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PubMed2000

Recent progress in psychiatric genetics-some hope but no hype.

The reputation of the field of psychiatric genetics has recently become tarnished in the view of many human geneticists. Too many linked loci were claimed and withdrawn, too many association studies published and not confirmed and, more recently, too many new and different chromosomal regions have been implicated for the same disorder. Here, we summarize recent trends, focusing on research that moves away from traditional linkage studies. Some promising strategies include psychopharmacogenetics, and consideration of endophenotypes such as neurophysiological and behavioral markers in addition to the clinical diagnosis. Utilization of rapid and automated methods for scoring genetic variants in large-scale association studies followed by multivariate analyses, which include environmental as well as genetic data, will likely fare better than traditional linkage analysis in disentangling the complex genetics of psychiatric disorders. Some notable areas of recent progress include quantification of the genetic complexity of autism, identification of genetic variants protecting individuals from alcoholism, and the description of several polymorphisms likely to be relevant to behavior and psychiatry. The most notable example may be a common variant that affects the transcription rate in the promoter for the serotonin transporter gene that may be relevant for individual differences in the response to common anti-depressants.

Epistasis, Genetic↗

PubMed2000

Dissection of behavior and psychiatric disorders using the mouse as a model.

Mouse genetic models have played an important role in the elucidation of molecular pathways underlying human disease. This approach is becoming an increasingly popular way to study the genetic underpinning of psychiatric disorders. Genes within candidate regions for susceptibility to psychiatric illness can be evaluated through the phenotypic assessment of mutants mapped to the corresponding regions in the mouse genome. Alternatively, one can search for mouse mutants displaying characteristics that might correspond to physiological and behavioral markers of a psychiatric disorder, sometimes referred to as endophenotypes. Mice with anomalies in these traits can be generated by targeted mutagenesis in known genes (gene-based mutagenesis or reverse genetics), or can be identified among progeny of mice in a random mutagenesis screen (phenotype-based mutagenesis or forward genetics). In this review, we discuss recently generated behavioral mutants in the mouse. We also give an overview of several robust and commonly used behavioral phenotypes, their relevance to human disease and lessons learned from recent successes in mouse behavioral genetics.

Animals↗

PubMed2003

Association of extreme blood lipid profile phenotypic variation with 11 reverse cholesterol transport genes and 10 non-genetic cardiovascular disease risk factors.

This study explored the genetic basis of the combination of extreme blood levels of HDL-C and LDL-C, a well-studied endophenotype for CVD, which has several attractive features as a target for genetic analysis: (1) the trait is moderately heritable; (2) non-genetic risk factors account for a significant but still limited portion of the phenotypic variance; (3) it is known to be moderated by a number of gene products. We exhaustively surveyed 11 candidate genes for allelic variation in a random population-based sample characterized for known CVD risk factors and blood lipid profiles. With the goal of generating specific etiological hypotheses, we compared two groups of subjects with extreme lipid phenotypes, from the same source population, using a case-control design. Cases (n=186) were subjects, within the total sample of 1708 people, who scored in the upper tertile of LDL-C and the lowest tertile of HDL-C, while controls (n=185) scored in the lowest tertile of LDL-C and the upper tertile of HDL-C. We used logistic regression and a four-tiered, systematic model building strategy with internal cross-validation and bootstrapping to investigate the relationships between the trait and 275 genetic variants in the presence of 10 non-genetic risk factors. Our results implicate a subset of nine genetic variants, spanning seven candidate genes, together with five environmental risk factors, in the etiology of extreme lipoprotein phenotypes. We propose a model involving these 14 genetic and non-genetic risk factors for evaluation in future independent studies.

Adult↗

PubMed2004

Evidence of common and specific genetic effects: association of the muscarinic acetylcholine receptor M2 (CHRM2) gene with alcohol dependence and major depressive syndrome.

