, between 51/55 (92.7%) genes and 38/54 (70.4%) chemicals, putatively relevant for ASD, were discovered. ABCB1, ABCG2, CYP2C19, GSTM1, CYP2D6, and SLC3A2 were the genes that interacted with more chemicals, while valproic acid, benzo(a)pyrene (b(a)p), bisphenol A, particulate matter and perfluorooctane sulfonic acid (PFOS) were the top chemicals.DiscussionThe identified genes code for functionally diverse proteins, ranging from enzymes that increase the degradability of xenobiotics (CYP450s, UGTs and GSTs), to transporters (ABCs and SLCs), proteins that regulate the correct function of barriers (claudins and dyneins) and placental hormones. The identified gene-environment interactions may reflect the fact that some genes and chemicals are understudied and that the potential neurotoxicity of many substances is unreported. We suggest that environmental factors can have pathogenic effects when individuals carry variants targeting these genes and discuss the potential mechanisms by which these genes can influence ASD risk.ConclusionWe reinforce the hypothesis that gene-environment interactions are relevant, at least, for a subset of ASD cases. Given that no treatment exists for the pathology, the identification of relevant modifiable exposures can contribute to the development of preventive strategies for health management policies in ASD.

scholarly journals Gene–gene and gene-environment interactions on cord blood total IgE in Chinese Han children

2021 ◽  
Vol 17 (1) ◽  
Author(s):  
Li Hua ◽  
Quanhua Liu ◽  
Jing Li ◽  
Xianbo Zuo ◽  
Qian Chen ◽  
...  
Keyword(s):  
Environmental Factors ◽  
Cord Blood ◽  
Synergistic Effects ◽  
Gene Interaction ◽  
Independent Effect ◽  
Environment Interaction ◽  
Nucleotide Polymorphisms ◽  
Chinese Han ◽  
Gene Environment Interaction ◽  
Gene Environment

Abstract Background IL13, IL4, IL4RA, FCER1B and ADRB2 are susceptible genes of asthma and atopy. Our previous study has found gene–gene interactions on asthma between these genes in Chinese Han children. Whether the interactions begin in fetal stage, and whether these genes interact with prenatal environment to enhance cord blood IgE (CBIgE) levels and then cause subsequent allergic diseases have yet to be determined. This study aimed to determine whether there are gene–gene and gene-environment interactions on CBIgE elevation among the aforementioned five genes and prenatal environmental factors in Chinese Han population. Methods 989 cord blood samples from a Chinese birth cohort were genotyped for nine single-nucleotide polymorphisms (SNPs) in the five genes, and measured for CBIgE levels. Prenatal environmental factors were collected using a questionnaire. Gene–gene and gene-environment interactions were analyzed with generalized multifactor dimensionality methods. Results A four-way gene–gene interaction model (IL13 rs20541, IL13 rs1800925, IL4 rs2243250 and ADRB2 rs1042713) was regarded as the optimal one for CBIgE elevation (testing balanced accuracy = 0.5805, P = 9.03 × 10–4). Among the four SNPs, only IL13 rs20541 was identified to have an independent effect on elevated CBIgE (odds ratio (OR) = 1.36, P = 3.57 × 10–3), while the other three had small but synergistic effects. Carriers of IL13 rs20541 TT, IL13 rs1800925 CT/TT, IL4 rs2243250 TT and ADRB2 rs1042713 AA were estimated to be at more than fourfold higher risk for CBIgE elevation (OR = 4.14, P = 2.69 × 10–2). Gene-environment interaction on elevated CBIgE was found between IL4 rs2243250 and maternal atopy (OR = 1.41, P = 2.65 × 10–2). Conclusions Gene–gene interaction between IL13 rs20541, IL13 rs1800925, IL4 rs2243250 and ADRB2 rs1042713, and gene-environment interaction between IL4 rs2243250 and maternal atopy begin in prenatal stage to augment IgE production in Chinese Han children.

Gene–environment interplay in the etiology of psychosis

2018 ◽  
Vol 48 (12) ◽  
pp. 1925-1936 ◽  
Author(s):  
Alyson Zwicker ◽  
Eileen M. Denovan-Wright ◽  
Rudolf Uher
Keyword(s):  
Environmental Factors ◽  
Genetic Risk ◽  
Environmental Exposures ◽  
Response To Treatment ◽  
Human Potential ◽  
Specific Gene ◽  
Environment Interaction ◽  
Gene Environment ◽  
Increased Risk ◽  
The Impact

AbstractSchizophrenia and other types of psychosis incur suffering, high health care costs and loss of human potential, due to the combination of early onset and poor response to treatment. Our ability to prevent or cure psychosis depends on knowledge of causal mechanisms. Molecular genetic studies show that thousands of common and rare variants contribute to the genetic risk for psychosis. Epidemiological studies have identified many environmental factors associated with increased risk of psychosis. However, no single genetic or environmental factor is sufficient to cause psychosis on its own. The risk of developing psychosis increases with the accumulation of many genetic risk variants and exposures to multiple adverse environmental factors. Additionally, the impact of environmental exposures likely depends on genetic factors, through gene–environment interactions. Only a few specific gene–environment combinations that lead to increased risk of psychosis have been identified to date. An example of replicable gene–environment interaction is a common polymorphism in theAKT1gene that makes its carriers sensitive to developing psychosis with regular cannabis use. A synthesis of results from twin studies, molecular genetics, and epidemiological research outlines the many genetic and environmental factors contributing to psychosis. The interplay between these factors needs to be considered to draw a complete picture of etiology. To reach a more complete explanation of psychosis that can inform preventive strategies, future research should focus on longitudinal assessments of multiple environmental exposures within large, genotyped cohorts beginning early in life.

