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.     

Inheritance mechnisam of gene SNCA for alcohol dependence

SNCA gene is located in a quantitative trait locus for alcohol preference. Alpha-synuclein coded by SNCA gene can regulate the function of dopamine in multiple levels, and dopamine is an important neurotransmitter in alcohol preference. Variation has been found in SNCA gene carried by alcohol-dependent patients. Meanwhile, significant increase of SNCA gene expression also occurs in alcohol-dependent patients, which is closely associated with the level of alcohol dependence. Therefore, SNCA gene is believed to contribute to genetic mechanism of alcohol dependence. Here, the relationship between SNCA gene and dopamine, the variation and expression of SNCA gene in alcohol-dependent patients were reviewed.     

SNCA基因在酒精依赖遗传机制中的研究进展

SNCA 基因定位于酒精依赖数量性状位点之上, 其编码的蛋白-α-synuclein 可以在多个水平上调节多巴胺的功能, 而后者是酒精依赖中重要的神经递质。研究还发现酒精依赖者SNCA 基因存在多处基因变异, 同时, 酒精依赖者SNCA 基因的表达水平也存在显著增高, 并且增高的程度与酒精依赖程度密切相关, 因此, SNCA 基因被认为参与酒精依赖的遗传机制。文章对SNCA 基因与多巴胺的关系和酒精依赖者SNCA 基因变异以及基因表达的研究进展做一综述。     

Alcohol dependence and polymorphisms of serotonin-related genes

Genetic factors have a non-specific but significant impact on the risk of alcohol-dependence. Molecular genetic analyses are now less devoted to the genes involved in the metabolism of ethanol, focusing on core concepts of addiction, such as arousal, pleasure, reward, craving, and impulsivity. Indeed, the neuro-cognitive functions, temperament traits and psycho-behavioral specificities of patients with alcohol abuse or dependence led to select new sets of candidate genes. One of them are related to serotonin transmission, as serotonin modulates dopaminergic pathways, and is also stimulated by many addictive susbtances. The genetic analyses of serotonin in alcohol-dependence are mainly focused on the serotonin transporter gene (5-HTT), as one polymorphism within the promoter has a functional impact. From the 16 case-control association studies yet performed, many are positive, and one family-based study showed a large excess of transmission of the short allele. We performed a meta-analysis of the case-control studies showing that the S allele could be a risk factor for a phenotype related to alcohol-dependence (OR=1.31), with still unknown boundaries. Other genes coding for serotonin receptors were analysed with mainly negative results, for example the 5-HT2A, 5-HT2C, 5-HT5A and 5-HT7 receptors. The 5-HT1B could be more interesting as being located in a locus linked to alcohol preference in rodents, and associated with antisocial alcoholism in two human studies. Genetics may thus provide new insights about the different mechanisms which explain why some subjects are more at risk for the development of alcohol abuse or dependence. Genes involved in the transmission, reuptake and metabolism of serotonin constitute a set of candidate genes that could be involved in core aspects of alcoholism, such as the tendency to prefer immediate reward, despite negative consequences.     

5' UTR polymorphism of dopamine receptor D1 (DRD1) associated with severity and temperament of alcoholism

Multiple dopamine receptors in the dopaminergic system may be prime candidates for genetic influence on alcohol abuse and dependence due to their involvement in reward and reinforcing mechanisms. Genetic polymorphisms in dopamine receptor genes are believed to influence the development and/or severity of alcoholism. To examine the genetic effects of the Dopamine Receptor D1 (DRD) gene family (DRD1-DRD5) in the Korean population, 11 polymorphisms in the DRD gene family were genotyped and analyzed in 535 alcohol-dependent subjects and 273 population controls. Although none of the polymorphisms of DRD1-5 genes were found to be associated with the risk of alcoholism, one 5' UTR polymorphism in the DRD1 (DRD1-48A>G) gene was significantly associated with severity of alcohol-related problem, as measured by the Alcohol Use Disorders Identification Test (AUDIT) in a gene dose-dependent manner, i.e., 24.37 (+/-8.19) among patients with -48A/A genotype, 22.37 (+/-9.49) among those with -48A/G genotype, and 17.38 (+/-8.28) among those with -48G/G genotype (P=0.002). The genetic effects of DRD1-48A>G were further analyzed with other phenotypes among alcohol-dependent subjects. Interestingly, the DRD1-48A>A genotype was also found to be associated with novelty seeking (NC), harm avoidance (HA), and persistence (P) (P =0.01, 0.02, and 0.003, respectively). The information derived from this study could be valuable for understanding the genetic factors involved in alcoholic phenotypes and genetic distribution of the DRD gene family, and could facilitate further investigation in other ethnic groups.     

