Gene-environment interactions in rare diseases that include common birth defects

Rare syndromes often feature specific types of birth defects that frequently are major diagnostic clues to the presence of a given disorder. Despite this specificity, not everyone with the same syndrome is equally or comparably affected, and not everyone with a specific birth defect manifests the same syndrome or is affected with all the features of a particular syndrome. A symposium sponsored by the National Institutes of Health Office of Rare Diseases, and the National Toxicology Program Center for the Evaluation of Risks to Human Reproduction attempted to explore how much of this variability is due to genetic factors and how much is due to environmental factors. The specific types of birth defects examined included cardiovascular defects, holoprosencephaly, clefts of the lip and/or palate, neural tube defects, and diaphragmatic hernias.     

Gene-environment interactions in atherosclerosis

The importance of environment and genetics working together to shape an individual's risk for atherosclerosis seems intuitively obvious. However, it is only recently that research strategies have begun to evolve that attempt to answer questions related to apportionment of risk that is due to specific environmental and genetic factors. These factors may impact upon risk either singly or, more likely, through a complex interaction that affects the metabolic history of the whole organism. Because the genetic bases of lipid and lipoprotein metabolism have been well-studied, and because of the epidemiologic and pathobiochemical associations between genetic disorders of lipid metabolism and atherosclerosis, researchers have searched for gene-environment interactions within animal and human systems in which the phenotype is defined by some index of lipoprotein metabolism. From work done in the lipoprotein area to this point a clear case can be made for: 1) the genetic influence over the phenotypic response to an environmental stimulus; 2) the environmental modulation of the phenotypic expression of severe genetic defects. In the realm of gene-environment interactions that affect lipoprotein phenotype, diet is the best-studied environmental factor.     

Gene-environment interactions in sporadic Parkinson's disease

Much has been learned in recent years about the genetics of familial Parkinson's disease. However, far less is known about those malfunctioning genes which contribute to the emergence and/or progression of the vast majority of cases, the 'sporadic Parkinson's disease', which is the focus of our current review. Drastic differences in the reported prevalence of Parkinson's disease in different continents and countries suggest ethnic and/or environmental-associated multigenic contributions to this disease. Numerous association studies showing variable involvement of multiple tested genes in these distinct locations support this notion. Also, variable increases in the risk of Parkinson's disease due to exposure to agricultural insecticides indicate complex gene-environment interactions, especially when genes involved in protection from oxidative stress are explored. Further consideration of the brain regions damaged in Parkinson's disease points at the age-vulnerable cholinergic-dopaminergic balance as being involved in the emergence of sporadic Parkinson's disease in general and in the exposure-induced risks in particular. More specifically, the chromosome 7 ACHE/PON1 locus emerges as a key region controlling this sensitive balance, and animal model experiments are compatible with this concept. Future progress in the understanding of the genetics of sporadic Parkinson's disease depends on globally coordinated, multileveled studies of gene-environment interactions.     

Gene-environment interactions and the affected-sib-pair designs

In genetic mapping of complex traits, the affected-sib-pair method (ASP) and the transmission disequilibrium test (TDT) are two methods of choice. The major appeal of both ASP and TDT is that they do not require the knowledge of mode of inheritance underlying the trait in question. The relative ease and economy for data collection also is the reason for their popularity. The basic idea of the ASP is to identify genes or chromosomal regions through identifying genetic similarity based on phenotypical similarity. TDT, on the other hand, detects susceptibility genes through detecting unusual transmission patterns in families. Since phenotypic similarity can also be caused by environmental similarity, we investigate how the presence of gene-environment interaction (GEI) affects the power of both methods. For a simple one-locus-one-risk-factor model, our results indicate that, in the presence of GEI, methods developed based on marginal penetrance functions (i.e. ignoring the risk factor) can give spurious results. The triangular restriction on allele-sharing probability may no longer be valid. If the environment effect is strong, using exposure-discordant affected sib pairs may have advantage over other designs. Above all, a genetic model involving both genetic and environmental factors behaves differently from a single-locus genetic model.     