Several correlated phenotypes, alcohol dependence, major depressive syndrome, and an endophenotype of electrophysiological measurements, event-related oscillations (EROs), have demonstrated linkage on the long arm of chromosome 7. Recently, we reported both linkage and association between polymorphisms in the gene encoding the muscarinic acetylcholine receptor M2 (CHRM2) and EROs. In this study, we evaluated whether genetic variation in the CHRM2 gene is also a risk factor for the correlated clinical characteristics of alcoholism and depression. The CHRM2 gene contains a single coding exon and a large 5' untranslated region encoded by multiple exons that can be alternatively spliced. Families were recruited through an alcohol dependent proband, and multiplex pedigrees were selected for genetic analyses. We examined 11 single nucleotide polymorphisms (SNPs) spanning the CHRM2 gene in these families. Using the UNPHASED pedigree disequilibrium test (PDTPHASE), three SNPs (one in intron 4 and two in intron 5) showed highly significant association with alcoholism (P=0.004-0.007). Two SNPs (both in intron 4) were significantly associated with major depressive syndrome (P=0.004 and 0.017). Haplotype analyses revealed that the most common haplotype (>40% frequency), T-T-T (rs1824024-rs2061174-rs324650), was under-transmitted to affected individuals with alcohol dependence and major depressive syndrome. Different complementary haplotypes were over-transmitted in alcohol dependent and depressed individuals. These findings provide strong evidence that variants within or close to the CHRM2 locus influence risk for two common psychiatric disorders.

Alcoholism↗

PubMed2004

Five latent factors underlying schizophrenia: analysis and relationship to illnesses in relatives.

Clinical signs and symptoms in a sample of 1,043 individuals with schizophrenia or schizoaffective disorder were subjected to latent class factor analysis. Positive, negative, disorganized, and affective factors were similar in content to factors described in a number of other studies, while a fifth factor representing early onset/developmental signs provided a new area for investigation. The five sets of factor scores were logistically regressed on psychiatric illness indicators in first and second degree relatives. Relatives of probands with higher positive or negative symptom factor scores had a lower risk of depressive illness. Higher affective factor scores in probands predicted more mania and depression in relatives. Both the disorganized and the early onset/developmental factors were related to increased risk of psychiatric hospitalization in relatives, as well as increased risk of psychosis (marginally so for the disorganization factor). Increased early onset/developmental signs in the proband were also associated with increased risk for depression in relatives. These findings suggest a possible endophenotypic role for the factor scores in future studies.

Adult↗

PubMed2025

FAM13A polymorphism is associated with a usual interstitial pneumonia pattern in patients with systemic sclerosis-associated interstitial lung disease.

OBJECTIVES: The MUC5B promoter single nucleotide polymorphism (SNP) rs35705950 has been associated with idiopathic pulmonary fibrosis (IPF) and RA-related interstitial lung disease (ILD), but not with SSc-ILD. We hypothesized that the MUC5B promoter polymorphism or other IPF susceptibility loci are associated with an increased risk for the uncommon SSc-usual interstitial pneumonia (UIP) endophenotype, rather than SSc-ILD in general. METHODS: We performed a cross-sectional study of SSc-ILD patients from four US Scleroderma Programs to investigate the frequency of MUC5B rs35705950 and 12 additional IPF susceptibility loci. SSc-ILD patients were stratified by high resolution chest CT (HRCT) imaging findings into UIP and non-UIP groups. Analysis of HRCTs performed by a thoracic radiologist blinded to participants' characteristics classified each scan as definite UIP, probable UIP, indeterminate or alternative diagnosis, according to American Thoracic Society criteria. RESULTS: Four-hundred and eighty-nine SSc-ILD patients were included; 80% were female and 75% were White. Twenty-three (4.7%) patients had a definite UIP pattern. The MUC5B SNP rs35705950 was not associated with a definite UIP pattern in SSc-ILD. In contrast, patients carrying two copies of the IPF risk gene FAM13A minor allele rs2609255 had significantly higher odds of a definite UIP pattern compared with the other patterns (odds ratio 3.40, 95% CI 1.19-9.70), and compared with an alternative diagnosis (odds ratio 3.65, 95% CI 1.25-10.65). CONCLUSION: We demonstrated a novel association between FAM13A and SSc-UIP. Contrary to IPF and RA-ILD, the MUC5B promoter polymorphism was not associated with a definite UIP pattern in SSc-ILD.

Humans↗

PubMed1994

Single indicator of risk for schizophrenia: probable fact or likely myth?

