Genetic determinants of aggression and impulsivity in humans

Human aggression/impulsivity-related traits have a complex background that is greatly influenced by genetic and non-genetic factors. The relationship between aggression and anxiety is regulated by highly conserved brain regions including amygdala, which controls neural circuits triggering defensive, aggressive, or avoidant behavioral models. The dysfunction of neural circuits responsible for emotional control was shown to represent an etiological factor of violent behavior. In addition to the amygdala, these circuits also involve the anterior cingulated cortex and regions of the prefrontal cortex. Excessive reactivity in the amygdala coupled with inadequate prefrontal regulation serves to increase the likelihood of aggressive behavior. Developmental alterations in prefrontal-subcortical circuitry as well as neuromodulatory and hormonal abnormality appear to play a role. Imbalance in testosterone/serotonin and testosterone/cortisol ratios (e.g., increased testosterone levels and reduced cortisol levels) increases the propensity toward aggression because of reduced activation of the neural circuitry of impulse control and self-regulation. Serotonin facilitates prefrontal inhibition, and thus insufficient serotonergic activity can enhance aggression. Genetic predisposition to aggression appears to be deeply affected by the polymorphic genetic variants of the serotoninergic system that influences serotonin levels in the central and peripheral nervous system, biological effects of this hormone, and rate of serotonin production, synaptic release and degradation. Among these variants, functional polymorphisms in the monoamine oxidase A (MAOA) and serotonin transporter (5-HTT) may be of particular importance due to the relationship between these polymorphic variants and anatomical changes in the limbic system of aggressive people. Furthermore, functional variants of MAOA and 5-HTT are capable of mediating the influence of environmental factors on aggression-related traits. In this review, we consider genetic determinants of human aggression, with special emphasis on genes involved in serotonin and dopamine metabolism and function.     

Genetics of human aggressive behaviour

A consideration of the evolutionary, physiological and anthropological aspects of aggression suggests that individual differences in such behaviour will have important genetic as well as environmental underpinning. Surveys of the likely pathways controlling the physiological and neuronal processes involved highlight, as obvious targets to investigate, genes implicated in sexual differentiation, anxiety, stress response and the serotonin neurotransmitter pathway. To date, however, association studies on single candidates have provided little evidence for any such loci with a major effect size. This may be because genes do not operate independently, but function against a background in which other genetic and environmental factors are crucial. Indeed, a series of recent studies, particularly concentrating on the serotonin and norepinephrine metabolising enzyme, monoamine oxidase A, has emphasised the necessity of examining gene by environmental interactions if the contributions of individual loci are to be understood. These findings will have major significance for the interpretation and analysis of data from detailed whole genome association studies. Functional imaging studies of genetic variants affecting serotonin pathways have also provided valuable insights into potential links between genes, brain and aggressive behaviour.     

Molecular psychogenetics of deviant aggressive behavior in humans

The review considers the known candidate gene loci that are involved in the dopamine, serotonin, and androgen systems and are associated with human deviant aggressive behavior. Both positive and negative correlations with deviant aggressive behavior have been observed for almost all of the candidate gene loci. Many genes of the neurotransmitter and androgen system and intricate interactions among them may influence the propensity to aggression. Further studies should focus not only on individual gene polymorphisms, but also on complex interactions among the alleles of all candidate genes that have functionally important polymorphisms affecting their expression and function. A complex analysis should be performed to study the association of the homozygous genotypes at all candidate gene markers with various forms of human deviant aggressive behavior. The approach will make it possible to assess the individual reactivity to various environmental stimuli that provoke aggression and to develop a means of predicting and preventing deviant aggressive behavior in humans.     