Genetics of dopamine receptors and drug addiction

Dopamine plays a key role in reward behavior, yet the association of drug dependence as a chronic, relapsing disorder with the genes encoding the various dopaminergic receptor subtypes remains difficult to delineate. In the context of subsequent genome-wide association (GWAS) research and post-GWAS investigations, we summarize the novel data that link genes encoding molecules involved in the dopaminergic system (dopamine receptors, transporter and enzymes in charge of its metabolism) to drug addiction. Recent reports indicate that the heritability of drug addiction should be high enough to allow a significant role for a specific set of genes, and the available genetic studies, which might not be already conclusive because of the heterogeneity of designs, methods and recruited samples, should support the idea of a significant role of at least one gene related to dopaminergic system. Evolutionary changes in primates and non-primate animals of genes coding for molecules involved in dopaminergic system highlight why addictive disorders are mainly limited to humans. Restricting the analyses to more specific intermediate phenotypes (or endophenotypes) such as attention allocation, stress reactivity, novelty seeking, behavioral disinhibition and impulsivity, instead of the broad addictive disorder concept can be instrumental to identify novel genes associated with these traits in the context of genome-wide studies.     

Obstructive Sleep Apnea Syndrome: From Phenotype to Genetic Basis

Obstructive sleep apnea syndrome (OSAS) is a complex chronic clinical syndrome, characterized by snoring, periodic apnea, hypoxemia during sleep, and daytime hypersomnolence. It affects 4-5% of the general population. Racial studies and chromosomal mapping, familial studies and twin studies have provided evidence for the possible link between the OSAS and genetic factors and also most of the risk factors involved in the pathogenesis of OSAS are largely genetically determined. A percentage of 35-40% of its variance can be attributed to genetic factors. It is likely that genetic factors associated with craniofacial structure, body fat distribution and neural control of the upper airway muscles interact to produce the OSAS phenotype. Although the role of specific genes that influence the development of OSAS has not yet been identified, current researches, especially in animal model, suggest that several genetic systems may be important. In this chapter, we will first define the OSAS phenotype, the pathogenesis and the risk factors involved in the OSAS that may be inherited, then, we will review the current progress in the genetics of OSAS and suggest a few future perspectives in the development of therapeutic agents for this complex disease entity.Key Words: Obstructive sleep apnea, genetic, hypopnea, AHI, snoring, risk factors, phenotype, multifactorial disease.     

Heritability and the risk of developing androgen excess

Androgen excess is one of the most common reproductive endocrinologic abnormalities of women. Excluding specific etiologies such as androgen-secreting neoplasms and non-classic adrenal hyperplasia, the majority of androgen excess is functional in nature. It is clear that studies concerned with the heritability of this disorder greatly depend on how it is defined. Patients with the PolyCystic Ovary Syndrome (PCOS) are clearly included. However, we argue that ovulatory women with hirsutism and hyperandrogenemia should also be considered as affected which, together with PCOS, comprise the population of women we define as having Functional Androgen Excess (FAE). Our data, and that of others, suggests that FAE/PCOS is a familial disorder, with a single autosomal dominant gene effect and a variable phenotype. Inheritance appears to be equally probable from the maternal as from the paternal side of the family. Nonetheless, our data also suggests that the affection rate among mothers is less than expected, which may be due to decreased fertility of affected mothers, or to our inability to detect the disorder in older, menopausal or hormonally treated individuals. Finally, it appears that a woman’s risk for developing PCOS is approximately 40% if her sister is affected. While considering FAE/PCOS to be a dominant genetic disorder with a high degree of expressivity, its highly variable phenotype suggests that besides a single genetic mutation other factors must be contributing to the development and expression of the disorder. These factors may include environmental influences (such as fat and carbohydrate consumption) exercise level, peripubertal stress and/or hormonal exposure; and additional genetic defects, such as those that regulate insulin secretion or determine body type.     

