抑郁的多基因遗传基础

抑郁具有复杂的、非孟德尔式的多基因遗传模式, 但是目前多数抑郁的遗传研究集中于考察单个候选基因, 不能全面揭示遗传因素的作用机制。近年来, 多基因遗传得分研究和基因−基因交互研究分别为抑郁的多基因累加效应和交互效应提供了新的证据。多基因不仅直接影响抑郁, 还通过与环境因素的交互作用影响抑郁的发生发展, 并且这一复杂交互作用存在性别差异。抑郁的内表型研究发现多基因可能通过认知因素、人格、压力荷尔蒙等间接影响个体的抑郁水平。未来研究应更加关注多基因与多种环境因素如何相互作用影响抑郁, 探索多基因遗传机制的性别差异, 考察多基因对抑郁影响随年龄的发展动态变化。     

Activity-Based Accounts of Mechanism and the Threat of Polygenic Effects

Accounts of ontic explanation have often been devised so as to provide an understanding of mechanism and of causation. Ontic accounts differ quite radically in their ontologies, and one of the latest additions to this tradition proposed by Peter Machamer, Lindley Darden and Carl Craver reintroduces the concept of activity. In this paper I ask whether this influential and activity-based account of mechanisms is viable as an ontic account. I focus on polygenic scenarios—scenarios in which the causal truths depend on more than one cause. The importance of polygenic causation was noticed early on by Mill (1893). It has since been shown to be a problem for both causal-law approaches to causation (Cartwright 1983) and accounts of causation cast in terms of capacities (Dupré 1993; Glennan 1997, pp. 605–626). However, whereas mechanistic accounts seem to be attractive precisely because they promise to handle complicated causal scenarios, polygenic causation needs to be examined more thoroughly in the emerging literature on activity-based mechanisms. The activity-based account proposed in Machamer et al. (2000, pp. 1–25) is problematic as an ontic account, I will argue. It seems necessary to ask, of any ontic account, how well it performs in causal situations where—at the explanandum level of mechanism—no activity occurs. In addition, it should be asked how well the activity-based account performs in situations where there are too few activities around to match the polygenic causal origin of the explanandum. The first situation presents an explanandum-problem and the second situation presents an explanans-problem—I will argue—both of which threaten activity-based frameworks.     

精神分裂症遗传学研究的理性思辨

精神分裂症是一种常见的重性精神障碍,属于复杂的多基因遗传性疾病。随着分子生物学技术和遗传学数据分析方法的进步,精神分裂症易感基因方面的研究取得了一定的进展,但是至今还没有一个精神分裂症的易感基因得到准确定位。系统生物学是采用系统科学的方法研究一个生物系统的一种大科学,为寻找精神分裂症等复杂疾病的易感基因提供一种新的思路。     

Ecology And The Science Of Psychology

This study explored the feasibility of discriminating among subtypes of mental retardation on the basis of observable behavior. The major focus was on discrimination between Ss whose low I.Q. could be attributed to normal chromosomal or single locus genetic defects. Concurrently the study sought t o distinguish among diagnostic subgroups of the second category. Three groups of institutionalized subjects were used: Undifferentiated (presumed polygenic segregants), PKU, and Down's Syndrome.     

精神分裂症遗传学内表型研究的启示

精神分裂症是一种常见的重性精神障碍,属于复杂的多基因遗传性疾病。随着分子生物学技术和遗传学数据分析方法的进步,精神分裂症易感基因方面的研究取得了一定的进展,但是至今还没有一个精神分裂症的易感基因得到准确定位。近年来精神分裂症的遗传学研究中越来越多地引入了内表型概念,而旨在阐明不同的基因变异引起精神疾病的相应功能障碍的内表型研究将为分裂症的诊断和治疗提供了较为客观的生物学指标,也对该复杂疾病的病因学、诊断和治疗学产生重要影响。     

儿童对立违抗性障碍研究的进展及启示

随着基因技术及生物工程技术的迅速发展,人们逐渐发现与冲动行为相关基因的存在,研究认为DA、5-HT、MAO等基因多态性与冲动行为有关,从而进一步认识到ODD与遗传因素有关且属于多基因遗传。对儿童对立违抗性障碍(ODD)的生物学机制及社会心理应激因素进行了系统的分析,对进一步探讨ODD的发病机制有所启示。     

Resolving the paradox of common, harmful, heritable mental disorders: which evolutionary genetic models work best?

