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PubMed2006

Features associated with excessive exercise in women with eating disorders.

OBJECTIVE: Excessive exercise and motor restlessness are observed in a substantial number of patients with eating disorders. This trait has been studied extensively among animal models of activity anorexia nervosa (AN) and may hold particular interest as an endophenotype for AN. We explored features associated with excessive exercise across subtypes of eating disorders. METHOD: Participants were female probands and affected female relatives from the multi-site international Price Foundation Genetic Studies with diagnoses of AN, bulimia nervosa (BN), and both AN and BN or eating disorder not otherwise specified (ED-NOS) (N=1,857). Excessive exercise was defined based on responses to the Structured Interview for Anorexic and Bulimic Disorders (SIAB). RESULTS: Among the eating disorder diagnostic groups, excessive exercise was most common among the purging subtype of AN. Individuals who reported excessive exercise also reported lower minimum BMI, younger age at interview, higher scores on anxiety, perfectionism, and eating disorder symptom measures, more obsessions and compulsions, and greater persistence. CONCLUSION: Excessive exercise may be associated particularly with the purging subtype of AN as well as with a constellation of anxious/obsessional temperament and personality characteristics among women with eating disorders.

Adult↗

PubMed2026

Eating Disorders and Parkinson's Disease-2: Genetic Epidemiology and Shared Genomics.

OBJECTIVE: Individuals with anorexia nervosa (AN) share premorbid traits with Parkinson's Disease (PD) (e.g., anxiety) and exhibit a two-fold relative risk of a reported family history of PD. Published estimates of intra- and inter-disorder genetic architecture were extracted and compared prior to conducting novel analyses to provide evidence for cross-disorder genetic risk. METHODS: National register or meta-analytic familial, twin, and common variant genome-wide studies were searched; estimates and findings were extracted and compared. Novel cross-disorder conditional and conjunctional false discovery rate analyses were performed. RESULTS: Sibling relative risks and additive genetic estimates of the two disorders were similar. AN had greater common variant heritability than PD whether measured via infinitesimal model (linkage disequilibrium score regression, LDSC) or causal mixture model (MiXeR). AN had greater polygenicity than PD (mean (SD) 2.50E-03 (1.64E-04) versus 2.72E-4 (1.47E-05), p < 0.001), but lower discoverability than PD (4.20E-05 (2.69E-06) versus 1.40E-04 (6.95E-06), p < 0.001). Global genetic correlation was significant (e.g., bivariate LDSC rg = 0.10, p = 0.0033). Novel analyses identified cross-disorder enrichment, and cross-disorder risk at chr3p21.31. CONCLUSIONS: Cross-disorder AN and PD research identified shared risk variants at chr3p21.31, genes and mechanisms (e.g., conditioning, fear, and reward) linked to a shared endophenotype.

Parkinson's disease↗

PubMed2005

Linkage mapping methods applied to the COGA data set: presentation Group 4 of Genetic Analysis Workshop 14.

Presentation Group 4 participants analyzed the Collaborative Study on the Genetics of Alcoholism data provided for Genetic Analysis Workshop 14. This group examined various aspects of linkage analysis and related issues. Seven papers included linkage analyses, while the eighth calculated identity-by-descent (IBD) probabilities. Six papers analyzed linkage to an alcoholism phenotype: ALDX1 (four papers), ALDX2 (one paper), or a combination both (one paper). Methods used included Bayesian variable selection coupled with Haseman-Elston regression, recursive partitioning to identify phenotype and covariate groupings that interact with evidence for linkage, nonparametric linkage regression modeling, affected sib-pair linkage analysis with discordant sib-pair controls, simulation-based homozygosity mapping in a single pedigree, and application of a propensity score to collapse covariates in a general conditional logistic model. Alcoholism linkage was found with > or =2 of these approaches on chromosomes 2, 4, 6, 7, 9, 14, and 21. The remaining linkage paper compared the utility of several single-nucleotide polymorphism (SNP) and microsatellite marker maps for Monte Carlo Markov chain combined oligogenic segregation and linkage analysis, and analyzed one of the electrophysiological endophenotypes, ttth1, on chromosome 7. Linkage was found with all marker sets. The last paper compared the multipoint IBD information content of several SNP sets and the microsatellite set, and found that while all SNP sets examined contained more information than the microsatellite set, most of the information contained in the SNP sets was captured by a subset of the SNP markers with approximately 1-cM marker spacing. From these papers, we highlight three points: a 1-cM SNP map seems to capture most of the linkage information, so denser maps do not appear necessary; careful and appropriate use of covariates can aid linkage analysis; and sources of increased gene-sharing between relatives should be accounted for in analyses.