Gene-environment interactions in complex diseases: genetic models and methods for QTL mapping in multiple half-sib populations

An interval quantitative trait locus (QTL) mapping method for complex polygenic diseases (as binary traits) showing QTL by environment interactions (QEI) was developed for outbred populations on a within-family basis. The main objectives, within the above context, were to investigate selection of genetic models and to compare liability or generalized interval mapping (GIM) and linear regression interval mapping (RIM) methods. Two different genetic models were used: one with main QTL and QEI effects (QEI model) and the other with only a main QTL effect (QTL model). Over 30 types of binary disease data as well as six types of continuous data were simulated and analysed by RIM and GIM. Using table values for significance testing, results show that RIM had an increased false detection rate (FDR) for testing interactions which was attributable to scale effects on the binary scale. GIM did not suffer from a high FDR for testing interactions. The use of empirical thresholds, which effectively means higher thresholds for RIM for testing interactions, could repair this increased FDR for RIM, but such empirical thresholds would have to be derived for each case because the amount of FDR depends on the incidence on the binary scale. RIM still suffered from higher biases (15-100% over- or under-estimation of true values) and high standard errors in QTL variance and location estimates than GIM for QEI models. Hence GIM is recommended for disease QTL mapping with QEI. In the presence of QEI, the model including QEI has more power (20-80% increase) to detect the QTL when the average QTL effect is small (in a situation where the model with a main QTL only is not too powerful). Top-down model selection is proposed in which a full test for QEI is conducted first and then the model is subsequently simplified. Methods and results will be applicable to human, plant and animal QTL mapping experiments.     

Protein interactions in human genetic diseases

We present a novel method that combines protein structure information with protein interaction data to identify residues that form part of an interaction interface. Our prediction method can retrieve interaction hotspots with an accuracy of 60% (at a 20% false positive rate). The method was applied to all mutations in the Online Mendelian Inheritance in Man (OMIM) database, predicting 1,428 mutations to be related to an interaction defect. Combining predicted and hand-curated sets, we discuss how mutations affect protein interactions in general.     

Gene-environment interactions in psychiatry: joining forces with neuroscience

Gene-environment interaction research in psychiatry is new, and is a natural ally of neuroscience. Mental disorders have known environmental causes, but there is heterogeneity in the response to each causal factor, which gene-environment findings attribute to genetic differences at the DNA sequence level. Such findings come from epidemiology, an ideal branch of science for showing that a gene-environment interactions exist in nature and affect a significant fraction of disease cases. The complementary discipline of epidemiology, experimental neuroscience, fuels gene-environment hypotheses and investigates underlying neural mechanisms. This article discusses opportunities and challenges in the collaboration between psychiatry, epidemiology and neuroscience in studying gene-environment interactions.     

Gene-environment interactions differentially affect mouse strain behavioral parameters

Systematic phenotyping of mouse strains and mutants generated through genome-wide mutagenesis programs promises to deliver a wealth of functional genetic information. To this end, the appropriation of a standard series of phenotyping protocols is desirable to produce data sets that are consistent within and across laboratories and across time. Standard phenotyping protocols such as EMPReSS (European Mouse Phenotyping Resource for Standardised Screens) provide a series of protocols aimed at phenotyping multiple body systems that could realistically be adopted and/or reproduced in any laboratory. This includes a series of neurologic and behavioral screens, bearing in mind that this class of phenotype is well represented in targeted mutants and mutagenesis screens. Having cross-validated screening batteries in a number of laboratories and in a number of commonly used inbred strains, our group was interested in establishing whether subtle changes in cage environment could affect behavioral test outcome. Aside from unavoidable quantitative differences in test outcome, we identified significant and distinct genotype-environment-test interactions. For example, specific strain order in open-field center entries and total distance traveled can be reversed depending on the form of enrichment used, while prepulse inhibition of the acoustic startle response is, even quantitatively, unaffected by the enrichment condition. Our findings argue that unless systematically recorded, behavioral studies conducted under subtle variations in cage environment may lead to data misinterpretation, although this could be limited to particular behaviors. Further investigations into the extent and limits of genetic and environmental variables are critical for the realization of both behavioral and functional genomics endpoints.     

Gene-environment interactions in addictive disorders: epidemiological and methodological aspects

The gene-environment interactions' approach could explain some epidemiological and clinical factors associated with addictive behaviours. Twin studies first help to disentangle the respective roles of environment and genetic effects, finding convincing evidence for common genetic vulnerability in several addictive behaviours, and helping to delimit what syndrome could belong to the addictive disorder spectrum. Assessing gene x environment interaction (G x E) needs specifically designed studies, using multiplicative or additive approaches. Focusing on this G x E interaction already showed its relevancy in many recent studies, using both epidemiological and molecular approaches. For example, in a non-human primate model of alcohol dependence assessing the respective role of genetic vulnerability (having the short allele located in the promoter region of the gene coding for the serotonin transporter) and severe fostering conditions (as locked up in a cage with other inmates for the first six months of life), the only group of monkeys that has a significant risk of using spontaneously alcohol is the one that gathers both risk factors, i.e. being peer-raised and having the short allele. Such approach could help to more accurately select specific candidate genes, to identify more homogenous subgroups of patients (as sharing the same genetic vulnerability), to understand how genetic factors mediate the risk of associated psychiatric disorders, and ultimately, may lead to more focused, i.e. more efficient, prevention strategies.     