The longitudinal followup strategy in high-risk research is being increasingly complemented by the use of psychosis-proneness scales to select subjects for study who might be vulnerable to schizophrenia and who show differences on laboratory measures that could act as endophenotypic markers for use in genetic investigations. Three types of experimental paradigm have been adopted, drawn from cognitive psychology, psychophysiology, and the neuropsychology of hemisphere function. Results adopting each of these approaches are examined, alongside recent factor-analytic evidence that psychosis-proneness scales currently in use tap up to four different components that map onto the clinical heterogeneity of schizophrenia (and possibly other forms of psychosis). No one of these components clearly emerges as, or points to, a single indicator of risk, though some aspect of neurocognitive functioning seems a likely candidate. Even so, it is argued, the clinical expression of vulnerability must be due to a convergence in an individual of several components of risk since individually (and notably so for "susceptibility to positive symptoms") they are very common in the healthy population. In evaluating the evidence, attention is drawn to two crucially different ways that investigators in schizophrenia research have construed the notion of continuity (1) as subclinical defect (or forme fruste of disease) having varying expression or (2) as biologically based personality dimensions that simultaneously describe the dispositions to aberrations of function leading to degree of illness. It is noted that the model of continuity chosen can significantly shape the way the results of risk research are interpreted and the theories of psychosis to which they give rise.

Genetic Markers↗

PubMed1996

Nicotinic receptor function in schizophrenia.

Schizophrenia can be partially characterized by deficits in sensory processing. Biochemical, molecular, and genetic studies of one such endophenotype, the P50 auditory-evoked potential gating deficit, suggest that one of the neuronal nicotinic receptors, the alpha 7 nicotinic receptor, may function in an inhibitory neuronal pathway involved in this phenotype. The P50 deficit is normalized in nongating subjects by nicotine. Although most schizophrenia patients are heavy smokers, the effects of nicotine may be transient, as alpha 7 receptors are known to desensitize rapidly. In an animal model of the P50 gating deficit, antagonists of the alpha 7 nicotinic receptor block normal gating of the second of paired auditory stimuli. Regional localization of receptor expression includes areas known to function in sensory filtering. An inhibitory mechanism, in the hippocampus, may involve nicotinic stimulation of gamma-aminobutyric acid (GABA)ergic interneurons, resulting in decreased response to repetitive stimuli. Expression of the alpha 7 receptor is decreased in hippocampal brain tissue, dissected postmortem, from schizophrenia subjects. The P50 deficit is inherited in schizophrenia pedigrees, but it is not sufficient for disease development and thus represents a predisposition factor. Linkage analysis between the P50 deficit in multiplex schizophrenia pedigrees and deoxyribonucleic acid (DNA) markers throughout the genome yielded positive lod scores to DNA markers mapping to a region of chromosome 15 containing the alpha 7 nicotinic receptor gene. Elucidation of possible interactions of the P50 with other factors, known to be important in the etiology of the disease, is important in determining an overall pathobiology of schizophrenia.

Animals↗

PubMed2005

A collaborative approach to targeted treatment development for schizophrenia: a qualitative evaluation of the NIMH-MATRICS project.

INTRODUCTION: In 2002, the National Institute of Mental Health (NIMH) initiated a multistakeholder research process designed to stimulate the development and evaluation of medications targeting the cognitive deficits associated with schizophrenia. The first phase, Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS), sought consensus on laboratory measures for cognition, clinical trial outcome measures, and drug registration requirements. MATRICS constitutes a unique drug development model because it targeted a specific endophenotype of schizophrenia and because it engaged academic, industry, and government stakeholders in a consensus-oriented process. This study offers a preliminary qualitative evaluation of the NIMH-MATRICS project. METHOD: Interview data are used to describe how MATRICS participants regard 3 aspects of the development of cognitive medications: the definition of the treatment target, stakeholders' role in the early development process, and anticipated dissemination complexities. RESULTS: MATRICS participants describe the treatment target in highly varied ways and envision a wide range of public health benefits. MATRICS is perceived as inclusive, despite minimal representation from some end users. According to informants, clinical detection, documentation, and monitoring of cognition and functioning may prove problematic. More thoroughly than non-industry-employed informants, industry-employed MATRICS participants articulate strategies by which treatments can be integrated into clinical practice. DISCUSSION: The MATRICS process did not produce a clinical concept of cognitive impairment in schizophrenia, and significant challenges remain to be addressed regarding the rational clinical use of novel pharmaceuticals for cognition. Broader inclusion of end users in translational science projects may streamline implementation and facilitate improvements in real-world outcomes.

Biomedical Research↗

PubMed2006

Distinguishing neurocognitive functions in schizophrenia using partially ordered classification models.

