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PubMed2005

Quantitative genome scan and Ordered-Subsets Analysis of autism endophenotypes support language QTLs.

Autism is a neurodevelopmental syndrome with early childhood onset and deficits in three behavioral and cognitive dimensions: language, social skills and repetitive or restrictive behaviors. We hypothesized that using these endophenotypes would provide more power to detect linkage than the diagnosis of autism. Previously, we reported results for a nonparametric quantitative trait locus (QTL) genome scan in 152 families with autism, which revealed a linkage peak related to spoken language on 7q35. Here, we present the results of a nonparametric QTL scan of autism endophenotypes in 291 multiplex families, including the original 152. The strongest evidence for an 'age at first word' QTL was on chromosomes 3q at 147 cM (Z=3.10, P<0.001), and 17q at 93 cM (Z=2.84, P=0.002), both represent novel susceptibility loci for autism endophenotypes. There was also support for a previously identified autism peak on chromosome 17 at 43 cM (Z=2.22, P=0.013) with 'age at first phrase'. The 7q35 language peak was attenuated (Z=2.05, P=0.02) compared with the original finding. To explore the possibility of increased heterogeneity resulting from the addition of 135 families to the sample, we conducted an Ordered-Subsets Analysis on chromosome 7; these results suggest that the 132 autism families with the earliest average age at first word are responsible for the QTL on 7q35. This locus on 7q35 may harbor a gene contributing variability in spoken language that is not uniquely related to language delay in autism.

Autistic Disorder↗

PubMed2005

Are endophenotypes based on measures of executive functions useful for molecular genetic studies of ADHD?

BACKGROUND: Behavioral genetic studies provide strong evidence that attention-deficit/hyperactivity disorder (ADHD) has a substantial genetic component. Yet, due to the complexity of the ADHD phenotype, questions remain as to the specific genes that contribute to this condition as well as the pathways from genes to behavior. Endophenotypes, or phenotypes that are more closely linked to the neurobiological substrate of a disorder, offer the potential to address these two issues simultaneously (Freedman, Adler, & Leonard, 1999). Thus far, potential endophenotypes for ADHD have not been systematically studied. METHOD: The current paper reviews evidence supporting the use of deficits on neurocognitive measures of executive functions for this purpose. RESULTS: Such deficits are a correlate of ADHD and show preliminary evidence of heritability and association with relevant candidate genes. Nonetheless, studies that have assessed the familial and genetic overlap of neurocognitive impairments with ADHD have yielded inconsistent results. CONCLUSIONS: In order for executive function deficits to be used as an endophenotype for ADHD, we recommend greater attention to the neurocognitive heterogeneity of this disorder and to the precision of measurement of the neuropsychological tests employed. We also discuss empirical strategies that may be necessary to allow such research to progress prior to full resolution of the pathophysiological basis of ADHD.

Attention Deficit Disorder with Hyperactivity↗

PubMed2002

Neurobiological measures of schizotypal personality disorder: defining an inhibitory endophenotype?

OBJECTIVE: Subjects with schizotypal personality disorder demonstrate deficits in inhibition when assessed on prepulse inhibition, P50 suppression, and antisaccade paradigms. This study determined if distinct subgroups of subjects with schizotypal personality disorder could be identified on the basis of performance on these measures and whether endophenotypes could be defined for future genetic study by using measures of inhibitory function. METHOD: Prepulse inhibition, P50 suppression, and antisaccade paradigms were assessed in 21 subjects with schizotypal personality disorder. RESULTS: Seven subjects with schizotypal personality disorder had deficits on each paradigm; seven had no deficits on any paradigm. P50 and antisaccade deficits were present in five of the same subjects and significantly correlated. CONCLUSIONS: These results suggest that P50 and antisaccade performance reflects a common endophenotype and that prepulse inhibition identifies a separate endophenotype reflecting different neurobiological substrate(s) in subjects with schizotypal personality disorder. This pattern may generalize to schizophrenia spectrum disorder patients.

Acoustic Stimulation↗

PubMed2006

The adrenergic receptor alpha-2A gene (ADRA2A) and neuropsychological executive functions as putative endophenotypes for childhood ADHD.

