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PubMed2005

Sensory abnormalities in unaffected relatives in familial adult-onset dystonia.

Somatosensory abnormalities are found in adult-onset primary torsion dystonia (PTD). Therefore we assessed spatial discrimination thresholds (SDT), a measure of spatial acuity, in four multiplex families with adult-onset PTD. In family members aged 20 to 45 years vs controls (mean + 2.5 SD), abnormal SDTs were found in four of five affected with adult-onset PTD and in 12 of 49 unaffected relatives. Sensory abnormalities may be an endophenotype, possibly expressed later as adult-onset PTD.

Adult↗

PubMed2002

Minnesota Twin Family Study.

The Minnesota Twin Family Study is a longitudinal study of 11-year-old and 17-year-old twins and their parents designed to examine factors related to the etiology of substance abuse and related problems. At study intake, the twins and their parents participate in a day-long assessment in our laboratory that includes measures of endophenotypes (e.g., event-related potentials, EEG, autonomic nervous system reactivity, startle eye-blink), psychopathology, personality, cognitive ability, anthropometry, and environmental risk/protective factors. DNA derived from blood is also collected. A parallel longitudinal study of adolescent adoptive siblings, biologically related siblings, and their parents is also underway. Over 1500 twin families and 350 adoptive and biological sibling families have already entered the longitudinal phase of the study. This article provides an overview of study methods, highlights published findings, and describes procedures in place to foster collaboration with other investigators.

Adolescent↗

PubMed2005

Eating disorders: from twin studies to candidate genes and beyond.

Substantial effort has been put into the exploration of the biological background of eating disorders, through family, twin and molecular genetic studies. Family studies have shown that anorexia (AN) and bulimia nervosa (BN) are strongly familial, and that familial etiologic factors appear to be shared by both disorders. Twin studies often focus on broader phenotypes or subthreshold eating disorders. These studies consistently yielded moderate to substantial heritabilities. In addition, there has been a proliferation of molecular genetic studies that focused on Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV; American Psychiatric Association, 1994) AN and BN. Seven linkage regions have been identified in genome-wide screens. Many genetic association studies have been performed, but no consistent association between a candidate gene and AN or BN has been reported. Larger genetic association studies and collaborations are needed to examine the involvement of several candidate genes and biological pathways in eating disorders. In addition, twin studies should be designed to assist the molecular work by further exploring genetic determinants of endophenotypes, evaluating the magnitude of contribution to liability of measured genotypes as well as environmental risk factors related to eating disorders. In this manner twin and molecular studies can move the field forward in a mutually informative way.

Anorexia↗

PubMed2006

Angiotensinogen G(-6)A polymorphism is associated with the elevation of blood pressure in the hypertensive disorders of pregnancy.

The objective of the present study was to determine whether angiotensinogen G(-6)A polymorphism is associated with the elevation of blood pressure (BP) in the hypertensive disorders of pregnancy in Korean population. The subjects included 201 cases with the hypertensive disorders of pregnancy and 160 healthy controls. The medical records of subjects were reviewed. Cases were classified into the four subtypes (transient hypertension, preeclampsia, chronic hypertension, and preeclampsia superimposed on chronic hypertension) by the diagnostic criteria suggested by the National High Blood Pressure Education Program Working Group. Cases were also divided into the high and low BP group by the elevation of BP (diastolic BP greater than or equal to 110 mmHg). Maternal angiotensinogen G(-6)A polymorphism was determined by restriction fragment length polymorphism. Frequencies of AA genotype were significantly higher in the high than in the low BP group in the preeclampsia, superimposed preeclampsia, and the combined group (N = 201), suggesting that the angiotensinogen G(-6)A allele was significantly associated with the elevation of BP in the hypertensive disorders of pregnancy among South Korean women. The present findings imply that the elevation of BP can serve as an endophenotype for a spectrum of hypertensive conditions in pregnancy.

Analysis of Variance↗

PubMed2006

Imaging phenotypes and genotypes in schizophrenia.

Schizophrenia is associated with subtle structural and functional brain abnormalities. Both recent and classical data suggest that it is a heterogeneous disorder that is clearly heritable. The cause and course of schizophrenia are poorly understood, and classical categories of clinical symptoms have not been particularly useful in identifying its pathophysiology or predicting its treatment. The possible genetic risk factors for schizophrenia are numerous; however, the connection between the genotype and the time-course, or the multifaceted symptoms of the disease, has yet to be established. Brain imaging methods that study the structure or function of the cortical and subcortical regions have also identified distinct patterns that distinguish schizophrenics from controls, and that may identify meaningful subtypes of schizophrenia. The predictive relationship between these imaging phenotypes and disease characteristics such as treatment response is only beginning to be revealed. The emergence of the field of imaging genetics, combining genetic, and neuroimaging data, holds much promise for the deeper understanding and improved treatment of diseases such as schizophrenia. In this article we review some of the key findings in imaging phenotyping and genotyping of schizophrenia, and the initial endeavors at their combination into more meaningful and predictive patterns, or endophenotypes identifying the relationships among clinical symptoms, course, genes, and the underlying pathophysiology.

