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PubMed1999

Schizophrenia: refining the phenotype, resolving endophenotypes.

The conceptual history of the diagnosis of schizophrenia is reviewed and the current definition of the illness is examined (e.g. DSM-IV). A dimensional alternative to the traditional categorical model of diagnosis is discussed with a specific emphasis on the four dimensions of psychopathology represented by reality distortion (hallucinations, delusions), disorganization (positive formal thought disorder, bizarre behavior), negative symptoms (flattened affect, avolition, alogia, asociality), and premorbid social functioning. Also discussed is the development of structured psychiatric interviews that emerged from the clinical/research context that gave rise to explicit (i.e. operational) diagnostic criteria for schizophrenia. The general methodological approach used to detect valid endophenotypes for schizophrenia liability--i.e. indicators of liability not visible to the unaided naked eye--as well as their potential diagnostic and research utility is presented in overview. The rationale for linking such indicators to schizophrenia liability, which is conceptualized as a latent construct, is also reviewed. Future directions in the development and refinement of the diagnostic approach to schizophrenia and schizophrenia liability are highlighted.

Diseases in Twins↗

PubMed2003

Spatial working memory as an endophenotype for schizophrenia.

BACKGROUND: Spatial working memory impairments are among the neurocognitive deficits that may mark genetic predisposition toward schizophrenia. We previously reported that impairment on the spatial span subtask of the Wechsler Adult Intelligence Scale-Revised increased in a dose-dependent manner with increasing genetic predisposition toward schizophrenia in a sample of discordant twins; however, it remains to be determined whether these deficits reflect difficulties with encoding, maintenance, manipulation, time-tagging of visual spatial information, storage capacity, or complex motor response. METHODS: We developed a spatial delayed response task in which memory set size was parametrically varied, holding constant manipulation and decision processes. We then reassessed 80 of the previously studied twins (17 probands with 8 monozygotic co-twins and 13 dizygotic co-twins, and 42 healthy twins). RESULTS: The spatial delayed response task was sensitive to genetic loading for schizophrenia but did not provide evidence for capacity limitations in probands or their co-twins. CONCLUSIONS: The findings suggest that deficits in the encoding or storage aspects of short-term spatial mnemonic processing may be an effective endophenotypic marker for schizophrenia.

Female↗

PubMed2001

Early, non-psychotic deviant behavior in schizophrenia: a possible endophenotypic marker for genetic studies.

Early non-psychotic deviance occurs in some, but not all, pre-schizophrenic patients and has been linked to the later course of the disorder, suggesting its relationship with the schizophrenia syndrome. However, early deviance has rarely been explored as an endophenotypic marker in large samples of schizophrenic patients. We characterized the early childhood behavior and syndrome history of 205 adults with DSM-IV schizophrenia. Sixty percent of our sample had poor socialization, extreme fears/chronic sadness, and/or attention impairment/learning disabilities beginning before age 10. The remaining 40% were without behavioral difficulties until the onset of schizophrenia. Logistic regression analyses suggested that the risk of syndrome onset before age 17 was 2.5 times more likely among patients with poor socialization beginning before age 10. Schizoaffective disorder was 3.75 times greater among patients with extreme fears/chronic sadness in childhood, and schizophrenic patients with early attention impairment/learning disabilities were 2 times more likely to have a 1 degrees, 2 degrees or 3 degrees relative with schizophrenia. We concluded that early deviant behavior indicated a distinct subgroup of patients, and was linked to syndrome characteristics specifically relevant to genetic studies, in particular age at onset and family history of schizophrenia. Since early syndrome onset has been associated with specific genetic anomalies in other complex neuropathologic disorders, it may prove valuable to regard these early deviant behaviors as an indicator of early syndrome onset for future genetic studies of schizophrenia.

Adolescent↗

PubMed2001

Family and twin strategies as a head start in defining prodromes and endophenotypes for hypothetical early-interventions in schizophrenia.