There is resurgent interest in the psychiatric literature in endophenotypes, variables thought to more strongly reflect the effects of candidate genes than do manifest disorders. In a sample of 176 children with attention deficit hyperactivity disorder (ADHD) and 52 of their siblings, we examined the validity of several putative endophenotypes for ADHD that represent commonly used clinical measures of multiple cognitive/neuropsychological domains of executive functions (EFs). We review their distributional normality, their relations to ADHD symptoms in probands and unaffected siblings relative to nonADHD controls, and their correlation in siblings. We also tested theEF measures' associations with the ADRA2A gene and whether they mediated or moderated the associations between ADHD and ADRA2A. Several EF measures showed association with ADRA2A, as well as moderation, but not mediation, of its association with ADHD. Implications of the results for evaluating the validity and utility of putative endophenotype measures and for finding candidate gene effects on ADHD are discussed.

Attention Deficit Disorder with Hyperactivity↗

PubMed2005

["Persistence" as possible psychogenetic endophenotype].

For some human traits heritability estimates are well known based on results from twin studies. However, the study of connecting these characteristics to candidate genes in the Human Genome has just been started. The main goal of the recently formulated Human Fenom Project is to define "endophenotypes", characteristics that have considerable heritable component, and can be empirically measured with objective tools, standardized across cultures. Based on our recent findings the VNTR polymorphism in the coding region of the dopamine D4 receptor gene is a candidate gene of the "persistence" trait. Individuals carrying the 7-repeat polymorphism of this allele describe themselves as less persistent. In line with these results the 7-repeat polymorphism was associated to the "persistence" trait as measured by the Junior version of the TCI in a psychiatric sample of children diagnosed with ADHD. Based on these findings our main goal was to define an objective, behavioral measure which could be used as an "endophenotype" in genetic association studies. "Persistence" could be related to responsiveness in a reaction time task demanding sustained attention, for example. This hypothesis was tested using a sample of 35 healthy Caucasian subjects, participating in a extended cognitive reaction time task and filling out the TCI personality questionnaire. Non-invasive DNA sampling was used to determine the candidate polymorphism of the DRD4-VNTR. Results using self-report data replicated our previous findings: the 7-repeat polymorphism was significantly associated to lower "persistence" scores. Individual differences of reaction time were compared using the 7-repeat present/absent grouping as well. Results indicate that responses of individuals with the 7-repeat allele were significantly slower and more variable than of those without this candidate allele. Based on self-report and behavioural measures "persistence" trait is a possible endophenotype of psychogenetic associations.

Character↗

PubMed2005

Endophenotypes in the personality disorders.

The identification of endophenotypes in the personality disorders may provide a basis for the identification of underlying genotypes that influence the traits and dimensions of the personality disorders, as well as susceptibility to major psychiatric illnesses. Clinical dimensions of personality disorders that lend themselves to the study of corresponding endophenotypes include affective instability, impulsivity, aggression, emotional information processing, cognitive disorganization, social deficits, and psychosis. For example, the propensity to aggression can be evaluated by psychometric measures, interview, laboratory paradigms, neurochemical imaging, and pharmacological studies. These suggest that aggression is a measurable trait that may be related to reduced serotonergic activity. Hyperresponsiveness of amygdala and other limbic structures may be related to affective instability, while structural and functional brain alterations underlie the cognitive disorganization in psychotic-like symptoms of schizotypal personality disorder. Thus, an endophenotypic approach not only provides clues to underlying candidate genes contributing to these behavioral dimensions, but may also point the way to a better understanding of pathophysiological mechanisms.

Genetic Predisposition to Disease↗

PubMed2002

Endophenotypes in bipolar disorder.

The search for genes in bipolar disorder has provided numerous genetic loci that have been linked to susceptibility to developing the disorder. However, because of the genetic heterogeneity inherent in bipolar disorder, additional strategies may need to be employed to fully dissect the genetic underpinnings. One such strategy involves reducing complex behaviors into their component parts (endophenotypes). Abnormal neurophysiological, biochemical, endocrinological, neuroanatomical, cognitive, and neuropsychological findings are characteristics that often accompany psychiatric illness. It is possible that some of these may eventually be useful in subdefining complex genetic disorders, allowing for improvements in diagnostic assessment, genetic linkage studies, and development of animal models. Findings in patients with bipolar disorder that may eventually be useful as endophenotypes include abnormal regulation of circadian rhythms (the sleep/wake cycle, hormonal rhythms, etc.), response to sleep deprivation, P300 event-related potentials, behavioral responses to psychostimulants and other medications, response to cholinergics, increase in white matter hyperintensities (WHIs), and biochemical observations in peripheral mononuclear cells. Targeting circadian rhythm abnormalities may be a particularly useful strategy because circadian cycles appear to be an inherent evolutionarily conserved function in all organisms and have been implicated in the pathophysiology of bipolar disorder. Furthermore, lithium has been shown to regulate circadian cycles in diverse species, including humans, possibly through inhibition of glycogen synthase kinase 3-beta (GSK-3beta), a known target of lithium.