Given that natural selection is so powerful at optimizing complex adaptations, why does it seem unable to eliminate genes (susceptibility alleles) that predispose to common, harmful, heritable mental disorders, such as schizophrenia or bipolar disorder? We assess three leading explanations for this apparent paradox from evolutionary genetic theory: (1) ancestral neutrality (susceptibility alleles were not harmful among ancestors), (2) balancing selection (susceptibility alleles sometimes increased fitness), and (3) polygenic mutation-selection balance (mental disorders reflect the inevitable mutational load on the thousands of genes underlying human behavior). The first two explanations are commonly assumed in psychiatric genetics and Darwinian psychiatry, while mutation-selection has often been discounted. All three models can explain persistent genetic variance in some traits under some conditions, but the first two have serious problems in explaining human mental disorders. Ancestral neutrality fails to explain low mental disorder frequencies and requires implausibly small selection coefficients against mental disorders given the data on the reproductive costs and impairment of mental disorders. Balancing selection (including spatio-temporal variation in selection, heterozygote advantage, antagonistic pleiotropy, and frequency-dependent selection) tends to favor environmentally contingent adaptations (which would show no heritability) or high-frequency alleles (which psychiatric genetics would have already found). Only polygenic mutation-selection balance seems consistent with the data on mental disorder prevalence rates, fitness costs, the likely rarity of susceptibility alleles, and the increased risks of mental disorders with brain trauma, inbreeding, and paternal age. This evolutionary genetic framework for mental disorders has wide-ranging implications for psychology, psychiatry, behavior genetics, molecular genetics, and evolutionary approaches to studying human behavior.     

Genetics of human episodic memory: dealing with complexity

Episodic memory is a polygenic behavioral trait with substantial heritability estimates. Despite its complexity, recent empirical evidence supports the notion that behavioral genetic studies of episodic memory might successfully identify trait-associated molecules and pathways. The development of high-throughput genotyping methods, of elaborated statistical analyses and of phenotypic assessment methods at the neural systems level will facilitate the reliable identification of novel memory-related genes. Importantly, a necessary crosstalk between behavioral genetic studies and investigation of causality by molecular genetic studies will ultimately pave the way towards the identification of biologically important, and hopefully druggable, genes and molecular pathways related to human episodic memory.     

Sex differences in the causes of self-reported adolescent delinquency

Sex differences in the causes of self-reported adolescent delinquency were examined in full and half siblings born to a nationally representative sample of women in the United States. Qualitative sex differences in the genes that influence delinquency were not detected. Similarly, the proportions of variance in both aggressive and nonaggressive delinquency attributable to genetic and environmental influences did not differ significantly between girls and boys. Nonetheless, total variance in delinquency was greater among boys, and a scalar sex-differences model suggested that genetic and environmental influences on delinquency have less effect on population variation in delinquency among girls. Similarly, a test of the polygenic multiple threshold model suggested that girls require greater causal liability for the expression of delinquency than boys.     

An evolutionary look at oddity and schizotypy: How the rise of social brain informs clinical practice

A prominent facet of schizotypy is the recurrence of odd cognitions, emotions, and behaviors. This paper aims to present an evolutionary interpretation of oddity as a risk-minimizing and uniqueness-maximizing strategy for facing the complexity of our hyper-affiliative species. I discuss this hypothesis by exploring the intertwined role of social safety and social cognition in preventing or triggering psychopathology. Since schizotypy is reputed to be a polygenic dimension, its underlying genes are likely involved in both adaptive and maladaptive traits. Consequently, the oddity is presented as both an evolutionary trade-off and a possible advantage in the rise of our complex social brain. The clinical implications of conceptualizing schizotypy and supporting those struggling with maladaptive forms of oddity are discussed.     

Sex differences in genetic and environmental influences on DSM-III-R attention-deficit/hyperactivity disorder

Approximately 5% of children are affected by attention-deficit/hyperactivity disorder (ADHD), and more boys are affected than girls. This study examined the magnitude of genetic and environmental influences on ADHD and several questions regarding sex differences in its prevalence and liability. The participants were 2,391 twin and sibling pairs from Australia, ages 3-18. ADHD symptoms in the general population were highly heritable (h2 = .85-.90), as were deviant ADHD scores in the selected population. The magnitude of familial influences was similar for boys and girls, although there were shared environmental influences on ADHD in girls but not boys and dominance genetic influences on ADHD in boys but not girls. Specific genetic and environmental influences were highly similar for boys and girls. Evidence supported the polygenic multiple threshold model rather than the constitutional variability model of sex differences in ADHD.     