In an effort to share the experiences of 'genotype-hunters'-who have approached the difficult task of forecasting future schizophrenia in the young offspring or other relatives of index cases, in new samples guided by the prior probabilities of 15% in offspring or 50% in identical co-twins-with 'early-interventionists'-who focus on purported prodromal symptoms in children who would be treated pharmacologically to prevent the development of schizophrenia-we provide a focused review that emphasizes the hazards of false positives in both approaches. Despite the advantages prospective high-risk strategies have had from clinical and laboratory findings that implicate some prodromal signs and endophenotypes, e.g. attention, memory, and information processing evaluations, the yields are not sufficient for practical applications involving antipsychotic drugs for undiagnosed children. Even more caution than usual is required, given the suggestions that the developing neocortex is vulnerable to dopaminergic exposure.

Adolescent↗

PubMed2003

Searching for a structural endophenotype in psychosis using computational morphometry.

Structural cerebral abnormalities are frequently observed in schizophrenia. These abnormalities may indicate vulnerability for the disorder, as evidenced by reports of familial clustering of measures identified through region-of-interest analyses using manual outlining procedures. We used computational morphometry to detect structural differences within the entire brain to further examine possible structural endophenotypes. Magnetic resonance imaging scans were obtained in 31 psychotic patients, 32 non-psychotic first-degree relatives of psychotic patients and 27 healthy controls. The images were processed using an automated procedure, yielding global grey matter, white matter, CSF and total brain volume. The relative distribution of grey matter was compared between groups on a clustered-voxel basis. Global grey matter and total brain volume did not differ between the groups. White matter volume was significantly higher and CSF volume significantly lower in relatives compared to both cases and controls. The clustered-voxel based group comparison yielded evidence for significant grey matter deficits in fronto-thalamic-cerebellar regions, in psychotic patients, whereas the most prominent deficits in relatives involved the cerebellum. Patients with psychosis and first-degree healthy relatives of patients with psychosis show cerebellar abnormalities, which may constitute a marker of genetic transmission.

Adolescent↗

PubMed2005

Genetic associations of alcohol dehydrogenase with alcohol use disorders and endophenotypes in white college students.

Associations of alcohol dehydrogenase (ADH) gene polymorphisms (ADH1B*2 and ADH1C*1) with a lifetime alcohol use disorder (AUD) were examined in White college students. Alcohol-related endophenotypes likely to be influenced by elevations in acetaldehyde were also assessed. Individuals with an ADH1B*2 allele had lower rates of AUDs, consumed a lower maximum number of drinks in a 24-hr period, reported a greater level of response to alcohol, were more likely to have experienced alcohol-induced headaches following 1 or 2 drinks, and reported more severe hangovers than those lacking this allele. These findings are consistent with the hypothesis that enhanced sensitivity to alcohol and lower levels of alcohol use reflect the mechanism by which ADH1B*2 protects against developing an AUD.

Acetaldehyde↗

PubMed2005

Visual-perceptual dysfunctions are possible endophenotypes of schizophrenia: evidence from the psychophysical investigation of magnocellular and parvocellular pathways.

Visual information processing is impaired in schizophrenia patients and their biological relatives. The authors measured vernier thresholds in 72 schizophrenia patients, their 86 siblings, and 60 healthy control subjects. Subjects were asked to detect the direction of the horizontal displacement of 2 stimuli (left or right). During magnocellular (M) pathway tests, stimuli were dots with low contrast (5%) or counterphase-modulated gratings (25 Hz). For parvocellular (P) pathway tests, isoluminant blue-red dots with yellow-green background were used. Results revealed that patients with schizophrenia and their siblings were more impaired in M pathway conditions than in P pathway conditions. There was no color-specific impairment. The patients and their siblings displayed lower performances on tests of executive functions, psychomotor speed, and verbal memory compared with the controls. Visual-perceptual and neuropsychological data did not correlate. In conclusion, M pathway dysfunction is a potential endophenotype of schizophrenia.

Analysis of Variance↗

PubMed2003

Deficient response inhibition as a cognitive endophenotype of ADHD.