Systemic Regulation of RAS/MAPK Signaling by the Serotonin Metabolite 5-HIAA

Human cancer is caused by the interplay of mutations in oncogenes and tumor suppressor genes and inherited variations in cancer susceptibility genes. While many of the tumor initiating mutations are well characterized, the effect of genetic background variation on disease onset and progression is less understood. We have used C. elegans genetics to identify genetic modifiers of the oncogenic RAS/MAPK signaling pathway. Quantitative trait locus analysis of two highly diverged C. elegans isolates combined with allele swapping experiments identified the polymorphic monoamine oxidase A (MAOA) gene amx-2 as a negative regulator of RAS/MAPK signaling. We further show that the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), which is a product of MAOA catalysis, systemically inhibits RAS/MAPK signaling in different organs of C. elegans. Thus, MAOA activity sets a global threshold for MAPK activation by controlling 5-HIAA levels. To our knowledge, 5-HIAA is the first endogenous small molecule that acts as a systemic inhibitor of RAS/MAPK signaling.     

Investigation of the functional effect of monoamine oxidase polymorphisms in human brain

Monoamine oxidase A and monoamine oxidase B ( MAOA and MAOB) have been suggested to play a role in psychiatric disorders and/or behavioral traits. We have investigated whether different polymorphisms can account for variations in enzyme activity and/or mRNA levels in human brain. Whereas several association studies have been reported previously, this is the first study of the functional effect of MAO DNA variants in human brain. Four polymorphic changes were analyzed: a VNTR located in the MAOA promoter, a VNTR located in the first intron of the MAOA gene, and two single nucleotide polymorphisms located in exon 8 of MAOA and in intron 13 of MAOB. We studied the association of the variants and the resulting haplotypes, with expression levels and enzyme activities of both monoamine oxidases in human cortical brain autopsies. We did not find a significant association of any single MAOA polymorphism with expression levels or enzyme activity in human brain. We did, however, find an association of a particular haplotype with MAOA enzyme levels ( P=0.03). Our results suggest that a novel functional polymorphism that affects enzyme activity in human brain may exist in MAOA. For MAOB, we found a significant association ( P=0.02) between the MAOB intron 13 alleles and different levels of MAOB enzyme activity in human brain. We postulate that there may be a cis-regulatory element in linkage disequilibrium with the B-SNP13 polymorphisms that alters MAOB enzyme activity in human brain.     

Evidence for genetic influences on neurotransmitter content of identified neurones of Lymnaea stagnalis

Neurotransmitter content was measured in two identified giant neurones in isogenic and wild-type populations of the freshwater pond snail Lymnaea stagnalis. The paired serotonergic cerebral giant neurones (LC1 and RC1) have higher transmitter levels and less variability in inbred animals than in wild-type animals. The transmitter content of the unpaired dopaminergic right pedal giant neurone (RPeD1) does not differ between inbred and wild-type animals in either level or variability. It is proposed that serotonin content of the cerebral giant neurones is under partial genetic control, and that animals of the wild-type population may possess a number of different alleles for the genes influencing serotonin levels. Inbreeding resulted in fixation of an allele promoting high serotonin levels. This particular wild-type population is probably already isogenic for genes influencing dopamine content in the right pedal giant neurone.     

偏头痛相关酶和KEGG通路分析

搜集与偏头痛相关的编码酶的基因,利用KEGG通路分析目标基因的分布和功能,促进偏头痛遗传学研究和新药靶点研究。以＂gene name＂AND migraine检索PUBMED数据库,从原始文献中搜集并整理偏头痛相关酶基因数据,用DAVID在线分析工具对数据进行处理。搜索得到31个偏头痛酶基因,对7条KEGG代谢通路进行了分析：色氨酸代谢通路、酪氨酸代谢通路、精氨酸和脯氨酸代谢通路、叶酸一碳单位循环代谢通路、药物代谢通路、外源物质细胞色素P450代谢通路、肾素血管紧张素代谢通路。其中药物代谢通路包括9个药物,又以高选择性5-羟色胺重摄取抑制剂西酞普兰的应用前景最大。DDC、DBH、MTHFD1等6个偏头痛相关基因需要完善多态性研究。CYP450和单胺氧化酶在偏头痛的病理和治疗中都占有重要的地位。通过分析疾病相关酶基因的代谢通路,有助于了解疾病的分子病理基础,并为新药设计提供可靠靶点。     

Genetic susceptibility for individual cooperation preferences: the role of monoamine oxidase A gene (MAOA) in the voluntary provision of public goods