Current methods for statistical analysis of neuropsychological test data in schizophrenia are inherently insufficient for revealing valid cognitive impairment profiles. While neuropsychological tests aim to selectively sample discrete cognitive domains, test performance often requires several cognitive operations or "attributes." Conventional statistical approaches assign each neuropsychological score of interest to a single attribute or "domain" (e.g., attention, executive, etc.), and scores are calculated for each. This can yield misleading information about underlying cognitive impairments. We report findings applying a new method for examining neuropsychological test data in schizophrenia, based on finite partially ordered sets (posets) as classification models. A total of 220 schizophrenia outpatients were administered the Positive and Negative Symptom Scale (PANSS) and a neuropsychological test battery. Selected tests were submitted to cognitive attribute analysis a priori by two neuropsychologists. Applying Bayesian classification methods (posets), each patient was classified with respect to proficiency on the underlying attributes, based upon his or her individual test performance pattern. Twelve cognitive "classes" are described in the sample. Resulting classification models provided detailed "diagnoses" into "attribute-based" profiles of cognitive strength/weakness, mimicking expert clinician judgment. Classification was efficient, requiring few measures to achieve accurate classification. Attributes were associated with PANSS factors in the expected manner (only the negative and cognition factors were associated with the attributes), and a double dissociation was observed in which divergent thinking was selectively associated with negative symptoms, possibly reflecting a manifestation of Kraepelin's hypothesis regarding the impact of volitional disturbances on thought. Using posets for extracting more precise cognitive information from neuropsychological data may reveal more valid cognitive endophenotypes, while dramatically reducing the amount of testing required.

Adult↗

PubMed2006

Factors mediating cognitive deficits and psychopathology among siblings of individuals with schizophrenia.

Schizotypal traits and cognitive disturbances are known to be present in first-degree relatives of people with schizophrenia. However, there is little understanding of how these endophenotypes are related to each other. We explored the nature of this relationship in individuals with schizophrenia, their full siblings, community controls, and their siblings. All participants were assessed in the domains of working memory, attention, episodic memory, and executive function, as well as in their level of positive, negative, and disorganization symptoms. Schizophrenia probands were significantly impaired on all cognitive domains, as compared with the other 3 groups, and displayed the highest levels of positive, negative, and disorganization symptoms. Proband siblings performed significantly worse than controls on tasks of working memory, episodic memory, and executive function, and they displayed significantly more positive and negative symptoms as compared with controls. Poorer task performance across all 4 cognitive domains was most strongly correlated with increased negative symptoms. Mediation analyses revealed that working memory, episodic memory, and executive function deficits partially mediated increases in negative symptoms among proband siblings. Negative symptoms fully mediated deficits in working memory and episodic memory but only partially mediated deficits in executive function. Results suggest that there is a complex relationship between cognitive and clinical factors in this high-risk population.

Adult↗

PubMed2004

Eye movements in neurodevelopmental disorders.

PURPOSE OF REVIEW: The aim of this paper is to review the literature on eye-movement abnormalities associated with neurodevelopmental disorders. Eye-movement testing is a non-invasive quantitative approach for evaluating brain systems across the age spectrum. It thus provides a promising methodology for characterizing and documenting maturational abnormalities in brain systems associated with neurodevelopmental disorders. RECENT FINDINGS: Recent oculomotor studies have made significant contributions to the understanding of neurodevelopmental disorders, most notably in autism, attention-deficit/hyperactivity disorder, and Tourette's syndrome. Notably different patterns of deficits have been found in these disorders and have helped to clarify their pathophysiology. SUMMARY: Eye-movement studies have begun to serve as a useful approach for studying cognitive and neurophysiological aspects of neurodevelopmental disorders. They also have potential as a strategy for establishing quantitative endophenotypes for genetic research, and for monitoring beneficial and adverse effects of pharmacotherapies. Studies are needed that involve larger patient populations, longitudinal characterization of developmental failures, patients free from central nervous system-active medications, and that use functional imaging, as patients perform eye-movement tasks, for direct identification of clinically relevant abnormalities in brain systems.

Attention Deficit Disorder with Hyperactivity↗

PubMed2002

Psychiatric disturbances in children of parents with bipolar disorder.