OBJECTIVE: To investigate whether a deficient response inhibition is a cognitive endophenotype of attention-deficit/hyperactivity disorder (ADHD). The authors hypothesized that nonaffected siblings of ADHD probands would have a response inhibition between that of ADHD probands and normal controls, although they resembled the controls at a behavioral level. METHOD: Participants were 25 ADHD probands with a family history of ADHD, their nonaffected siblings (n = 25), and 48 normal controls matched for age and IQ. All participants were between 6 and 17 years of age. The nonaffected siblings were compared with their ADHD siblings and with controls on measures reflecting different types of response inhibition. RESULTS: The nonaffected siblings had results similar to those of the ADHD probands, who differed from the controls on all inhibition measures (p <.05). CONCLUSIONS: Siblings of ADHD probands, while not behaviorally expressing the disorder, have ADHD-associated deficits in response inhibition. This suggests that subtyping based on measures of response inhibition can help identify genetic susceptibility to ADHD. Children with a genetic vulnerability to ADHD may have hidden cognitive deficits in the absence of manifest behavioral symptoms. Therefore, they should be monitored to detect possible learning problems.

Adolescent↗

PubMed2006

Neurocognition as a stable endophenotype in bipolar disorder and schizophrenia.

Linkage and association studies have paid increasing attention to neurocognition as a putative endophenotype. However, there exists little documentation of its trait stability in schizophrenia or bipolar disorder. Our aim was to determine the longitudinal stability of neurocognitive performance in bipolar versus schizophrenia probands. We administered a neurocognitive battery at two time points, approximately 5 years apart, in 16 schizophrenia and 16 bipolar disorder age-matched subjects. There were no significant changes over time on variables including education, estimated IQ, depression, psychosis, global functioning, or medication status. Schizophrenia subjects showed significant deterioration in one measure of executive functioning but no significant changes in seven of eight other domains. Bipolar patients showed stability over time in attentional measures but greater variability in other domains. These preliminary findings suggest that neurocognitive domains appear longitudinally stable across broad domains in schizophrenia. In contrast, stable functioning may be more limited to attentional domains in bipolar disorder.

Adult↗

PubMed2002

Admixture analysis of smooth pursuit eye movements in probands with schizophrenia and their relatives suggests gain and leading saccades are potential endophenotypes.

Abnormalities during a smooth pursuit eye movement task (SPEM) are common in schizophrenic patients and their relatives. This study assessed various components of SPEM performance in first-degree unaffected relatives of schizophrenic patients. One hundred individuals with schizophrenia, 137 unaffected first-degree relatives, and 69 normal controls completed a 16.7 degrees/s SPEM task. Smooth pursuit gain, catch-up saccades (CUS), large anticipatory saccades, and leading saccades (LS) were identified. Groups were compared with parametric and admixture analyses. Schizophrenic patients performed more poorly than unaffected relatives and normals on gain, CUS, and LS. Unaffected relatives were more frequently impaired than normals only on gain and LS. Relatives of childhood-onset and adult-onset probands had similar impairments. Gain and frequency of leading saccades may be genetic endophenotypes in childhood-onset and adult-onset schizophrenia.

Adolescent↗

PubMed2003

The study of cytosolic phospholipase A2 gene polymorphism in schizophrenia using eye movement disturbances as an endophenotypic marker.

Phospholipase A(2) (PLA2) is a key enzyme of the phospholipid metabolism which shows alteration in schizophrenia. Eye movement disturbances occur in a majority of patients with schizophrenia and in a proportion of their first-degree relatives, and they have been suggested as an endophenotypic marker in genetic studies of this illness. Here we report an association between the BAN I polymorphism of the cytosolic PLA2 gene (single nucleotide polymorphism in the first intron of the gene) and the intensity of eye movement disturbances (fixation and smooth pursuit) observed in 126 schizophrenic patients. The mean intensity of both kinds of eye movement disturbances was significantly higher in individuals homozygous for the A2 genotype compared with the remaining phenotypes. There was also a trend for greater A2 allele frequency in schizophrenic patients with a higher degree of eye movement disturbances. The relative frequency of the A2/A2 genotype was higher in patients with a greater degree of eye movement disturbances occurring during both fixation and smooth pursuit tests. Our results correspond to the other studies showing an association between the cPLA2 polymorphism and schizophrenia (predominance of the A2 allele in schizophrenic subjects).

Adolescent↗

PubMed2006

Modelling facets of mania--new directions related to the notion of endophenotypes.