Gene-environment interactions between CRHR1 variants and physical assault in suicide attempts

Risk factors for suicidal behaviors are partly heritable, including genetic variants that drive diathesis-stress in addition to, or by interaction with, exposure to certain stressful life events (SLEs). Hypothalamic-pituitary-adrenal (HPA) axis regulatory genes are candidates for association with suicide as well as its endophenotypes. Using a family-based design of offspring who attempted suicide (SA) and both parents, we investigated gene-environment interactions (G×Es) of SLE exposures with single nucleotide polymorphisms (SNPs) in corticotropin-releasing hormone receptor-1 (CRHR1), a major HPA axis regulatory gene. We observed a novel G×E among predominantly female SA between 5'-SNP rs7209436 and childhood/adolescence physical assault or attack (PA), as well as a second novel and male-specific G×E between 3'-SNP rs16940665 and adulthood PA exposure. A third male-specific G×E previously reported by us among depressed SA, between SNP rs4792887 and cumulative SLEs, was also further confirmed. The two novel G×Es presented here shared the SA characteristic of aggression, while showing differences on other aspects of SA heterogeneity. We conclude that different SA subjects were observed to differentially associate with two novel G×Es involving exposures to PA with different life timing and SNPs located in opposite ends of CRHR1. Concerning sex differences, we observed three subsets of distinct male SA that associated with each of the three observed G×Es, whereas female SAs were affected by only one of the G×Es. These results are consistent with a diathesis-stress model of suicidal behavior and may help to explain SA heterogeneity.     

Gene-environment interactions in a mutant mouse kindred with native airway constrictor hyperresponsiveness

We mutagenized male BTBR mice with N-ethyl-N-nitrosourea and screened 1315 of their G3 offspring for airway hyperresponsiveness. A phenovariant G3 mouse with exaggerated methacholine bronchoconstrictor response was identified and his progeny bred in a nonspecific-pathogen-free (SPF) facility where sentinels tested positive for minute virus of mice and mouse parvovirus and where softwood bedding was used. The mutant phenotype was inherited through G11 as a single autosomal semidominant mutation with marked gender restriction, with males exhibiting almost full penetrance and very few females phenotypically abnormal. Between G11 and G12, facility infection eradication was undertaken and bedding was changed to hardwood. We could no longer detect airway hyperresponsiveness in more than 37 G12 offspring of 26 hyperresponsive G11 males. Also, we could not identify the mutant phenotype among offspring of hyperresponsive G8–G10 sires rederived into an SPF facility despite 21 attempts. These two observations suggest that both genetic and environmental factors were needed for phenotype expression. We suspect that rederivation into an SPF facility or altered exposure to pathogens or other unidentified substances modified environmental interactions with the mutant allele, and so resulted in disappearance of the hyperresponsive phenotype. Our experience suggests that future searches for genes that confer susceptibility for airway hyperresponsiveness might not be able to identify some genes that confer susceptibility if the searches are performed in SPF facilities. Experimenters are advised to arrange for multigeneration constancy of mouse care in order to clone mutant genes. Indeed, we were not able to map the mutation before losing the phenotype.     

Gene-environment interactions of CETP gene variation in a high cardiovascular risk Mediterranean population

Genome-wide association studies show that cholesteryl ester transfer protein (CETP) single nucleotide polymorphisms (SNPs) are more strongly associated with HDL cholesterol (HDL-C) concentrations than any other loci across the genome. However, gene-environment interactions for clinical applications are still largely unknown. We studied gene-environment interactions between CETP SNPs and dietary fat intake, adherence to the Mediterranean diet, alcohol consumption, smoking, obesity, and diabetes on HDL-C in 4,210 high cardiovascular risk subjects from a Mediterranean population. We focused on the −4,502C>T and the TaqIB SNPs in partial linkage disequilibrium (D''= 0.88; P < 0.001). They were independently associated with higher HDL-C (P < 0.001); this clinically relevant association was greater when their diplotype was considered (14% higher in TT/B2B2 vs. CC/B1B1). No gene-gene interaction was observed. We also analyzed the association of these SNPs with blood pressure, and no clinically relevant associations were detected. No statistically significant interactions of these SNPs with obesity, diabetes, and smoking in determining HDL-C concentrations were found. Likewise, alcohol, dietary fat, and adherence to the Mediterranean diet did not statistically interact with the CETP variants (independently or as diplotype) in determining HDL-C. In conclusion, the strong association of the CETP SNPs and HDL-C was not statistically modified by diet or by the other environmental factors.     