Genetic Counseling as a Tool for Type 2 Diabetes Prevention: A Genetic Counseling Framework for Common Polygenetic Disorders

Advances in genetic epidemiology have increased understanding of common, polygenic preventable diseases such as type 2 diabetes. As genetic risk testing based on this knowledge moves into clinical practice, we propose that genetic counselors will need to expand their roles and adapt traditional counseling techniques for this new patient set. In this paper, we present a genetic counseling intervention developed for a clinical trial [Genetic Counseling/Lifestyle Change for Diabetes Prevention, ClinicalTrials.gov identifier: NCT01034319] designed to motivate behavioral changes for diabetes prevention. Seventy-two phenotypically high-risk participants received counseling that included their diabetes genetic risk score, general education about diabetes risk factors, and encouragement to participate in a diabetes prevention program. Using two validated genetic counseling scales, participants reported favorable perceived control and satisfaction with the counseling session. Our intervention represents one model for applying traditional genetic counseling principles to risk testing for polygenetic, preventable diseases, such as type 2 diabetes.     

Linear genetics,non-linear epigenetics: Complementary approaches to understanding complex diseases

Recent discoveries and rediscoveries in molecular and cell biology, in population and evolutionary biology, and in disease natural history raise new doubts about the ability of genetic analysis alone to predict multifactorial (polygenic) human diseases and other complex phenotypes. These doubts serve to redirect our attention to epigenetic regulation as a second informational system in parallel with the genome. Epigenetic regulation is now viewed by many biologists as a process that includes mechanisms capable of constraining the genome and providing for new patterns of gene expression. Epigenetic networks, both intra- and inter-cellular, provide a basis for nonlinear and chaotic views of cellular and tissue level differentiation and organization, and thus provide a more dynamic approach to understanding the creation of complex phenotypes, even from isogeneic conditions. The reality of regulatory networks within cells inserted, as it were, between genome and phenome, also helps explain the difficulties now encountered when prediction and diagnosis of complex disease omits epigenetic considerations and depends entirely on gene causality. For a complete reference guide, see reviews by R.C. Strohman cited below.     

Obsessive-compulsive disorder: boundary issues

The boundaries between obsessive-compulsive disorder (OCD) and other neuropsychiatric disorders remain unresolved and may well differ from one disorder to another. Endophenotypes are heritable, quantitative traits hypothesized to more closely represent genetic risk for complex polygenic mental disorders than overt symptoms and behaviors. They may have a role in identifying how closely these disorders are associated with another and with other mental disorders with which they share major comorbidity. This review maps the nosological relationships of OCD to other neuropsychiatric disorders, using OCD as the prototype disorder and endophenotype markers, such as cognitive, imaging, and molecular data as well as results from demographic, comorbidity, family, and treatment studies. Despite high comorbidity rates, emerging evidence suggests substantial endophenotypic differences between OCD and anxiety disorders, depression, schizophrenia, and addictions, though comparative data is lacking and the picture is far from clear. On the other hand, strong relationships between OCD, Tourette syndrome, body dysmorphic disorder, hypochondriasis, grooming disorders, obsessive-compulsive personality disorder, and pediatric autoimmune neuropsychiatric disorders associated with streptococcus are likely. Studies designed to delineate the cause, consequences, and common factors are a challenging but essential goal for future research in this area.     

Unifying diseases from a genetic point of view: the example of the genetic theory of infectious diseases

In the contemporary biomedical literature, every disease is considered genetic. This extension of the concept of genetic disease is usually interpreted either in a trivial or genocentrist sense, but it is never taken seriously as the expression of a genetic theory of disease. However, a group of French researchers defend the idea of a genetic theory of infectious diseases. By identifying four common genetic mechanisms (Mendelian predisposition to multiple infections, Mendelian predisposition to one infection, and major gene and polygenic predispositions), they attempt to unify infectious diseases from a genetic point of view. In this article, I analyze this explicit example of a genetic theory, which relies on mechanisms and is applied only to a specific category of diseases, what we call “a regional genetic theory.” I have three aims: to prove that a genetic theory of disease can be devoid of genocentrism, to consider the possibility of a genetic theory applied to every disease, and to introduce two hypotheses about the form that such a genetic theory could take by distinguishing between a genetic theory of diseases and a genetic theory of Disease. Finally, I suggest that network medicine could be an interesting framework for a genetic theory of Disease.     