The lack of appropriate animal models is a major limitation in research of bipolar disorder (BPD): at this time there are very few models for this devastating disease. Whereas limited attempts have been made to develop comprehensive models for BPD, the new notion of endophenotypes encourages us to explore the possibility of developing separate models for separate facets of the disorder. Since more models are available for depression, there is a dire need for models for mania that will be relatively easy and simple to induce and test and will therefore be practical for purposes of screening possible new drugs or mutant mice that are developed based on novel molecular theories. Such models may already be tentatively available as they were developed in the context of other disorders, but there is a need to validate them for mania. The present paper proposes such models for most of the facets of mania including: increased energy, activity or restlessness; extreme irritability; reduced sleep; provocative, intrusive or aggressive behaviour; increased sexual drive; abuse of drugs; distractibility, reduced ability to concentrate; and unrealistic beliefs in one's abilities and powers resulting in poor judgement. Validating these models may demand a major research effort but it may be worthy as validated models for the different facets of mania could then be used efficiently and may be utilized to construct a standard battery of tests that can serve to explore the various components of manic-like behaviour in rodents.

Aggression↗

PubMed2005

The endophenotype of impulsivity: reaching consilience through behavioral, genetic, and neuroimaging approaches.

Impulsivity is a multidimensional construct with implications for understanding the etiology and treatment of multiple forms of psychopathology. As a multidimensional construct, however, the processes underlying impulsivity, particularly behavioral inhibition, must be separated to allow for investigations into its neurogenetic bases. Evidence from both animal and human studies supports the role of dopamine in impulsivity, and neuroimaging research is elucidating brain regions involved in behavioral inhibition. Evidence is now emerging that suggests an interaction between dopamine system genes and frontal brain regions in underlying individual differences in behavioral inhibition. However, to reach a comprehensive understanding of the neurogenetic bases of behavioral inhibition, an appropriate framework is required. Therefore, it is proposed that by identifying intervening variables more sensitive to the effects of genetic variation, known as an endophenotype approach, we will be able to overcome many of the methodological limitations that prevent a better understanding at present.

Adult↗

PubMed2005

Including endophenotypes as covariates in variance component heritability and linkage analysis.

The purpose of these analyses was to determine if incorporating or adjusting for covariates in genetic analyses helped or hindered in genetic analyses, specifically heritability and linkage analyses. To study this question, two types of covariate models were used in the simulated Genetic Analysis Workshop 14 dataset in which the true gene locations are known. All four populations of one replicate were combined for the analyses. The first model included typical covariates of sex and cohort (population) and the second included the typical covariates and also those related endophenotypes that are thought to be associated with the trait (phenotypes A, B, C, D, E, F, G, H, I, J, K, and L). A final best fit model produced in the heritability analyses was used for linkage. Linkage for disease genes D1, D3, and D4 were localized using models with and without the covariates. The use of inclusion of covariates did not appear to have any consistent advantage or disadvantage for the different phenotypes in regards to gene localization or false positive rate.

Genetic Linkage↗

PubMed2005

Testing assumptions for endophenotype studies in ADHD: reliability and validity of tasks in a general population sample.

BACKGROUND: Advances in both genetic and cognitive-experimental studies on attention deficit hyperactivity disorder (ADHD) have opened new opportunities for cognitive endophenotype research. In such genetic designs the focus is on individual differences in characteristics, associated with ADHD, that can be measured reliably over time. Genetic studies that take a 'quantitative trait loci' approach hypothesise that multiple susceptibility genes contribute to a continuous dimension of ADHD symptoms. As an important initial step, we aimed to investigate the underlying assumptions that (1) key cognitive-experimental tasks indicate adequate test-retest reliability and (2) ADHD symptom scores in a general population sample are associated with performance on these tasks. METHODS: Forty-nine children were assessed on a go/no-go task and a reaction time task (the 'fast task') that included manipulations with event rate and incentives. The children were assessed twice, with a test-retest interval of two weeks. RESULTS: The majority of the task variables demonstrated moderate-to-good test-retest reliability. The correlations between teacher ratings of ADHD symptoms and key task variables were .4-.6: ADHD symptoms were associated with poor performance (especially high reaction time variability) in a slow baseline condition, whereas there was low or no association in conditions with a faster event rate or incentives. In contrast, no clear pattern of findings emerged based on parent ratings of ADHD symptoms. CONCLUSION: The data support the usefulness of the go/no-go and fast tasks for genetic studies, which require reliable and valid indices of individual differences. The overall pattern of associations between teacher ratings of ADHD symptoms and task variables is consistent with effects of event rate and incentives on performance, as predicted by the model of activation and arousal regulation. The lack of a clear pattern of findings with parent ratings of ADHD symptoms warrants further study.