Identification of molecular genetic factors that influence migraine

Migraine is a common neurological disorder with a strong genetic basis. However, the complex nature of the disorder has meant that few genes or susceptibility loci have been identified and replicated consistently to confirm their involvement in migraine. Approaches to genetic studies of the disorder have included analysis of the rare migraine subtype, familial hemiplegic migraine with several causal genes identified for this severe subtype. However, the exact genetic contributors to the more common migraine subtypes are still to be deciphered. Genome-wide studies such as genome-wide association studies and linkage analysis as well as candidate genes studies have been employed to investigate genes involved in common migraine. Neurological, hormonal and vascular genes are all considered key factors in the pathophysiology of migraine and are a focus of many of these studies. It is clear that the influence of individual genes on the expression of this disorder will vary. Furthermore, the disorder may be dependent on gene–gene and gene–environment interactions that have not yet been considered. In addition, identifying susceptibility genes may require phenotyping methods outside of the International Classification of Headache Disorders II criteria, such as trait component analysis and latent class analysis to better define the ambit of migraine expression.     

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.     

A Cytogenetic Abnormality and Rare Coding Variants Identify ABCA13 as a Candidate Gene in Schizophrenia, Bipolar Disorder, and Depression

Schizophrenia and bipolar disorder are leading causes of morbidity across all populations, with heritability estimates of ∼80% indicating a substantial genetic component. Population genetics and genome-wide association studies suggest an overlap of genetic risk factors between these illnesses but it is unclear how this genetic component is divided between common gene polymorphisms, rare genomic copy number variants, and rare gene sequence mutations. We report evidence that the lipid transporter gene ABCA13 is a susceptibility factor for both schizophrenia and bipolar disorder. After the initial discovery of its disruption by a chromosome abnormality in a person with schizophrenia, we resequenced ABCA13 exons in 100 cases with schizophrenia and 100 controls. Multiple rare coding variants were identified including one nonsense and nine missense mutations and compound heterozygosity/homozygosity in six cases. Variants were genotyped in additional schizophrenia, bipolar, depression (n > 1600), and control (n > 950) cohorts and the frequency of all rare variants combined was greater than controls in schizophrenia (OR = 1.93, p = 0.0057) and bipolar disorder (OR = 2.71, p = 0.00007). The population attributable risk of these mutations was 2.2% for schizophrenia and 4.0% for bipolar disorder. In a study of 21 families of mutation carriers, we genotyped affected and unaffected relatives and found significant linkage (LOD = 4.3) of rare variants with a phenotype including schizophrenia, bipolar disorder, and major depression. These data identify a candidate gene, highlight the genetic overlap between schizophrenia, bipolar disorder, and depression, and suggest that rare coding variants may contribute significantly to risk of these disorders.     

Molecular Description of Familial Defective APOB-100 in Malaysia

Familial ligand-defective apolipoprotein B-100 is characterized by elevated plasma low-density lipoprotein levels and premature heart disease. This study aims to determine apolipoprotein B gene mutations among Malaysians with clinical diagnoses of familial hypercholesterolemia and to compare the phenotype of patients with apolipoprotein B gene mutations to those with a low-density lipoprotein receptor gene mutation. A group of 164 patients with a clinical diagnosis of familial hypercholesterolemia was analyzed. Amplicons in exon 26 and exon 29 of the apolipoprotein B gene were screened for genetic variants using denaturing gradient high-performance liquid chromatography; 10 variants were identified. Five novel mutations were detected (p.Gln2485Arg, p.Thr3526Ala, p.Glu3666Lys, p.Tyr4343CysfsX221, and p.Arg4297His). Those with familial defective apolipoprotein had a less severe phenotype than those with familial hypercholesterolemia. An apolipoprotein gene defect is present among Malaysian familial hypercholesterolemics. Those with both mutations show a more severe phenotype than those with one gene defect.     

Zebrafish: a model for the study of addiction genetics

Drug abuse and dependence are multifaceted disorders with complex genetic underpinnings. Identifying specific genetic correlates is challenging and may be more readily accomplished by defining endophenotypes specific for addictive disorders. Symptoms and syndromes, including acute drug response, consumption, preference, and withdrawal, are potential endophenotypes characterizing addiction that have been investigated using model organisms. We present a review of major genes involved in serotonergic, dopaminergic, GABAergic, and adrenoreceptor signaling that are considered to be directly involved in nicotine, opioid, cannabinoid, and ethanol use and dependence. The zebrafish genome encodes likely homologs of the vast majority of these loci. We also review the known expression patterns of these genes in zebrafish. The information presented in this review provides support for the use of zebrafish as a viable model for studying genetic factors related to drug addiction. Expansion of investigations into drug response using model organisms holds the potential to advance our understanding of drug response and addiction in humans.     