The early symptoms of bipolar disorder in children and adolescents are often qualitatively different from the classic symptoms of mania and depression that present in adults, complicating the diagnosis of the disorder in younger populations. The focus of this article is the evaluation and treatment of children with bipolar parents who begin to develop behavioral and other psychiatric problems. The authors first review the current criteria available for diagnosing bipolar disorder in children. They consider issues related to how the DSM-IV criteria have been applied in this population, in particular the increase in the number of children diagnosed with bipolar disorder as a result of the decision to allow a "manic" episode to be diagnosed in the absence of expansive or elated mood. The practice parameters for the diagnosis and treatment of bipolar disorder in children and adolescents developed by the American Academy of Child and Adolescent Psychiatry are also discussed. The literature concerning children of parents with bipolar disorder is reviewed and indicates that these children are at increased risk for a wide range of psychiatric disorders, including bipolar disorders, other affective disorders, disruptive behavior disorders, and other psychiatric illnesses. The authors then review what is known about treatment for the early symptoms of bipolar disorder in this population and discuss the utility of mood stabilizers. The authors then discuss the role genomic screening may play in the future in identifying children at the highest risk for developing bipolar disorder. The article concludes with a summary of several endophenotypic expressions of bipolar disorder that have been described in children of parents with bipolar disorder.

Journal Article↗

PubMed2006

Pain insensitivity in schizophrenia: trait or state marker?

OBJECTIVES: As early as the turn of the 20th century, clinicians observed patients with schizophrenia failing to respond to the pain of a myocardial infarction, ruptured appendix, or perforated bowel. Although this pain insensitivity in individuals with psychosis has been described in the literature for many years, the phenomenon is still poorly understood. We therefore reviewed the literature for findings concerning whether pain insensitivity in schizophrenia represents a state or a trait marker. METHODS: A comprehensive Medline search of the literature on pain insensitivity in subjects with schizophrenia was conducted. RESULTS: While the literature contains anecdotal observations, case reports, and a few rigorous clinical studies concerning patients with schizophrenia being relatively indifferent to pain, there is a dearth of empirical, well-controlled studies in this area. Although early studies that examined the response of individuals with schizophrenia to thermal or electrical pain were constrained by a variety of methodological confounders, studies on this topic suggest that the higher pain thresholds observed in schizophrenia are best explained by a complex, multifactorial model. Most intriguing are the results of one recent study that found pain insensitivity in family members of persons with schizophrenia, suggesting that this phenomenon may be a trait or endophenotype rather than being due to a psychotic state. CONCLUSIONS: Pain insensitivity in individuals with schizophrenia, which is associated with increased morbidity and mortality, is poorly understood. It is possible that pain insensitivity might serve as a prodromal predictor of susceptibility for schizophrenia. Future studies are needed to further clarify the neurobiology, pathophysiology, and practical clinical implications of this phenomenon.

Acute Disease↗

PubMed2004

Differential effects of ethanol on gamma-aminobutyric acid-A receptor-mediated synaptic currents in congenic strains of inbred long and short-sleep mice.

BACKGROUND: Ethanol enhances gamma-aminobutyric acid (GABA)A receptor-mediated responses in the brain, and this enhancement is greater in a mouse line behaviorally more sensitive to ethanol (long sleep) than in a line (short sleep) behaviorally less ethanol sensitive (assayed by loss of righting; sleep time). Quantitative trait locus (QTL) analysis of inbred long sleep (ILS) and inbred short sleep (ISS) phenotypes revealed four chromosomal regions (Lore1, Lore2, Lore4, and Lore5) that together account for approximately 50% of ethanol-induced sleep-time variance. Congenic strains were generated, each of which is homozygous for one of four ISS Lore QTLs on the ILS background. These congenic mouse strains are ideally suited for asking which QTL regions might correlate with other phenotypes that differ between ILS and ISS mice. Here we used the congenics to investigate altered GABAA responses to ethanol. METHODS: Evoked GABAA receptor-mediated inhibitory postsynaptic currents (IPSCs) were measured by whole-cell voltage-clamp recording procedures in CA1 pyramidal neurons in hippocampal brain slices. RESULTS: GABAA IPSC responses in hippocampal brain slices from ILS mice were significantly enhanced by 80 mM ethanol, whereas those from ISS mice were not affected. ILS.Lore2 and ILS.Lore5 congenic strains were significantly enhanced by 80 mM ethanol, similar to the background (control) ILS mice. However, ethanol had no significant effect on GABAA responses in ILS.Lore1 and ILS.Lore4 congenic mice, similar to the ISS mice, thus reflecting the influence of ISS alleles on the ILS phenotype. CONCLUSIONS: Our results suggest that alleles located in the Lore1 and Lore4 QTL regions confer ethanol sensitivity of GABAA receptor-mediated IPSCs. Thus, for these QTLs, GABAA IPSCs may represent an endophenotype of sedative/hypnotic sensitivity to ethanol. Although the Lore2 and Lore5 QTL regions have a significant effect on sleep time, they do not play a significant role in the differential ethanol enhancement of GABAA IPSCs between ILS and ISS mice.