Gene-environment interactions in wet beriberi: effects of thiamine depletion in CD36-defect rats

Selective vulnerability to thiamine deficiency is known to occur between individuals and within different tissues. However, no comprehensive explanation for this has been found, and there are no reports that reproduce the cardiovascular manifestations of human wet beriberi in animals. We hypothesized that the distinction of substrate reliance, namely, the primary dependency on glucose as substrate, could be an underlying factor in the selective vulnerability of thiamine deficiency. In the setting of impaired fatty acid entry, which occurs in CD36-defect rats, substrate reliance shifts from fatty acid to glucose, which would be expected to lead to a susceptibility to thiamine deficiency. Genomic DNA was analyzed for CD36 defects in three cognate strains of rats [spontaneously hypertensive rats (SHR)/NCrj, SHR/Izm, and Wistar-Kyoto (WKY)/NCrj], which identified the presence of a CD36 defect in SHR/NCrj rats but not in SHR/Izm and WKY/NCrj rats. Treatment with 2 wk of thiamine-depleted chow on 4-wk-old rats of each of these strains resulted in increased body and lung weight in the SHR/NCrj rats but not in the SHR/Izm and WKY/NCrj rats. The increased lung weight in the SHR/NCrj rats was accompanied with histological changes of congestive vasculopathy, which were not observed in either the SHR/Izm or the WKY/NCrj rats. Thiamine-deficient 12-wk-old SHR/NCrj rats demonstrated increased body weight (305.6 +/- 6.2 g in thiamine-deficient rats vs. 280.8 +/- 9.1 g in control; P < 0.0001), lactic acidemia (pH, 7.322 +/- 0.026 in thiamine-deficient rats vs. 7.443 +/- 0.016 in control; P < 0.0001; lactate, 2.42 +/- 0.28 mM in thiamine-deficient rats vs. 1.20 +/- 0.11 mM in control; P < 0.0001) and reduced systemic vascular resistance (4.61 +/- 0.42 x 104 dyn.s.cm-5 in thiamine-deficient rats vs. 6.55 +/- 1.36 x 104 dyn.s.cm-5 in control; P < 0.0001) with high cardiac output (186.0 +/- 24.7 ml in thiamine-deficient rats vs. 135.4 +/- 27.2 ml in control; P < 0.0019). In conclusion, SHR/NCrj rats harboring a genetic defect of long-chain fatty acid uptake present the relevant clinical cardiovascular signs of human wet beriberi, strongly indicating a close gene-environment interaction in wet beriberi.     

Gene-environment interactions, not neonatal growth hormone deficiency, time puberty in female rhesus monkeys

The factors that influence the timing of puberty and the onset of adult fertility are poorly understood. While focus on the juvenile period has provided insights into how growth-related cues affect pubertal timing, growth velocity during infancy that is sustained into the juvenile period may be important. On the other hand, social factors, specifically exposure to psychosocial stressors, can delay sexual maturation, possibly by altering growth velocities during development. Using female rhesus monkeys, the present study used a prospective analysis to determine how neonatal growth hormone (GH) inhibition with a sandostatin analog or suppression of the pituitary-gonadal axis with a GnRH analog affected growth and sexual maturation. A separate retrospective analysis was done assessing the effects of social dominance status during development on pubertal timing. Because a specific polymorphism in the gene encoding the serotonin (5HT) reuptake transporter increases vulnerability to psychosocial stressors, females were also genotyped and were then classified as socially dominant, having both alleles for the long promoter variant or having at least one allele for the short promoter variant, or as socially subordinate, having the long variant or having the short variant. Neonatal treatments were not balanced for social status or genotype, so analyses were performed separately. Although the neonatal treatments reduced GH secretion postnatally and through the juvenile period, neither growth nor sexual maturation was affected. In contrast, the retrospective analysis showed sexual maturation was delayed significantly in subordinate females carrying at least one allele of the short promoter variant in the gene encoding the 5HT reuptake transporter, and this delay was associated with reduced GH and leptin secretion during the juvenile phase but not with differences in growth velocities from birth. These data suggest that decreased neonatal GH secretion does not adversely affect sexual maturation, but that polymorphisms in the gene encoding the 5HT transporter modulate the adverse consequences of social subordination on the timing of puberty in female rhesus monkeys.