Advances in the Molecular Genetics of Non-syndromic Syndactyly

Syndactyly, webbing of adjacent digits with or without bony fusion, is one of the most common hereditary limb malformations. It occurs either as an isolated abnormality or as a component of more than 300 syndromic anomalies. There are currently nine types of phenotypically diverse nonsyndromic syndactyly. Non-syndromic syndactyly is usually inherited as an autosomal dominant trait, although the more severe presenting types and subtypes may show autosomal recessive or X-linked pattern of inheritance. The phenotype appears to be not only caused by a main gene, but also dependant on genetic background and subsequent signaling pathways involved in limb formation. So far, the principal genes identified to be involved in congenital syndactyly are mainly involved in the zone of polarizing activity and sonic hedgehog pathway. This review summarizes the recent progress made in the molecular genetics, including known genes and loci responsible for non-syndromic syndactyly, and the signaling pathways those genetic factors involved in, as well as clinical features and animal models. We hope our review will contribute to the understanding of underlying pathogenesis of this complicated disorder and have implication on genetic counseling.     

Early exposure to paraquat sensitizes dopaminergic neurons to subsequent silencing of PINK1 gene expression in mice

Environmental exposure, genetic modification, and aging are considered risky for Parkinson's disease (PD). How these risk factors cooperate to induce progressive neurodegeneration in PD remains largely unknown. Paraquat is an herbicide commonly used for weed and grass control. Exposure to paraquat is associated with the increased incidence of PD. In contrast to familial PD, most sporadic PD cases do not have genetic mutation, but may suffer from partial dysfunction of neuron-protective genes as aging. Using conditional transgenic RNAi, we showed that temporal silencing of PINK1 expression in adult mice increased striatal dopamine, the phenotype that could not be induced by constitutive gene silencing. Moreover, early exposure to paraquat sensitized dopaminergic neurons to subsequent silencing of PINK1 gene expression, leading to a significant loss of dopaminergic neurons. Our findings suggest a novel pathogenesis of PD: exposure to environmental toxicants early in the life reduces the threshold of developing PD and partial dysfunction of neuron-protective genes later in the life initiates a process of progressive neurodegeneration to cross the reduced threshold of disease onset.     

Advances in the discovery of genetic risk factors for complex forms of neurodegenerative disorders: contemporary approaches,success, challenges and prospects

Neurodegenerative diseases constitute a large proportion of disorders in elderly, majority being sporadic in occurrence with \(\sim \)5–10% familial. A strong genetic component underlies the Mendelian forms but nongenetic factors together with genetic vulnerability contributes to the complex sporadic forms. Several gene discoveries in the familial forms have provided novel insights into the pathogenesis of neurodegeneration with implications for treatment. Conversely, findings from genetic dissection of the sporadic forms, despite large genomewide association studies and more recently whole exome and whole genome sequencing, have been limited. This review provides a concise account of the genetics that we know, the pathways that they implicate, the challenges that are faced and the prospects that are envisaged for the sporadic, complex forms of neurodegenerative diseases, taking four most common conditions, namely Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and Huntington disease as examples. Poor replication across studies, inability to establish genotype–phenotype correlations and the overall failure to predict risk and/or prevent disease in this group poses a continuing challenge. Among others, clinical heterogeneity emerges as the most important impediment warranting newer approaches. Advanced computational and system biology tools to analyse the big data are being generated and the alternate strategy such as subgrouping of case–control cohorts based on deep phenotyping using the principles of Ayurveda to overcome current limitation of phenotype heterogeneity seem to hold promise. However, at this point, with advances in discovery genomics and functional analysis of putative determinants with translation potential for the complex forms being minimal, stem cell therapies are being attempted as potential interventions. In this context, the possibility to generate patient derived induced pluripotent stem cells, mutant/gene/genome correction through CRISPR/Cas9 technology and repopulating the specific brain regions with corrected neurons, which may fulfil the dream of personalized medicine have been mentioned briefly. Understanding disease pathways / biology using this technology, with implications for development of novel therapeutics are optimistic expectations in the near future.     