Alcoholism↗

PubMed2005

Association mapping: methodologies, strategies, and issues.

Recent advances in molecular genetic technology allow for detailed characterization of genetic variation and easy cost-efficient accumulation of such data, even for large human samples. One such advance that presents incredible opportunities for identifying associations between genetic polymorphisms and disease-related phenotypes is the ability to quickly type a large number of single-nucleotide polymorphisms (SNPs). Contributors to Group 10 of Genetic Analysis Workshop 14 explored the potential of SNP genotypes for the association mapping of disease-related genes in family-based studies. Using both real data involving alcoholism susceptibility, made available by the Collaborative Study on the Genetics of Alcoholism (COGA), and simulated data involving personality-disorder susceptibility, group members investigated specific methodological issues involved in association mapping, such as multiple testing, single SNPs vs. combinations and haplotypes, and the effect of linkage disequilibrium on SNP-based linkage; evaluated existing methodologies for association mapping using SNPs, short-tandem repeats (STRs), or a combination of the two; and introduced new or modified association-mapping methods, including a gamma random effects (GRE) model and the quantitative trait linkage disequilibrium (QTLD) test. These papers are unified by the application of association-based methods to analyze SNPs, microsatellite markers, or both, to identify chromosomal regions harboring genes that contribute to quantitative endophenotype variation, and thus to disease risk. Their diversity attests to the breadth and flexibility of association-mapping approaches to the genetics of complex disease.

Alcoholism↗

PubMed2005

Alcoholism and related traits: a summary of Group 13 contributions.

Ten groups set out to study the genetics of alcoholism, using various measures of alcohol dependence such as Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria, and related endophenotypes such as the electrophysiological evaluation of event-related potentials. The groups used both genome-wide microsatellite and single-nucleotide polymorphism (SNP) genotyping data in families selected from the Collaborative Study on the Genetics of Alcoholism. The majority of investigators studied alcohol-related phenotypes and chose linkage rather than association analysis. The analysis of SNP data presented several challenges, including marker linkage disequilibrium issues and computational limitations. Many groups pursued novel techniques, both in dealing with the SNP data and the definition of phenotypes. While there was a limited amount of concordance among linkage findings, it was very instructive to see so many new strategies at work. Generally the SNP genotype data seemed to yield more information for multipoint linkage analysis than the microsatellite data, a finding that will benefit the genetic analysis of complex disease in the future. A novel linkage peak was detected using the SNP markers.

Alcoholism↗

PubMed2005

Heterogeneity: GAW Group 15.

This paper summarizes the contributions to Group 15 of Genetic Analysis Workshop (GAW) 14, which focused on methods for dealing with heterogeneity in linkage and association analysis. A variety of methods were employed, ranging from manipulation of the phenotype and/or identification of endophenotypes prior to analysis, to statistical methods allowing for heterogeneity in the analysis of simple dichotomous phenotypes as provided with the data. Overall, it was difficult to draw broad conclusions from these applications. Groups that focused on the simulated data had fairly consistent success in mapping the major genes (but not the two minor genes). However, this appeared to be the case regardless of whether heterogeneity was explicitly modeled, either at the phenotypic or statistical level, with relatively crude statistical methods applied to the simulated simple dichotomous trait Kofendrerd personality disorder also enjoying considerable success.

Alcoholism↗

PubMed2007

Schimke immunoosseous dysplasia: suggestions of genetic diversity.