Animals↗

PubMed2006

Establishment of a battery of simple models for facets of bipolar disorder: a practical approach to achieve increased validity, better screening and possible insights into endophenotypes of disease.

The lack of appropriate animal models for bipolar disorder (BPD) hinders the translation of novel molecular and genetic findings into the development of new more efficient treatments. Attempts to develop a comprehensive model for BPD did not result in a practical and valid model and at present most studies utilize a limited number of models for specific components of the disorder. Whereas there is a higher availability of models for the depression pole of BPD, only a few models represent the manic pole with the most frequently used being psychostimulant-induced hyperactivity. This last model had been important in studies of the disease and has some validity but it is clear that by itself cannot be considered to represent mania. Additional models for facets of BPD are needed to allow better screening of new drugs and new mutant mice. Such models may also support the exploration of endophenotypes of BPD and the mechanisms of the disease. An advantage of a battery approach is that each model can be only partially valid when used alone but the combination of a few models may result in strong validity. The present study suggests that such a battery can be based on existing models previously developed in the context of studying normal behavior or other disorders after an initial validation in the context of BPD. An example for this idea is described using the resident-intruder test for aggression. Present results show that 3 weeks oral treatment with 1.2-2.4% lithium (increasing doses), or 20 g/kg daily dose of valproate, significantly reduced aggressive behavior in resident mice without affecting non-aggressive social interactions. Accordingly, it is suggested that the simplified resident-intruder paradigm may model the aggression related to mania as part of a test battery for facets of BPD. It is further speculated that, pending further research, this paradigm can be combined with additional methods to explore changes in the LHPA axis that may be linked to an important endophenotype of BPD.

Animals↗

PubMed2006

Beyond the DSM: defining endophenotypes for genetic studies of substance abuse.

Although substance-related disorders are heritable, the genetic factors contributing to vulnerability to these disorders are expected to be complex. Nonetheless, identifying genes underlying this vulnerability and understanding their relationship with environmental factors and behavior holds the promise of dramatic advances in diagnosis, prevention, and treatment. The search is complicated by a number of factors, however, including the weak validity of psychiatric diagnosis for identifying gene carriers, the complexity of the brain and behavior, and the numerous intervening variables between genetic transcription and its behavioral consequences. One strategy for bridging this theoretical gap is to study endophenotypes--biologic correlates of disorders that precede their overt development, may have higher reliability than behavioral measures, and present simpler relationships with a smaller number of genes. This article reviews research suggesting the usefulness of several putative endophenotypes for substance-related disorders, including 1) reduced P3 amplitude of the visual event-related potential, 2) increased EEG beta power, 3) a lowered level of response to an alcohol challenge, and 4) the inability to modulate autonomic nervous system reactivity under the stress of anticipating a predictable aversive stimulus.

Brain↗

PubMed2006

Is there an association between the COMT gene and P300 endophenotypes?

P300 wave anomalies correlate with genetic risk for schizophrenia and constitute a plausible endophenotype for the disease. The COMT gene is thought to influence cognitive performance and to be a susceptibility gene for schizophrenia. Unlike two previous studies, we found no significant influence of the COMT gene on P300 amplitude or latency in 189 individuals examined. The well-supported role of the COMT gene both in dopamine catabolism as well as in prefrontal cognition makes a strong theoretical case for the influence of COMT Val158Met polymorphism on P300 endophenotypes. However, the available neurophysiologic evidence suggests that any such association, if present, must be very subtle.

Adult↗

PubMed2006

Toward a definition of a cyclothymic behavioral endophenotype: which traits tap the familial diathesis for bipolar II disorder?