In the context of social dilemmas, previous research has shown that human cooperation is mainly based on the social norm of conditional cooperation. While in most cases individuals behave according to such a norm, deviant behavior is no exception. Recent research further suggests that heterogeneity in social behavior might be associated with varying genetic predispositions. In this study, we investigated the relationship between individuals' behavior in a public goods experiment and the promoter-region functional repeat polymorphism in the monoamine oxidase A gene (MAOA). In a dynamic setting of increasing information about others' contributions, we analyzed differences in two main components of conditional cooperation, namely the players' own contribution and their beliefs regarding the contribution of other players. We showed that there is a significant association between individuals' behavior in a repeated public goods game and MAOA. Our results suggest that male carriers of the low activity alleles cooperate significantly less than those carrying the high activity alleles given a situation where subjects had to rely on their innate beliefs about others' contributions. With increasing information about the others' cooperativeness, the genetic effect diminishes. Furthermore, significant opposing effects for female subjects carrying two low activity alleles were observed.     

X-linked borderline mental retardation with prominent behavioral disturbance: phenotype, genetic localization, and evidence for disturbed monoamine metabolism.

We have identified a large Dutch kindred with a new form of X-linked nondysmorphic mild mental retardation. All affected males in this family show very characteristic abnormal behavior, in particular aggressive and sometimes violent behavior. Other types of impulsive behavior include arson, attempted rape, and exhibitionism. Attempted suicide has been reported in a single case. The locus for this disorder could be assigned to the Xp11-21 interval between DXS7 and DXS77 by linkage analysis using markers spanning the X chromosome. A maximal multipoint lod score of 3.69 was obtained at the monoamine oxidase type A (MAOA) locus in Xp11.23-11.4. Results of 24-h urine analysis in three affected males indicated a marked disturbance of monoamine metabolism. These data are compatible with a primary defect in the structural gene for MAOA and/or monoamine oxidase type B (MAOB). Normal platelet MAOB activity suggests that the unusual behavior pattern in this family may be caused by isolated MAOA deficiency.     

A genetic signature of spina bifida risk from pathway-informed comprehensive gene-variant analysis

Despite compelling epidemiological evidence that folic acid supplements reduce the frequency of neural tube defects (NTDs) in newborns, common variant association studies with folate metabolism genes have failed to explain the majority of NTD risk. The contribution of rare alleles as well as genetic interactions within the folate pathway have not been extensively studied in the context of NTDs. Thus, we sequenced the exons in 31 folate-related genes in a 480-member NTD case-control population to identify the full spectrum of allelic variation and determine whether rare alleles or obvious genetic interactions within this pathway affect NTD risk. We constructed a pathway model, predetermined independent of the data, which grouped genes into coherent sets reflecting the distinct metabolic compartments in the folate/one-carbon pathway (purine synthesis, pyrimidine synthesis, and homocysteine recycling to methionine). By integrating multiple variants based on these groupings, we uncovered two provocative, complex genetic risk signatures. Interestingly, these signatures differed by race/ethnicity: a Hispanic risk profile pointed to alterations in purine biosynthesis, whereas that in non-Hispanic whites implicated homocysteine metabolism. In contrast, parallel analyses that focused on individual alleles, or individual genes, as the units by which to assign risk revealed no compelling associations. These results suggest that the ability to layer pathway relationships onto clinical variant data can be uniquely informative for identifying genetic risk as well as for generating mechanistic hypotheses. Furthermore, the identification of ethnic-specific risk signatures for spina bifida resonated with epidemiological data suggesting that the underlying pathogenesis may differ between Hispanic and non-Hispanic groups.     