Schimke immunoosseous dysplasia (SIOD), which is characterized by prominent spondyloepiphyseal dysplasia, T-cell deficiency, and focal segmental glomerulosclerosis, is a panethnic autosomal recessive multisystem disorder with variable expressivity. Biallelic mutations in switch/sucrose nonfermenting (swi/snf) related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1 (SMARCAL1) are the only identified cause of SIOD. However, among 72 patients from different families, we identified only 38 patients with biallelic mutations in the coding exons and splice junctions of the SMARCAL1 gene. This observation, the variable expressivity, and poor genotype-phenotype correlation led us to test several hypotheses including modifying haplotypes, oligogenic inheritance, or locus heterogeneity in SIOD. Haplotypes associated with the two more common mutations, R820H and E848X, did not correlate with phenotype. Also, contrary to monoallelic SMARCAL1 coding mutations indicating oligogenic inheritance, we found that all these patients did not express RNA and/or protein from the other allele and thus have biallelic SMARCAL1 mutations. We hypothesize therefore that the variable expressivity among patients with biallelic SMARCAL1 mutations arises from environmental, genetic, or epigenetic modifiers. Among patients without detectable SMARCAL1 coding mutations, our analyses of cell lines from four of these patients showed that they expressed normal levels of SMARCAL1 mRNA and protein. This is the first evidence for nonallelic heterogeneity in SIOD. From analysis of the postmortem histopathology from two patients and the clinical data from most patients, we propose the existence of endophenotypes of SIOD.

Algorithms↗

PubMed2004

Autism and 15q11-q13 disorders: behavioral, genetic, and pathophysiological issues.

New insights into biological factors that underlie autism may be gained by comparing autism to other neurodevelopmental disorders that have autistic features and relatively well-delineated genetic etiologies or neurobiological findings. This review moves beyond global diagnoses of autism and instead uses an endophenotypic approach to compare specific clusters of autistic symptomatology to features of chromosome 15q11-q13 disorders. Paternally or maternally derived deficiencies of 15q11-q13 result in Prader-Willi or Angelman syndromes, and we first use a global approach to review potential autism susceptibility genes in the 15q11-q13 region. We then use a more trait-based approach to suggest possible ties between specific phenotypic characteristics of autism and Prader-Willi syndrome, namely savant-like skills. We conclude with insights from pathophysiological studies that implicate altered development of specific neuron types and circuits in the cerebral cortex as part of the pathophysiological processes associated with autism and mental retardation.

Animals↗

PubMed2005

ADHD: strategies to unravel its genetic architecture.

Attention deficit/hyperactivity disorder (ADHD) is a common and impairing neuropsychiatric disorder with onset at preschool age and strong persistence over time. Its validity as a psychiatric disorder has been established according to Robins and Guze criteria. Genetic factors predominate in the etiology of ADHD. This paper summarizes the current status of genetic research into ADHD, and describes eight factors that complicate research into genetically complex disorders as ADHD. These factors are that multiple genes of small main effects are involved rather than main genes, the relevant phenotype is unknown, presence of clinical heterogeneity, presence of genetic heterogeneity, gene-environment correlation, gene-environment interaction, importance of endophenotypes, and importance of developmental factors. The further unraveling of the genetic architecture of ADHD will depend to a large extent on how well these complicating factors are handled or even used.

Attention Deficit Disorder with Hyperactivity↗

PubMed2005

Challenge studies in anxiety disorders.

In psychiatry, the use of pharmacological challenges in panic disorder is unique in that the clinical phenomenon of central interest (i.e., the panic attack) can be provoked readily and assessed in the clinical laboratory setting. During the past 20 years pharmacological challenge studies have increased our knowledge concerning the neurobiology of panic disorder remarkably and may ultimately result in novel and more causal treatment strategies. Moreover, the differences in sensitivity to certain panicogens such as serotonergic agents, lactate, carbon dioxide and cholecystokinin tetrapeptide are likely to be fruitful in serving as biological markers of subtypes of panic disorders and should be a major focus of research, as the identification of reliable endophenotypes is currently one of the major rate-limiting steps in psychiatric genetic studies.

Anxiety Disorders↗

PubMed2006

ADHD and the dopamine transporter: are there reasons to pay attention?