Brain↗

PubMed2005

Genetic contributions to human gyrification: sulcal morphometry in Williams syndrome.

Although gyral and sulcal patterns are highly heritable, and emerge in a tightly controlled sequence during development, very little is known about specific genetic contributions to abnormal gyrification or the resulting functional consequences. Williams syndrome (WS), a genetic disorder caused by hemizygous microdeletion on chromosome 7q11.23 and characterized by abnormal brain structure and striking cognitive (impairment in visuospatial construction) and behavioral (hypersocial/anxious) phenotypes, offers a unique opportunity to study these issues. We performed a detailed analysis of sulcal depth based on geometric cortical surface representations constructed from high-resolution magnetic resonance imaging scans acquired from participants with WS and from healthy controls who were matched for age, sex, and intelligence quotient, and compared between-group differences with those obtained from a voxel-based morphometry analysis. We found bilateral reductions in sulcal depth in the intraparietal/occipitoparietal sulcus (PS) in the brains of participants with WS, as well as in the collateral sulcus and the orbitofrontal region in the left hemisphere. The left-hemisphere PS in the WS group averaged 8.5 mm shallower than in controls. Sulcal depth findings in the PS corresponded closely to measures of reduced gray matter volume in the same area, providing evidence that the gray matter volume loss and abnormal sulcal geometry may be related. In the context of previous functional neuroimaging findings demonstrating functional alterations in the same cortical regions, our results further define the neural endophenotype underlying visuoconstructive deficits in WS, set the stage for defining the effects of specific genes, and offer insight into genetic mechanisms of cortical gyrification.

Adolescent↗

PubMed2006

Dopaminergic control of sleep-wake states.

Dopamine depletion is involved in the pathophysiology of Parkinson's disease, whereas hyperdopaminergia may play a fundamental role in generating endophenotypes associated with schizophrenia. Sleep disturbances are known to occur in both schizophrenia and Parkinson's disease, suggesting that dopamine plays a role in regulating the sleep-wake cycle. Here, we show that novelty-exposed hyperdopaminergic mice enter a novel awake state characterized by spectral patterns of hippocampal local field potentials that resemble electrophysiological activity observed during rapid-eye-movement (REM) sleep. Treatment with haloperidol, a D2 dopamine receptor antagonist, reduces this abnormal intrusion of REM-like activity during wakefulness. Conversely, mice acutely depleted of dopamine enter a different novel awake state characterized by spectral patterns of hippocampal local field potentials that resemble electrophysiological activity observed during slow-wave sleep (SWS). This dopamine-depleted state is marked by an apparent suppression of SWS and a complete suppression of REM sleep. Treatment with D2 (but not D1) dopamine receptor agonists recovers REM sleep in these mice. Altogether, these results indicate that dopamine regulates the generation of sleep-wake states. We propose that psychosis and the sleep disturbances experienced by Parkinsonian patients result from dopamine-mediated disturbances of REM sleep.

Animals↗

PubMed2006

An evaluation of the level of response to alcohol, externalizing symptoms, and depressive symptoms as predictors of alcoholism.

OBJECTIVE: The development of alcohol-use disorders (AUDs) reflects a complex relationship between genetic influences and environmental/cultural forces. Some genes operate through intermediate phenotypes, including a low level of response (LR) to alcohol, externalizing symptoms (EXT), and internalizing characteristics such as depressive syndromes (DEP). This article evaluates the impact of these three intermediate phenotypes and additional domains in a structural equation model (SEM). METHOD: Data were available from baseline at approximately age 20 for LR, as well as from additional domains at the 10- and 15-year follow-up periods for 393 men from the San Diego Prospective Study. Correlational analyses and an AMOS-based SEM were used to evaluate the development of alcohol problems, including AUDs, with the hypothetical model based on results from prior studies evaluating each key intermediate phenotype separately. RESULTS: The SEM explained 51% of the variance of the 15-year outcome, and had good fit characteristics. The family history ofAUDs (FHalc) was linked, directly or indirectly, to all three key domains. The combination of LR and EXT mediated the relationship between FHalc and 15-year alcohol outcomes, with a trend (p = .07) for LR to mediate between FHalc and the 10-year outcome. DEP, by itself, did not mediate FHalc to alcoholism. The LR predicted the 15-year outcome both through alcohol problems at 10 years and via drinking to cope (COPE), with each of these domains functioning as mediators. The relationship of EXT to outcome was mediated by alcohol expectations (EXPECT) and by COPE. DEP added to the model in the context of an FH of independent depressions, stress, and lower social supports, subsequently affecting COPE. CONCLUSIONS: The results indicate that the development of AUDs reflects several genetically influenced endophenotypes in the context of multiple additional domains. Both EXPECT and COPE represented important pathways through which the phenotypes influenced the AUD risk.