Adolescent↗

PubMed2001

Impaired attention as an endophenotype for molecular genetic studies of schizophrenia.

Attentional abnormalities have long been known to characterize patients with schizophrenia. The data discussed in this report suggest that impaired attention (at least as measured by a specific task, the Continuous Performance Test, Identical Pairs (CPT-IP) version) may also be an endophenotype of particular promise for use in molecular genetic studies of schizophrenia. This conclusion is based on findings indicating that the deficits in verbal and spatial attentional processing tapped by the CPT-IP are heritable, developmentally stable, independent of clinical state, and predict future spectrum disorders in the at-risk offspring of parents with schizophrenia.

Adolescent↗

PubMedDate not supplied

[Genetic background of ADHD: genes of the serotonergic system, other candidate genes, endophenotype].

Recent studies have shown that in the aetiology of attention-deficit hyperactivity disorder (ADHD) genetic factors may be of importance. Biochemical and pharmacological studies reveal a connection between abnormalities of dopaminergic, adrenergic and serotonergic system and ADHD. Therefore genes for enzymes synthesizing or degrading proper neurotransmitters, genes for adequate transporters and receptors and genes for other substances, which altered the level of neurotransmitters, are studied. Many authors describe the connection between ADHD development and the synaptosomal-associated protein 25 (SNAP-25) gene. This protein plays a role in catecholamine secretion. Its higher expression is specific for neurones. SNAP-25 gene mutation may change this protein level, function of synapse and neurotransmitters storage. Acetylcholine receptor alpha4 subunit gene stimulation increases the dopamine level. Therefore this receptor gene may be important in the aetiology of ADHD studies. Other possible factors in ADHD background are substance influence on brain maturation, including N-methyl-D aspartate glutamate receptor 2A gene polymorphism (GRIN2A) and brain derived neurotrophic factor (BDNF) gene. One of the greatest challenges in studying the genetic basis of psychiatric disorders is to find appropriate ways to define the relevant endophenotype. ADHD often coexists with other psychiatric disorders, including specific developmental disorders, conduct disorders, obsessive-compulsive disorder and early onset of bipolar disorder.

Attention Deficit Disorder with Hyperactivity↗

PubMed2006

Familial aggregation of eye-tracking endophenotypes in families of schizophrenic patients.

BACKGROUND: Abnormal smooth pursuit eye movements (SPEMs) are some of the most reproducible biological changes associated with the susceptibility for schizophrenia. Recent studies have suggested that deficit in predictive pursuit, a specific component of the SPEMs, marks schizophrenia susceptibility. OBJECTIVE: To test whether predictive pursuit contains less extraneous noise and may be under more direct genetic control than the traditional measure of overall pursuit performance using maintenance pursuit gain. DESIGN: Familial aggregation estimation of the predictive pursuit measure and the traditional maintenance pursuit measure in sibling pairs from families of schizophrenic patients. SETTING: Outpatient clinics. PARTICIPANTS: Patients with schizophrenia and their full siblings were recruited, provided that at least 1 sibling pair could be formed per family. Ninety-two siblings were recruited into the study. They formed 70 sibling pairs. Ninety healthy control subjects were also recruited using targeted local community advertisements based on patients' county of residence, aiming to capture the basic demographics of the regions from which the patients were recruited. MAIN OUTCOME MEASURES: Familial correlations and heritability estimates of 2 SPEM measures: maintenance pursuit gain and predictive pursuit gain. RESULTS: The sibling intraclass correlation coefficient of the predictive pursuit gain (r = 0.45-0.48) was significantly higher than that of maintenance pursuit gain (r = 0.02-0.20) (P = .005-.007). Variance component analysis suggested a high genetic loading for predictive pursuit (heritability = 0.90, SE = 0.22; P<.001) but relatively low heritability in the traditional maintenance pursuit measure (heritability = 0.27, SE = 0.21; P = .08). CONCLUSION: These results suggest that predictive pursuit may index stronger genetic effect and may be better suited for genetic studies than the traditional SPEM measure of maintenance pursuit gain.

Adult↗