The catecholamine dopamine (DA) plays an important role as a neurotransmitter in the brain in circuits linked to motor function, reward, and cognition. The presynaptic DA transporter (DAT) inactivates DA following release and provides a route for non-exocytotic DA release (efflux) triggered by amphetamines. The synaptic role of DATs first established through antagonist studies and more recently validated through mouse gene-knockout experiments, raises questions as to whether altered DAT structure or regulation support clinical disorders linked to compromised DA signaling, including drug abuse, schizophrenia, and attention deficit hyperactivity disorder (ADHD). As ADHD appears to have highly heritable components and the most commonly prescribed therapeutics for ADHD target DAT, studies ranging from brain imaging to genomic and genetic analyses have begun to probe the DAT gene and its protein for possible contributions to the disorder and/or its treatment. In this review, after a brief overview of ADHD prevalence and diagnostic criteria, we examine the rationale and experimental findings surrounding a role for human DAT in ADHD. Based on the available evidence from our lab and labs of workers in the field, we suggest that although a common variant within the human DAT (hDAT) gene (SLC6A3) is unlikely to play a major role in the ADHD, contributions of hDAT to risk maybe most evident in phenotypic subgroups. The in vitro and in vivo validation of functional variants, pursued for contributions to endophenotypes in a within family approach, may help elucidate DAT and DA contributions to ADHD and its treatment.

Adult↗

PubMed2006

Genetics of dystonia.

Primary torsion dystonia (PTD) has a broad clinical spectrum, with earlier onset of symptoms associated with more generalized muscle involvement. The causes for most dystonia are unknown although several monogenic subtypes have been identified. One important genetic cause of PTD is DYT1; a three base pair deletion in this gene is a major cause for early-onset dystonia. Its identification has allowed the development of cellular and animal models; it has also permitted studies that identify both "manifesting" and "non-manifesting" DYT1 mutation carriers. These studies have expanded our understanding of clinical expression to include psychiatric symptoms and also have enabled imaging studies of endophenotypes. These advances provide a widened platform for future research.

Age of Onset↗

PubMed2004

Gene-environment interplay in schizopsychotic disorders.

Genetic studies have sought to identify subtypes or endophenotypes of schizophrenia in an effort to improve the reliability of findings. A number of chromosomal regions or genes have now been shown to have had replicated linkage to schizophrenia susceptibility. Molecules involved in neurodevelopment or neurotransmitter function are coded by many of the genes that have been implicated in schizophrenia. Studies of neurotransmitter function have identified, among others, a possible role for GABA, glutamate and dopamine in animal models of schizophrenia. GABA neurons that co-express the calcium binding protein parvalbumin have been implicated as have glutamatergic metabotropic receptors and dopamine D3 receptors. Stress influences glutamate and dopamine providing another environmental factor that may interact with the influence of genes on neurotransmitter function. Neurotransmitter interactions include influences on signaling molecules and these too have been implicated in forms of learning thought to be affected in schizophrenia. Results continue to unravel the interplay of genes and environment in the etiology of schizophrenia and other psychotic disorders.

Animals↗

PubMed2004

Clinical phenotypes associated with DISC1, a candidate gene for schizophrenia.

Genetic factors play an important part in the development of schizophrenia and bipolar disorder, and linkage analyses in families have successfully identified several chromosomal regions containing candidate genes. A single large pedigree has been described in which schizophrenia and depression segregate with a balanced chromosomal translocation involving the long arm of chromosome 1 and the short arm of chromosome 11. The gene named DISC1, disrupted at the chromosome 1 breakpoint, is a novel candidate gene that may have a role in the pathogenesis of schizophrenia. The cellular location and function of the protein coded by DISC1 is currently being investigated. The phenotype associated with DISC1 in the t (1;11) translocation family includes schizophrenia, schizoaffective disorder, recurrent major depression and bipolar disorder. Hence this locus is one of several now reported apparently showing linkage to both schizophrenia and bipolar disorder. The study of intermediate phenotypes or "endophenotypes" may clarify the relations between phenotype and genotype. Auditory event related potentials are EEG based physiological measures widely studied in schizophrenia. In particular the cognitive evoked potential, the P300 response generated during an "odd-ball" two-tone discrimination task consistently shows reduced amplitude in schizophrenia compared to controls. In members of the family with the t (1;11) translocation, P300 amplitude was reduced in relatives who carried the translocation compared to relatives with a normal karyotype. Furthermore the amplitude reduction was independent of the presence or absence of symptoms because asymptomatic translocation carriers showed similar P300 amplitude reduction as was found in translocation carriers who were diagnosed with schizophrenia, bipolar disorder or unipolar depression. The results confirm that subjects with schizophrenia who carry the t (1;11) translocation have similar phenotype to unrelated subjects with schizophrenia and a normal karyotype. Furthermore P300 amplitude may be a useful intermediate phenotype detecting the neuropathology of schizophrenia in "at risk" individuals even in the absence of clinical symptoms.