Adaptation, Psychological↗

PubMed2005

The emergence of a new paradigm of pharmacogenomics.

A series of qualitatively new properties of the complex polygenic systems are transforming the dominant, genome-centric approach of pharmacogenomics towards a more integrative, holistic paradigm. The recent concepts of interposition of regulatory networks between genotype and phenotype, and the emergence of epigenotype as the locus of integration of genetic background with nutritional and lifestyle influences, render problematic any prediction of the consequences of individual gene alterations. In addition, the redefinition of the traditional boundaries of clinical phenotypes, with the promotion of the endophenotypes as methodological strategy, and the initiative of the phenome elucidation, reshape both the research, as well as the application, of pharmacogenomics. These concepts and developments can explain some of the complexity, and the multifactorial nature, of most drug responses and imply another understanding of education in the field, which aims at stimulating a critical reflection on these major shifts prior to a practical training on the immediate application of pharmacogenomics.

Humans↗

PubMed2003

Dopamine transporter genotype influences the attention deficit in Korean boys with ADHD.

Attention appears to be inheritable, stable and influenced by genetic factors. The use of the Continuous Performance Test (CPT), as an endophenotypic measure, is valuable for genetic studies because it may show increased sensitivity to specific dimensions in attention deficit hyperactivity disorder. However, few studies have been designed to examine the influence of the genotype on attention level measured by CPT in ADHD patients. This study examinee the difference between 10/10 and 10/* genotype in the attention deficits measured by the CPT in ADHD patients. Forty-four unrelated ADHD patients were recruited from the psychiatric outpatients' clinic at Kangbuk Samsung Hospital. Two child psychiatrists made the diagnoses of ADHD using the DSM- IV diagnostic criteria. The genomic DNA was extracted from the blood, and analyzed to determine the genotype. A 40- base pair variable number of tandem repeats (VNTR) polymorphism in the 3' untranslated region was amplified. The attention deficits were measured by the test of variables of attention (T.O.V.A.). Between the 10/10 genotype and 10/* genotype, standard scores of the T.O.V.A were compared using a Mann-Whiney test. A comparison with the 10/10 genotype and 10/* genotype showed that those patients with the 10/10 genotype made less omission errors in the first quarter of the test (p < 0.05, by Mann-Whiney test). No significant differences were observed in the errors of commission, response time, variability. This study found that the 10/10 genotype made less omission errors on the T.O.V.A. This suggests that the dopamine transporter genotype influences the attention deficits measured by T.O.V.A.

3' Untranslated Regions↗

PubMed2025

Profiling hippocampal neuronal populations reveals unique gene expression mosaics reflective of connectivity-based degeneration in the Ts65Dn mouse model of Down syndrome and Alzheimer's disease.

INTRODUCTION: Individuals with Down syndrome (DS) exhibit neurological deficits throughout life including the development of in Alzheimer's disease (AD) pathology and cognitive impairment. At the cellular level, dysregulation in neuronal gene expression is observed in postmortem human brain and mouse models of DS/AD. To date, RNA-sequencing (RNA-seq) analysis of hippocampal neuronal gene expression including the characterization of discrete circuit-based connectivity in DS remains a major knowledge gap. We postulate that spatially characterized hippocampal neurons display unique gene expression patterns due, in part, to dysfunction of the integrity of intrinsic circuitry. METHODS: We combined laser capture microdissection to microisolate individual neuron populations with single population RNA-seq analysis to determine gene expression analysis of CA1 and CA3 pyramidal neurons and dentate gyrus granule cells located in the hippocampus, a region critical for learning, memory, and synaptic activity. RESULTS: The hippocampus exhibits age-dependent neurodegeneration beginning at ~6 months of age in the Ts65Dn mouse model of DS/AD. Each population of excitatory hippocampal neurons exhibited unique gene expression alterations in Ts65Dn mice. Bioinformatic inquiry revealed unique vulnerabilities and differences with mechanistic implications coinciding with onset of degeneration in this model of DS/AD. CONCLUSIONS: These cell-type specific vulnerabilities may underlie degenerative endophenotypes suggesting precision medicine targeting of individual populations of neurons for rational therapeutic development.