BACKGROUND: Although the cyclothymic temperament appears to be related to the familial diathesis of bipolar disorder, exhibiting high sensitivity for bipolar II (BP-II) disorder, it is presently uncertain which of its constituent traits are specific for this disorder. METHODS: In a sample of 446 major depressive patients (BP-II and unipolar), in the French National EPIDEP study, the cyclothymic temperament was assessed by using clinician- and self-rated scales. We computed the frequency of individual traits and relative risk for family history of bipolarity. RESULTS: From both clinician- and self-rated scales, four items related to mood reactivity, energy, psychomotor and mental activity were significantly highly represented in the subgroup with positive family history of bipolarity. The item "rapid shifts in mood and energy" obtained the highest relative risk (OR=3.42) for positive family history of bipolarity. CONCLUSION: These findings delineate those cyclothymic traits which are most likely to tap a familial-genetic diathesis for BP-II, thereby identifying traits which can best serve as a behavioral endophenotype for this bipolar subtype. Such an endophenotype might underlie the cyclic course of bipolar disorder first described in France 150 years ago by Falret and Baillarger.

Bipolar Disorder↗

PubMedDate not supplied

Secondary verbal memory: a potential endophenotype of schizophrenia.

This study aimed at identifying neuropsychological endophenotypes of schizophrenia which met the criteria of stability and sensitivity. Twenty-six non-schizophrenic first-degree relatives together with their affected family members (all simplex-families) underwent assessment with a comprehensive neuropsychological test battery both at baseline and 13 months follow-up. Follow-up patients were in a state of stable remission. Further, 21 unrelated, demographically balanced, non-vulnerable controls were tested one at a time. A principal components analysis of our test battery resulted in four factors: (1) Vigilance, attention, and psychomotor, (2) secondary verbal memory, (3) immediate and working memory, and (3) abstraction and problem solving. At baseline testing our study revealed a pattern of selective cognitive deficits in the relative group that is less pronounced, yet qualitatively similar, to that found in the patient sample. The most severe deficits displayed both the patients and their relatives in the secondary verbal memory domain. The dysfunctions in secondary verbal memory at baseline testing significantly correlated with negative symptoms only. Secondary verbal memory deficits proved to be relatively independent of age at onset of illness, illness duration, and neuroleptic dosage. Longitudinally, dysfunctions in the patients' secondary verbal memory fluctuated over time and with negative symptoms, and persisted in remitted patients at the same level as in their relatives. In conclusion, the secondary verbal memory met the criteria of relative stability and sensitivity in our sample of simplex-families. Thus, the secondary verbal memory seems to be a potential endophenotypic marker of schizophrenia, even for cases with a hypothetically lower genetic loading.

Adult↗

PubMed2005

Lack of association between prepulse inhibition and antisaccadic deficits in chronic schizophrenia: implications for identification of schizophrenia endophenotypes.

Individuals with schizophrenia, compared to healthy individuals, are known to exhibit deficient prepulse inhibition (PPI) of the startle response as well as reduced performance on the antisaccade task. There is evidence for genetic transmission of both PPI and antisaccadic abnormalities in schizophrenia. It has been suggested that PPI and antisaccade measures identify separate endophenotypes, on the basis of a lack of relationship between PPI and antisaccade deficits in patients with schizotypal personality disorder. However, given that patients with schizotypal personality disorder are unlikely to manifest all the abnormalities associated with schizophrenia, it is important to determine that there is no relationship present between these two abnormalities in people affected with schizophrenia. The main objective of this investigation therefore was to establish the lack of the association between PPI and antisaccade deficits in schizophrenia in two independent studies. Study 1 involved 39 patients with schizophrenia and 14 healthy controls and study 2 involved 35 patients with schizophrenia and 22 healthy controls. PPI (uninstructed paradigm) of the acoustically elicited startle (eye blink) was measured electromyographically. Antisaccadic eye movements (standard, non-overlap version) were measured using infrared oculography. Patients displayed reduced PPI and a lower percentage of correct antisaccades relative to healthy controls in both studies. As expected, no relationship occurred between PPI and the percentage of correct antisaccade responses in either group. It is concluded that PPI and antisaccade abnormalities in schizophrenia represent separate endophenotypes, reflecting the functions of different genetic aetiologies and different or only partially overlapping neural systems.

Adult↗

PubMed2005

The neuropsychology of obsessive compulsive disorder: the importance of failures in cognitive and behavioural inhibition as candidate endophenotypic markers.