Event-Related Potentials, P300↗

PubMed2006

Substance use disorders and Schizophrenia: a question of shared glutamatergic mechanisms.

Schizophrenia is noted for the remarkably high prevalence of substance use disorders (SUDs) including nicotine (>85%), alcohol and stimulants. Mounting evidence supports the hypothesis that the endophenotype of schizophrenia involves hypofunction of a subpopulation of cortico-limbic NMDA receptors. Low doses of NMDA receptor antagonists such as ketamine replicate in normal volunteers positive, negative and cognitive symptoms of schizophrenia as well as associated physiologic abnormalities such as eye tracking and abnormal event related potentials. Genetic studies have identified putative risk genes that directly or indirectly affect NMDA receptors including D-amino acid oxidase, its modulator G72, proline oxidase, mGluR3 and neuregulin. Clinical trials have shown that agents that directly or indirectly enhance the function of the NMDA receptor at its glycine modulatory site (GMS) reduce negative symptoms and in the case of D-serine and sarcosine improve cognition and reduce positive symptoms in schizophrenic subjects receiving concurrent anti-psychotic medications. Notably, the GMS partial agonist D-cycloserine exacerbates negative symptoms in clozapine responders whereas full agonists, glycine and D-serine have no effects, suggesting clozapine may act indirectly as a full agonist at the GMS of the NMDA receptor. Clozapine treatment is uniquely associated with decreased substance use in patients with schizophrenia, even without psychologic intervention. Given the role of NMDA receptors in the reward circuitry and in substance dependence, it is reasonable to speculate that NMDA receptor dysfunction is a shared pathologic process in schizophrenia and co-morbid SUDs.

Acamprosate↗

PubMed2002

Recent advances in the genetics of schizophrenia.

The genetic etiology of schizophrenia, a common and debilitating psychiatric disorder, is supported by a wealth of data. Review of the current findings suggests that considerable progress has been made in recent years, with a number of chromosomal regions consistently implicated by linkage analysis. Three groups have shown linkage to 1q21-22 using similar models, with HLOD scores of 6.5, 3.2, and 2.4. Other replicated loci include 13q32 that has been implicated by two independent groups with significant HLOD scores (4.42) or NPL values (4.18), and 5pl4.1-13.1, 5q21-33, 8p2l-22, and 10p11-15, each of which have been reported as suggestive by at least three separate groups. Different studies have also replicated evidence for a modest number of candidate genes that were not ascertained through linkage. Of these, the greatest support exists for the DRD3 (3q13.3), HTR2A (13q14.2), and CHRNA7 (15q13-q14) genes. The refinement of phenotypes, the use of endophenotypes, reduction of heterogeneity, and extensive genetic mapping have all contributed to this progress. The rapid expansion of information from the human genome project will likely further accelerate this progress and assist in the discovery of susceptibility genes for schizophrenia. A greater understanding of disease mechanisms and the application of pharmacogenetics should also lead to improvements in therapeutic interventions.

Cytochrome P-450 Enzyme System↗

PubMed2006

Evaluation of reward processes in an animal model of depression.