Human disorders in N-glycosylation and animal models

Genes that cause human disorders in N-linked oligosaccharide biosynthesis have appeared much faster than animal model systems to study them. In most models, a single gene is altered or deleted while other genes and the environment are held constant. Since humans have variable genetic backgrounds and environments, model systems may only partially mimic the actual disorders. Mutations in seven of the 30-40 genes needed for the synthesis and transfer of oligosaccharides from the lipid donor to the nascent protein acceptors in the endoplasmic reticulum cause Type I Congenital Disorders of Glycosylation (CDG). Since all of these gene products ultimately contribute to the same final step, one might suspect that all the diseases would be very similar. However, even patients with mutations in the same gene show considerable phenotypic variability. Modifier, or susceptibility genes in the background likely explain some variations of the "primary" gene chosen for study. Add to this the stress of infections, dietary insufficiencies, and the demands of growth itself. These issues are particularly important during development when the temporal and spatial specific interplay of cell adhesions and signals has only a single opportunity. Multiple hypomorphic alleles of genes in the same pathway may have synergistic effects. Investigators designing model systems to study human glycosylation disorders may want to construct strains with several heterozygous hypomorphic alleles in rate-limiting steps in the glycosylation pathway.     

MAOA-L carriers are better at making optimal financial decisions under risk

Genes can affect behaviour towards risks through at least two distinct neurocomputational mechanisms: they may affect the value assigned to different risky options, or they may affect the way in which the brain adjudicates between options based on their value. We combined methods from neuroeconomics and behavioural genetics to investigate the impact that the genes encoding for monoamine oxidase-A (MAOA), the serotonin transporter (5-HTT) and the dopamine D4 receptor (DRD4) have on these two computations. Consistent with previous literature, we found that carriers of the MAOA-L polymorphism were more likely to take financial risks. Our computational choice model, rooted in established decision theory, showed that MAOA-L carriers exhibited such behaviour because they are able to make better financial decisions under risk, and not because they are more impulsive. In contrast, we found no behavioural or computational differences among the 5-HTT and DRD4 polymorphisms.     

Beyond pathways: genetic dissection of tocopherol content in maize kernels by combining linkage and association analyses

Although tocopherols play an important role in plants and animals, the genetic architecture of tocopherol content in maize kernels has remained largely unknown. In this study, linkage and association analyses were conducted to examine the genetic architecture of tocopherol content in maize kernels. Forty‐one unique quantitative trait loci (QTLs) were identified by linkage mapping in six populations of recombinant inbred lines (RILs). In addition, 32 significant loci were detected via genome‐wide association study (GWAS), 18 of which colocalized with the QTLs identified by linkage mapping. Fine mapping of a major QTL validated the accuracy of GWAS and QTL mapping results and suggested a role for nontocopherol pathway genes in the modulation of natural tocopherol variation. We provided genome‐wide evidence that genes involved in fatty acid metabolism, chlorophyll metabolism and chloroplast function may affect natural variation in tocopherols. These findings were confirmed through mutant analysis of a particular gene from the fatty acid pathway. In addition, the favourable alleles for many of the significant SNPs/QTLs represented rare alleles in natural populations. Together, our results revealed many novel genes that are potentially involved in the variation of tocopherol content in maize kernels. Pyramiding of the favourable alleles of the newly elucidated genes and the well‐known tocopherol pathway genes would greatly improve tocopherol content in maize.     