Alzheimer’s disease↗

PubMed2002

The development and evaluation of a computer-based program to test and to teach the recognition of facial affect.

Autism is a chronic pervasive neurodevelopmental disorder characterized by the early onset of social and communicative impairments as well as restricted, ritualized, stereotypic behavior. The endophenotype of autism includes neuropsychological deficits, for instance a lack of "Theory of Mind" and problems recognizing facial affect. In this study, we report the development and evaluation of a computer-based program to teach and test the ability to identify basic facially expressed emotions. 10 adolescent or adult subjects with high-functioning autism or Asperger-syndrome were included in the investigation. A priori the facial affect recognition test had shown good psychometric properties in a normative sample (internal consistency: rtt=.91-.95; retest reliability: rtt=.89-.92). In a prepost design, one half of the sample was randomly assigned to receive computer treatment while the other half of the sample served as control group. The training was conducted for five weeks, consisting of two hours training a week. The trained individuals improved significantly on the affect recognition task, but not on any other measure. Results support the usefulness of the program to teach the detection of facial affect. However, the improvement found is limited to a circumscribed area of social-communicative function and generalization is not ensured.

Adolescent↗

PubMed2004

The molecular medicine revolution and psychiatry: bridging the gap between basic neuroscience research and clinical psychiatry.

Recent years have witnessed a considerable increase in both fundamental knowledge and available experimental techniques in the basic neurosciences. Unfortunately, clinical translation of these findings vis-à-vis a direct benefit to patients who suffer from psychiatric diseases has not been as rapid. It is likely that this will change in the near future. We discuss some of the knowledge and expanding techniques of basic neuroscience, focusing on those that may be most promising regarding the future impact of the current molecular medicine revolution in psychiatry. Some of the more exciting findings (basic mechanisms, techniques, and clinical methodologies) that are expected to have a major impact on both our understanding of the biological underpinnings of psychiatric diseases and the development of novel and/or improved therapies include genetics, epigenetics, transcriptomics/proteomics, neuroimaging, animal models, and improved psychiatric endophenotypes.

Diagnostic Imaging↗

PubMed2026

Whole-genome sequencing implicates rare, low-frequency and structural non-coding variation at the SCN5A locus in Brugada syndrome.

Brugada syndrome (BrS) is an inherited cardiac condition characterized by a hallmark ECG pattern and an increased risk of sudden cardiac death. Central to the aetiology of BrS, the SCN5A region harbours both common non-coding risk variants and rare coding variants that are causative in approximately 20% of patients. However, rare non-coding genetic variation in this region remains largely unexplored. Here, we used whole-genome sequencing (WGS) of 752 European-ancestry BrS cases and 1,827 ancestry-matched controls to identify BrS-associated rare non-coding genetic variation at the SCN5A locus. Sliding-window and cis-regulatory element (CRE)-based rare-variant aggregate testing implicated three conserved CREs, including a dense aggregation of case singleton variants within a 178 bp enhancer in intron 17 of SCN5A which replicated in an independent BrS cohort. Prioritised BrS-associated rare and low-frequency non-coding variants within these elements were predicted to alter cardiac transcription factor motifs, and altered CRE activity in hiPSC-CM luciferase assays or were associated with BrS-relevant ECG endophenotypes in the UK Biobank. Single-variant analysis across the region identified a Bonferroni-significant five-fold case-enriched low-frequency variant within a known CRE in intron 1 of SCN5A, which replicated, was associated with slower cardiac conduction in the UK Biobank and accounted for part of the BrS GWAS signal at this locus. Structural variant analyses identified a 10.5 kb deletion upstream of SCN5A in a BrS case that encompassed a cardiac CRE and reduced sodium current density in a hiPSC-CM model, as well as a 6 kb BrS-enriched retrotransposon insertion in SCN5A that appeared to underlie part of the GWAS signal in this region. Together, these findings implicate rare and low-frequency non-coding variation at the SCN5A locus in BrS susceptibility and demonstrate the value of targeted WGS analysis of key disease loci.

Journal Article↗

PubMed2000

The relation between tendency for psychopathology and reduced frontal brain volume in healthy people.