Toward a developmental neurobiology of autism

Autism is a complex, behaviorally defined, developmental brain disorder with an estimated prevalence of 1 in 1,000. It is now clear that autism is not a disease, but a syndrome with a strong genetic component. The etiology of autism is poorly defined both at the cellular and the molecular levels. Based on the fact that seizure activity is frequently associated with autism and that abnormal evoked potentials have been observed in autistic individuals in response to tasks that require attention, several investigators have recently proposed that autism might be caused by an imbalance between excitation and inhibition in key neural systems including the cortex. Despite considerable ongoing effort toward the identification of chromosome regions affected in autism and the characterization of many potential gene candidates, only a few genes have been reproducibly shown to display specific mutations that segregate with autism, likely because of the complex polygenic nature of this syndrome. Among those, several candidate genes have been shown to control the early patterning and/or the late synaptic maturation of specific neuronal subpopulations controlling the balance between excitation and inhibition in the developing cortex and cerebellum. In the present article, we review our current understanding of the developmental mechanisms patterning the balance between excitation and inhibition in the context of the neurobiology of autism.     

Educational attainment-related loci identified by GWAS are associated with select personality traits and mathematics and language abilities

A recent genome-wide association study of educational attainment identified three significant single nucleotide polymorphisms (SNPs) (rs9320913, rs11584700, and rs4851266). In this study, we expanded this previous work by investigating behavioral correlates of these SNPs in a Han Chinese sample (rs9320913 was not available in our data and was thus replaced by rs12202969, which is in high linkage disequilibrium [i.e., correlations of alleles] with the former, r² = 0.96 in Han Chinese population based on the 1000 Genomes Project). Association analysis for individual SNPs showed significant associations between rs4851266 and a measure of language ability (Chinese word recognition), and between rs12202969 and a personality trait (fear of negative evaluation) and a measure of mathematical ability (number paired-associates learning). A polygenic score based on these three SNPs was also significantly associated with the measures of mathematical and language abilities. Specifically, educationally advantaged alleles identified in the previous study were associated with less fear of negative evaluation and higher mathematical and language abilities in the current study. This exploratory study provides evidence of psychological mechanisms for the association between genes and educational attainment.     

Predicting educational achievement from genomic measures and socioeconomic status

The two best predictors of children's educational achievement available from birth are parents’ socioeconomic status (SES) and, recently, children's inherited DNA differences that can be aggregated in genome‐wide polygenic scores (GPS). Here, we chart for the first time the developmental interplay between these two predictors of educational achievement at ages 7, 11, 14 and 16 in a sample of almost 5,000 UK school children. We show that the prediction of educational achievement from both GPS and SES increases steadily throughout the school years. Using latent growth curve models, we find that GPS and SES not only predict educational achievement in the first grade but they also account for systematic changes in achievement across the school years. At the end of compulsory education at age 16, GPS and SES, respectively, predict 14% and 23% of the variance of educational achievement. Analyses of the extremes of GPS and SES highlight their influence and interplay: In children who have high GPS and come from high SES families, 77% go to university, whereas 21% of children with low GPS and from low SES backgrounds attend university. We find that the associations of GPS and SES with educational achievement are primarily additive, suggesting that their joint influence is particularly dramatic for children at the extreme ends of the distribution.     

Development and Evaluation of a Telephone Communication Protocol for the Delivery of Personalized Melanoma Genomic Risk to the General Population

Communicating personalized genomic risk results for common diseases to the general population as a form of tailored prevention is novel and may require alternative genetic counseling service delivery models. We describe the development and evaluation of a communication protocol for disclosing melanoma genomic risk information to the asymptomatic general population and assess participants’ satisfaction and acceptability. Participants (n?=?117) were aged 22–69 years, living in New South Wales, Australia and unselected for family history. They provided a saliva sample and had genomic testing for melanoma for low to moderate penetrant melanoma susceptibility variants in 21 genes. Participants could choose to receive their results from a genetic counselor via telephone, followed by a mailed booklet or to receive their risk result via mailed booklet only with a follow-up call for those at high risk. A follow-up questionnaire was completed by 85% of participants 3-months later. Most participants (80%) elected to receive their result via telephone. Participants were highly satisfied with the delivery of results (mean 3.4 out of 4, standard deviation 0.5), and this did not differ by delivery mode, risk category, age or sex. On follow-up, 75% accurately recalled their risk category, 6% indicated a preference for a different delivery mode, either electronic or face-to-face. The process of disclosing genomic risk results to the general population over the telephone with accompanying written material was feasible and acceptable, and may be useful for communicating polygenic risk for common diseases in the context of increasing demands for genomic testing.