Ziele und Grenzen der Quantifizierung genetischer Risiken

This present article deals with the question of how meaningful statistical risk assessments in genetic counseling may be for the decision-making process of individuals who ask for genetic advice. Even in some Mendelian diseases and generally in the case of multifactorial diseases it is not satisfactory to provide an a priori risk for all affected families. The question of whether a given person or his or her future children may develop the disease in question with severe, possibly untreatable symptoms may largely depend on individual circumstances. Accordingly, the inclusion of such circumstances in the assessment of an individual’s a posteriori risk may largely deviate upwards or downwards from this a priori risk. Currently, the lack of such data often prevents the quantification of an individual a posteriori risk; it is, however, obvious that individual risk assessment will play an increasing role in future genetic counseling. Besides a better understanding of individual environmental influences our growing insight into the impact of epigenetic changes will enforce a re-evaluation of individual risks. Epigenetic changes acquired during fetal development or early childhood may lead to lasting physiological changes and, accordingly, may significantly affect the risk of an individual to develop a certain disease during his or her later life. Due to the complexity of genetic and epigenetic networks it is as inappropriate to categorize mutated genes or alleles which increase the risk for a certain disease as “bad” or “sick” genes as it is to consider genes with apparently health-promoting properties as “good” or “healthy” genes. Such rhetoric may foster feelings of either guilt or superiority in individuals and may have an even more politically dangerous impact by encouraging neo-eugenic thinking. In contrast, the goal of non-directive genetic counseling is to provide individuals seeking advice with reliable information which helps them arrive at a personal decision. Given their personal circumstances this decision should be ethically acceptable and realistically allow them to cope with their problem in their future lives. As seen in cases of Mendelian diseases, such as sickle cell anemia or thalassemias, heterozygous carriers may have selective advantages, in this particular case a natural resistance against Malaria tropica. This example demonstrates that a genetic burden may not have only disadvantages but also advantages for the health of a whole population. This consideration may hold for many alleles which have been present in the gene pool of a population for many generations, although they contribute to a genetic predisposition for a multifactorial disease. In debates about the heritability of a given trait, the heritability coefficient has often been used as an argument for and against the predominant impact of genes on the trait in question. The authors wish to remind their readers that this coefficient reflects the genetic variation measured in a given population divided by the variation of all possible parameters which affect the phenotypic trait. It neither gives an answer about the absolute influence of genes and other factors on this trait nor does it provide information about how unforeseen changes in the environment may affect the heritability of the trait in the future. Contrary to a common misunderstanding in public discussion this coefficient does not allow any conclusion on the interaction of genetic, epigenetic and environmental factors involved in the development of the trait in question in an individual. Finally, in the closing section the authors highlight the opportunities of risk-adapted disease prevention.     

Structure of the human gene for monoamine oxidase type A.

Monoamine oxidases, type A and type B, are principal enzymes for the degradation of biogenic amines, including catecholamines and serotonin. These isozymes have been implicated in neuropsychiatric disorders. Previously, cDNA clones for both MAO-A and MAO-B have been sequenced and the genes encoding them have been localized to human chromosome Xp11.23-Xp11.4. In this work, we isolated human genomic clones spanning almost all the MAOA gene from cosmid and phage libraries using a cDNA probe for MAO-A. Restriction mapping and sequencing show that the human MAOA gene extends over 70 kb and is composed of 15 exons. The exon structure of human MAOA is similar to that described by others for human MAOB. Exon 12 (bearing the codon for cysteine, which carries the covalently bound FAD cofactor) and exon 13 are highly conserved between human MAOA and MAOB genes (92% at the amino acid level). Earlier work revealed two species of MAO-A mRNA, 2.1 kb and 4.5-5.5 kb. We now report on further cDNA isolation and sequencing, which demonstrates that the longer message has an extension of 2.2 kb in the 3' noncoding region. This extended region is contained entirely within exon 15. The two messages therefore appear to be generated by the use of two alternative polyadenylation sites. Results from the present work should facilitate the mutational analysis of functional domains of MAO-A and MAO-B. Knowledge of the gene structure will also help in evaluating the role of genetic variations in MAO-A in human disease through the use of genomic DNA, which is more accessible than the RNA, as a template for PCR-amplification and sequencing.     

Caretaker tumour suppressor genes that defend genome integrity

Cancers arise as a result of genetic changes that impact upon cell proliferation through promoting cell division and/or inhibiting cell death. Tumour suppressor (TS) genes are the targets for many of these genetic changes. In general, both alleles of TS genes must be disrupted to observe a phenotypic effect. Broadly speaking, there are two types of TS gene: 'gatekeepers' and 'caretakers'. In contrast to gatekeepers, caretaker genes do not directly regulate proliferation, but act to prevent genomic instability. Thus, mutation of caretaker genes leads to accelerated conversion of a normal cell to a neoplastic cell. Many caretaker genes are required for the maintenance of genome integrity. This review focuses on those caretaker genes that play a role, directly or indirectly, in the repair of DNA strand breaks by the homologous recombination pathway, and that are associated with cancer-prone clinical syndromes, in particular ataxia telangiectasia, hereditary breast cancer, Bloom's syndrome and Werner's syndrome.