Association study of 37 genes related to serotonin and dopamine neurotransmission and neurotrophic factors in cocaine dependence

Cocaine dependence is a neuropsychiatric disorder in which both environmental and genetic factors are involved. Several processes, that include reward and neuroadaptations, mediate the transition from use to dependence. In this regard, dopamine and serotonin neurotransmission systems are clearly involved in reward and other cocaine‐related effects, whereas neurotrophic factors may be responsible for neuroadaptations associated with cocaine dependence. We examined the contribution to cocaine dependence of 37 genes related to the dopaminergic and serotoninergic systems, neurotrophic factors and their receptors through a case–control association study with 319 single nucleotide polymorphisms selected according to genetic coverage criteria in 432 cocaine‐dependent patients and 482 sex‐matched unrelated controls. Single marker analyses provided evidence for association of the serotonin receptor HTR2A with cocaine dependence [rs6561333; nominal P‐value adjusted for age = 1.9e?04, odds ratio = 1.72 (1.29–2.30)]. When patients were subdivided according to the presence or absence of psychotic symptoms, we confirmed the association between cocaine dependence and HTR2A in both subgroups of patients. Our data show additional evidence for the involvement of the serotoninergic system in the genetic susceptibility to cocaine dependence.     

Candidate-gene studies of the atherogenic lipoprotein phenotype: a sib-pair linkage analysis of DZ women twins.

There is a growing body of evidence supporting the roles of small, dense LDL and plasma triglyceride (TG), both features of the atherogenic lipoprotein phenotype, as risk factors for coronary heart disease. Although family studies and twin studies have demonstrated genetic influences on these risk factors, the specific genes involved remain to be determined definitively. The purpose of this study was to investigate genetic linkage between LDL size, TG, and related atherogenic lipoproteins and candidate genes known to be involved in lipid metabolism. The linkage analysis was based on a sample of 126 DZ women twin pairs, which avoids the potentially confounding effects of both age and gender, by use of a quantitative sib-pair linkage-analysis approach. Eight candidate genes were examined, including those for microsomal TG-transfer protein (MTP), hepatic lipase, hormone-sensitive lipase, apolipoprotein (apo) B, apo CIII, apo E, insulin receptor, and LDL receptor. The analysis suggested genetic linkage between markers for the apo B gene and LDL size, plasma levels of TG, of HDL cholesterol, and of apo B, all features of the atherogenic lipoprotein phenotype. Furthermore, evidence for linkage was maintained when the analysis was limited to women with a major LDL-subclass diameter >255 A, indicating that the apo B gene may influence LDL heterogeneity in the intermediate-to-large size range. In addition, linkage was found between the MTP gene and TG, among all the women. These findings add to the growing evidence for genetic influences on the atherogenic lipoprotein phenotype and its role in genetic susceptibility to atherosclerosis.     

Molecular mechanisms,prevalence, and molecular methods for familial combined hyperlipidemia disease: A review

Familial combined hyperlipidemia (FCHL) is the most common genetic dyslipidemia disorder which is accompanied by increasing of triglyceride and cholesterol. This disorder is a complex genetic disease although it also has monogenic forms. The familial form has several criteria for diagnosis that can be distinguished of nonfamilial position. It has been shown that a variety of internal and external risk factors are involved in the pathogenesis of FCHL. Environmental factors and the genetic background also play an important role in the FCHL pathogenesis. Many mechanisms and pathways are involved in lipid metabolism (ie, dysfunctional adipose tissue, hepatic fat and very low-density lipoprotein overproduction, triglyceride-rich lipoproteins, and clearance of low-density lipoprotein particles) that could lead to FCHL. Individuals with a positive family history like those who have a positive family history of cardiovascular diseases are more predispositions for this disorder. To date several methods have been used to identify the genetic background of the FCHL. In the current review, we summarized the prevalence and the molecular mechanisms involved in the FCHL disease. Moreover, we highlighted the used molecular methods for determining the genes involved in the FCHL.     

Testing concordance of clinical characteristics in familial studies with application to inflammatory bowel diseases

The etiology of chronic Inflammatory Bowel Diseases (IBD) remains unknown, with both genetic and environmental risk factors having been implicated. A recent collaborative study of IBD provides clinical data from families with three or more affected first-degree relatives. The scientific question is whether specific clinical characteristics aggregate among affected individuals within families. Gastroenterological researchers have examined the number of concordant familial pairs in familial aggregation studies, but methods and results have been discrepant. This article investigates concepts of concordance and gives a comprehensive statistical treatment for testing concordance of various clinical traits in familial studies. For dichotomous traits, the distribution of this statistic under the null hypothesis of no familial aggregation is obtained by three methods: asymptotic, probability generating function, and permutation. The permutation method is extended to analyze aggregation for non-dichotomous traits and co-aggregations between two traits. We apply the permutation method to analyze the aforementioned multiply-affected IBD family data. Evidence is found for familial clustering of various traits, some of which are not revealed in existing studies. Such analyses provide a basis for investigating the dependence of trait aggregation upon genetic or environmental risk factors.