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

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Andrea Maugeri ◽  
Martina Barchitta ◽  
Maria Grazia Mazzone ◽  
Francesco Giuliano ◽  
Antonella Agodi
Keyword(s):  
Public Health ◽  
Personalized Medicine ◽  
Macular Degeneration ◽  
Complement System ◽  
Genetic Variants ◽  
Age Related Macular Degeneration ◽  
Environment Interaction ◽  
Gene Environment Interaction ◽  
Age Related ◽  
Gene Environment

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.

Abstract MP11: Systematic Discovery Of Thousands Of Gene-Environment Interactions For Cardiometabolic Serum Biomarkers

Circulation ◽  
2021 ◽  
Vol 143 (Suppl_1) ◽  
Author(s):  
Kenneth E Westerman
Keyword(s):  
Genetic Variants ◽  
Cardiometabolic Risk ◽  
Interaction Analysis ◽  
Environmental Exposures ◽  
Cardiometabolic Health ◽  
Environment Interaction ◽  
Gene Environment Interaction ◽  
Gene Environment ◽  
A Genome ◽  
The Mean

Background: Gene-environment interaction (GEI) analysis enables us to understand how genetic variants modify the effects of environmental exposures on cardiometabolic risk factors, providing a foundation for genome-based precision medicine. Ideally, these interactions could be mapped comprehensively across all measured genetic variants, exposures, and outcomes, but this approach is computationally intensive and statistically underpowered. Recent studies have shown that variance-quantitative trait loci (vQTLs), or genetic variants that associate with differential variance of an outcome, are substantially enriched for underlying GEIs. Here, we sought to first identify vQTLs for cardiometabolic traits, then use this smaller genetic search space to uncover novel gene-environment interactions across thousands of environmental exposures. Methods: A two-stage, multi-ancestry analysis was conducted in 355,790 unrelated participants from the UK Biobank. First, we performed a genome-wide vQTL scan for each of 20 serum metabolic biomarkers, including but not limited to lipids, lipoproteins, and glycemic measures. This scan used Levene’s test to identify genetic markers whose genotypes are associated with the variance, rather than the mean, of the biomarker. Next, we collected over 2000 variables corresponding to socioeconomic, dietary, lifestyle, and clinical exposures, and conducted an interaction analysis for each combination of exposure and vQTL-biomarker pair. For each stage, the analysis was initially stratified by ancestry then meta-analyzed to generate the primary set of results. Results: vQTLs were identified at 514 independent regions in the genome, with most of these genetic variants already known to affect the mean biomarker level. In the subsequent gene-environment interaction analysis, we found 2,162 significant interactions passing a stringent significance threshold adjusted for multiple testing ( p < 0.05 / 578 vQTL-biomarker pairs / 2140 exposures = 4х10 -8 ). Some of these expanded on existing findings; for example, genetic marker rs2393775 in the HNF1A gene interacted with education level (as a proxy for socioeconomic status) to influence hsCRP ( p = 1.3х10 -10 ), building on a previous finding that HNF1A variants modify the effect of perceived stress on cardiovascular outcomes. Others highlighted novel biology, such as an interaction between variants near the fatty liver-associated gene TM6SF2 and oily fish intake on total and LDL-cholesterol levels ( p = 6.6х10 -9 ). Conclusions: Our systematic GEI discovery effort identified thousands of interactions that may impact cardiometabolic risk, both expanding on previous research and identifying novel biological mechanisms. This catalog of vQTLs and interactions can inform future mechanistic studies and provides a knowledge base for genome-centered precision approaches to cardiometabolic health.

scholarly journals Early-onset Alzheimer's disease in Scotland: environmental and familial factors

2001 ◽  
Vol 178 (S40) ◽  
pp. s53-s59 ◽  
Author(s):  
Lawrence J. Whalley
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Environmental Factors ◽  
Disease Model ◽  
Environmental Data ◽  
Paternal Age ◽  
Environment Interaction ◽  
Gene Environment Interaction ◽  
Gene Environment ◽  
Genetic And Environmental Factors

BackgroundAlzheimer's disease (AD) is a common, complex, age-related disorder in which both genetic and environmental factors are important.AimsTo integrate recent studies on genetic and environmental factors in AD into a multi-factorial disease model.MethodDisease models to explain gene-environment interaction in cardiovascular disease are related to observations on AD.ResultsInformative, community-based studies on the genetic epidemiology of AD are rare. Putative risk factors from the Scottish studies include increased paternal age in AD men and coal mining as paternal occupation in both AD and vascular dementia. Migration effects suggest that environmental factors in high-incidence AD areas are important during adult life.ConclusionsThe studies summarised do not provide sufficient data to support a single comprehensive disease model of gene-environment interaction in AD. Future studies will require very large (≥600) sample sizes, molecular genetic analysis, and environmental data that span neurodevelopment and the period between disease onset and appearance of clinical symptoms.

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