OBJECTIVE: We hypothesized that tendency toward psychopathology is associated with lower frontotemporal volumes. BACKGROUND: Although there is considerable evidence for structural abnormalities in patients with major psychiatric disorders and increased recognition that neural substrates may underlie individual differences in personality, there have been no studies in healthy people attempting to relate personality to volumetric measures of brain structure. METHOD: We used magnetic resonance imaging with an advanced method for automated segmentation of cranial compartments to gray matter, white matter, and cerebrospinal fluid. We examined the relation between frontal and temporal lobe volumes and Minnesota Multiphasic Personality Inventory measures of tendency toward psychopathology in 59 healthy individuals. RESULTS: As hypothesized, higher scores on the clinical scales were associated with lower average frontal lobe volume. When the sample was divided according to sex, however, these correlations were significant in men (n = 29) but not in women (n = 30). The highest correlation was observed between lower frontal white matter volume in men and high schizophrenia scale score (r[27] = -0.59, p <0.001). CONCLUSIONS: The findings suggest that personality dimensions in healthy people can be linked to neural substrates, which can potentially serve as endophenotypic markers of disposition to psychopathology. The sexually dimorphic effects are consistent with gender-related differences in the clinical manifestations of psychiatric disorders and may suggest sex hormone modulation of the psychopathologic processes.

Adult↗

PubMed2001

Visual p3 in female alcoholics.

BACKGROUND: The P300 (P3) component of the event related potential has been established as a sensitive risk marker of vulnerability to alcoholism. Most alcoholism studies have focused on men; recent studies indicate that women are equally vulnerable to developing alcoholism. METHODS: Visual P3 recorded from 31 electrode positions was evaluated in 44 alcoholic and 60 control women, 24-50 years of age. P3 amplitudes and latencies of the two groups were statistically compared using Analysis of Variance; source localization of surface amplitude values from each group were plotted using a low-resolution brain electromagnetic tomography. RESULTS: The results indicated that alcoholic women had significantly smaller P3 amplitudes in the frontal and central regions compared with controls. Source localization showed lowered activation in alcoholic women in right dorso-lateral prefrontal cortex and the ventro-medial fronto-central regions. CONCLUSIONS: The results suggest that P3 is an equally sensitive endophenotypic marker of vulnerability to alcoholism in women. The findings are discussed in terms of functional and physiologic significance of the P3 amplitude in alcoholic women and its relationship to drinking behaviors.

Adult↗

PubMed2001

Nonreplication of association between mu-opioid-receptor gene (OPRM1) A118G polymorphism and substance dependence.

In the present investigation we hypothesized the A118G (Asn40Asp) polymorphism of the mu-opioid receptor gene (OPRM1) as a particular vulnerability factor for heroin and alcohol dependence. Therefore, we tested this hypothesis in two independent large samples by two different methods: a case-control sample (comprising n = 287 heroin and n = 221 alcohol study subjects versus n = 365 nondependent controls) and a family-controlled sample of 111 parent-offspring trios of heroin-dependent study subjects and 75 parent-offspring trios of alcohol-dependent study subjects to avoid stratification artifacts. In both patient samples and by both methods we were unable to corroborate the hypothesis of OPRM1 A118G polymorphism as a particular risk factor for any kind of substance dependence including opioid addiction. In addition, there was no significant association between the endophenotype of the individuals under study (e.g., comorbidity, severity of illness) and a particular genotype of OPRM1.

Adenine↗

PubMed2001

Quantitative neural indicators of liability to schizophrenia: implications for molecular genetic studies.

While schizophrenia is substantially heritable, the disorder's molecular genetic basis remains elusive. These efforts have been hindered by an inability to detect nonclinically-penetrant carriers of the predisposing genes and by uncertainties concerning the nature of the non-genetic influences and the extent of locus heterogeneity. The "endophenotype" approach is an alternative method for measuring phenotypic variation that may facilitate the identification of susceptibility genes in the context of complexly-inherited traits. Here we describe the application of this method to measures of brain structure and function in samples of schizophrenia patients and their non-ill first-degree relatives (siblings and co-twins). Our results suggest that there are likely to be multiple heritable dimensions of the central nervous system pathology in schizophrenia, each under the influence of a partially distinct set of genes, one of which involves disturbances in the structure and functioning of frontal lobe systems involved in working memory and another of which appears to render the brain more susceptible to damage to subcortical systems involved in long-term memory following oxygen deprivation in utero. Measures sensitive to quantitative variation in these dimensions of the central nervous system compromise should allow non-penetrant gene carriers to become informative for genetic linkage and facilitate detection of different genetic loci contributing to discrete aspects of disease liability.

Birth Injuries↗