RATIONALE: Anhedonia is a core symptom of major depression. Deficits in reward function, which underlie anhedonia, can be readily assessed in animals. Therefore, anhedonia may serve as an endophenotype for understanding the neural circuitry and molecular pathways underlying depression. OBJECTIVE: Surprisingly, there is scant knowledge regarding alterations in brain reward function after olfactory bulbectomy (OB), an animal model which results in a behavioural syndrome responsive to chronic antidepressant treatment. Therefore, the present studies aimed to assess reward function after bulbectomy. MATERIALS AND METHODS: The present study utilized sucrose preference, cocaine-induced hyperlocomotion and intra-cranial self-stimulation (ICSS) responding to examine reward processes in the OB model. RESULTS: Bulbectomized animals showed a marked preference (>90%) for 0.8% sucrose solution compared with water; similar to the preference exhibited by sham controls. Importantly, there were pronounced deficits in brain reward function, as assessed using ICSS, which lasted 8 days before returning to baseline levels. Furthermore, bulbectomized animals were hyper-responsive to the locomotor stimulating properties of an acute and a repeated cocaine regimen. However, no difference in ICSS facilitation was observed in response to an acute cocaine injection. CONCLUSIONS: Taken together, these results suggest that bulbectomized rats display alterations in brain reward function, but these changes are not long-lasting and thus, not amenable to investigating the effects of pharmacological interventions. However, given that OB animals are hypersensitive to drugs of abuse, bulbectomy may be an appropriate inducing factor for the development of animal models of co-morbid depression and drug dependence.

Animals↗

PubMed2001

Human studies of prepulse inhibition of startle: normal subjects, patient groups, and pharmacological studies.

RATIONALE: Since the mid-1970s, cross-species translational studies of prepulse inhibition (PPI) have increased at an astounding pace as the value of this neurobiologically informative measure has been optimized. PPI occurs when a relatively weak sensory event (the prepulse) is presented 30-500 ms before a strong startle-inducing stimulus, and reduces the magnitude of the startle response. In humans, PPI occurs in a robust, predictable manner when the prepulse and startling stimuli occur in either the same or different modalities (acoustic, visual, or cutaneous). OBJECTIVE: This review covers three areas of interest in human PPI studies. First, we review the normal influences on PPI related to the underlying construct of sensori- (prepulse) motor (startle reflex) gating. Second, we review PPI studies in psychopathological disorders that form a family of gating disorders. Third, we review the relatively limited but interesting and rapidly expanding literature on pharmacological influences on PPI in humans. METHODS: All studies identified by a computerized literature search that addressed the three topics of this review were compiled and evaluated. The principal studies were summarized in appropriate tables. RESULTS: The major influences on PPI as a measure of sensorimotor gating can be grouped into 11 domains. Most of these domains are similar across species, supporting the value of PPI studies in translational comparisons across species. The most prominent literature describing deficits in PPI in psychiatrically defined groups features schizophrenia-spectrum patients and their clinically unaffected relatives. These findings support the use of PPI as an endophenotype in genetic studies. Additional groups of psychopathologically disordered patients with neuropathology involving cortico-striato-pallido-pontine circuits exhibit poor gating of motor, sensory, or cognitive information and corresponding PPI deficits. These groups include patients with obsessive compulsive disorder, Tourette's syndrome, blepharospasm, temporal lobe epilepsy with psychosis, enuresis, and perhaps posttraumatic stress disorder (PTSD). Several pharmacological manipulations have been examined for their effects on PPI in healthy human subjects. In some cases, the alterations in PPI produced by these drugs in animals correspond to similar effects in humans. Specifically, dopamine agonists disrupt and nicotine increases PPI in at least some human studies. With some other compounds, however, the effects seen in humans appear to differ from those reported in animals. For example, the PPI-increasing effects of the glutamate antagonist ketamine and the serotonin releaser MDMA in humans are opposite to the PPI-disruptive effects of these compounds in rodents. CONCLUSIONS: Considerable evidence supports a high degree of homology between measures of PPI in rodents and humans, consistent with the use of PPI as a cross-species measure of sensorimotor gating. Multiple investigations of PPI using a variety of methods and parameters confirm that deficits in PPI are evident in schizophrenia-spectrum patients and in certain other disorders in which gating mechanisms are disturbed. In contrast to the extensive literature on clinical populations, much more work is required to clarify the degree of correspondence between pharmacological effects on PPI in healthy humans and those reported in animals.

Humans↗