Animals↗

PubMed2005

Family history of alcoholism and response to amphetamine: sex differences in the effect of risk.

BACKGROUND: Individuals at risk for alcoholism exhibit an enhanced stimulant response to alcohol. It is not known whether individuals at risk also exhibit a heightened sensitivity to other drugs with stimulant properties. METHODS: Healthy young men and women each received, in separate sessions, placebo and 10 mg of d-amphetamine in counterbalanced order. Stimulant and sedative subjective effects were recorded before and three times after capsule administration using the Biphasic Alcohol Effects Scale. The sample comprised 19 family-history-positive (FHP; 58% women) and 53 family-history-negative (FHN; 51% women) participants. RESULTS: As compared with placebo, amphetamine increased ratings of stimulation in the sample as a whole. In addition, the ratings revealed an enhanced, as well as a protracted, stimulant response to amphetamine among FHP men, as compared with FHN men: for FHP men, ratings of stimulation made 3 and 6 hr after amphetamine administration were greater than baseline ratings. Moreover, in FHP men, the effect of amphetamine, as compared with placebo, was most evident 6 hr after capsule administration. In contrast, despite a dose x hour interaction in FHN men, post hoc comparisons revealed no differences between the baseline and any of the postamphetamine measurements or between amphetamine and placebo ratings at any of the time points. Among women, the drug effect did not differentiate the family-history groups. CONCLUSIONS: Consistent with previous research on alcohol, high-risk men exhibited a heightened stimulant response to amphetamine. Thus, for men, sensitivity to the stimulant properties of drugs may be an endophenotype for alcoholism. Whereas the present results suggest that women at risk do not exhibit an enhanced stimulant response to amphetamine, further study is needed, including evaluation at various points in the menstrual cycle.

Adult↗

PubMed2003

Early expression of a pathophysiological feature of schizophrenia: saccadic intrusions into smooth-pursuit eye movements in school-age children vulnerable to schizophrenia.

OBJECTIVE: Neurodevelopmental hypotheses of schizophrenia propose that the responsible pathology occurs much earlier than the usual onset of illness in late adolescence. Nonspecific neurocognitive and behavioral deficits found in children vulnerable to schizophrenia support this hypothesis. This report describes early deficits in a putative genetic endophenotype, saccadic intrusions into smooth-pursuit eye movements (SPEM). METHOD: SPEM were recorded in 189 children aged 6-15 years: 49 children with schizophrenia, 60 nonpsychotic first-degree relatives, and 80 typically developing children. RESULTS: Children with schizophrenia demonstrated poorer gain and a significantly increased frequency of leading saccades and large anticipatory saccades; however, only leading saccades differentiated first-degree relatives from typical children. Admixture analysis indicates that 94% of children with schizophrenia, 50% of first-degree relatives, and 19% of typically developing children have abnormally increased frequencies of leading saccades. CONCLUSIONS: Typically developing young school-age children have a leading saccade phenotype similar to that of adults, suggesting this brain function is fully developed by early school-age years. The abnormal leading saccade phenotype, a schizophrenia-associated familial brain dysfunction, is present by 6 years of age, more than a decade before the highest risk for onset of psychosis. Treatment and prevention strategies will need to consider the early neurodevelopmental nature of schizophrenia.

Age Factors↗

PubMed2004

Genetic and environmental contributions to stability and change of ADHD symptoms between 8 and 13 years of age: a longitudinal twin study.

OBJECTIVE: To study the genetic and environmental contributions to stability and change of attention-deficit/hyperactivity disorder (ADHD) symptoms between 8 and 9 and 13 and 14 years of age. METHOD: The sample included 1,480 twin pairs born in Sweden between May 1985 and December 1986. At wave 1 in 1994, when twins were 8-9 years old, 1,106 (75%) of the parents responded to a mailed questionnaire, and at wave 2 when the twins were 13-14 years old, 1,063 (73%) responded. A checklist with 14 items based on the 14 DSM-III-R symptoms for ADHD was completed. Structural equation modeling was used to analyze the data. RESULTS: A relatively high stability of ADHD symptoms over this 5-year period was found. This continuity was mainly due to the same genetic effects operating at both points in time. Change in symptoms between childhood and early adolescence was to a large extent due to new genetic effects in early adolescence but also due to new nonshared environmental effects that became important during adolescence. CONCLUSIONS: The genetic stability highlights the importance of the continuing search for genes and endophenotypes of ADHD.

Adolescent↗