Obsessive compulsive disorder (OCD) is a highly debilitating neuropsychiatric condition with estimated lifetime prevalence of 2-3%, more than twice that of schizophrenia. However, in contrast to other neuropsychiatric conditions of a comparable or lesser prevalence, relatively little is understood about the aetiology, neural substrates and cognitive profile of OCD. Despite strong evidence for OCD being familial, with risk to first-degree relatives much greater than for the background population, its genetic underpinnings have not yet been adequately delineated. Although cognitive dysfunction is evident in the everyday behaviour of OCD sufferers and is central to contemporary psychological models, theory-based studies of neurocognitive function have yet to reveal a reliable cognitive signature, and interpretation has often been confounded by failures to control for co-morbidities. The neuroimaging findings in OCD are amongst the most robust reported in the psychiatric literature, with structural and functional abnormalities frequently reported in orbitofrontal cortex, anterior cingulate cortex, and caudate nucleus. In spite of this, our relative lack of understanding of OCD neurochemical processes continues to impede progress in the development of novel pharmacological treatment approaches. Integrating the neurobiological, cognitive, and clinical findings, we propose that OCD might usefully be conceptualised in terms of lateral orbitofrontal loop dysfunction, and that failures in cognitive and behavioural inhibitory processes appear to underlie many of the symptoms and neurocognitive findings. We highlight existing limitations in the literature, and the potential utility of endophenotypes in overcoming these limitations. We propose that neurocognitive indices of inhibitory functions may represent a useful heuristic in the search for endophenotypes in OCD. This has direct implications not only for OCD but also for putative obsessive-compulsive spectrum conditions including attention deficit hyperactivity disorder, Tourette's syndrome, and trichotillomania (compulsive hair pulling).

Animals↗

PubMed2006

Sustained attention deficits in relation to psychometrically identified schizotypy: evaluating a potential endophenotypic marker.

Sustained attention deficits have been posited as a potential endophenotypic marker of vulnerability to schizophrenia. Prior studies have indicated that schizophrenia patients, their first-degree relatives, and psychosis-prone individuals, identified on the basis of measures of positive schizotypy, have demonstrated sustained attention deficits. To date, there have been no published reports of sustained attention deficits in individuals with negative schizotypy, as measured by the revised Social Anhedonia Scale. In this study, we examined sustained attention, measured with the CPT-Identical Pairs version, in 160 individuals with elevated scores on the Chapman Perceptual Aberration and/or Magical Ideation Scales, 96 individuals with elevated scales on the Social Anhedonia Scale, and 137 controls. Both psychosis-prone groups performed more poorly than the controls in terms of discrimination ability, as measured by d', though the groups did not differ in terms of either their reaction time or overall response criterion (lnbeta). These results provide evidence that both positive and negative aspects of schizotypy are associated with sustained attention deficits, as measured by the Continuous Performance Test. The findings add to the converging evidence indicating that sustained attention deficits are a potential endophenotypic indicator of a schizophrenia diathesis.

Adolescent↗

PubMed2006

Reaction time of the Continuous Performance Test is an endophenotypic marker for schizophrenia: a study of first-episode neuroleptic-naive schizophrenia, their non-psychotic first-degree relatives and healthy population controls.

Sustained attention has been proposed as an endophenotype of schizophrenia, and consequently may be useful as a quantitative trait in genetic studies. In the present study, we used the continuous performance test (CPT) to measure sustained attention in 112 first-episode and neuroleptic-naive schizophrenic patients, 296 of their non-psychotic first-degree relatives, and 452 normal controls. Compared with controls, probands with schizophrenia showed worse performance on all measures of CPT. Parents, siblings and offspring of probands were also impaired on 'hit reaction time', an index of psychomotor processing speed of the correct response. Hit reaction time was also independent of the acute clinical features of the disease, indicating it is a trait rather than a state marker. Our findings supported the use of the hit reaction time measure of the CPT as an endophenotype marker for schizophrenia.

Adolescent↗

PubMed2005

Platelet serotonergic markers as endophenotypes for obsessive-compulsive disorder.

Although compelling evidence has shown that obsessive-compulsive disorder (OCD) has a strong genetic component, its genetic basis remains to be elucidated. Identifying biological abnormalities in nonaffected relatives is one of the strategies advocated to isolate genetic vulnerability factors in complex disorders. Since peripheral serotonergic disturbances are frequently observed in OCD patients, the aim of this study was to investigate if they could represent endophenotypes, by searching for similar abnormalities in the unaffected parents of OCD patients. We assessed whole blood serotonin (5-HT) concentration, platelet 5-HT transporter (5-HTT) and 5-HT2A receptor-binding characteristics, and platelet inositol trisphosphate (IP3) content in a sample of OCD probands (n = 48) and their unaffected parents (n = 65), and compared them with sex- and age-matched controls (n = 113). Lower whole blood 5-HT concentration, fewer platelet 5-HTT-binding sites, and higher platelet IP3 content were found in OCD probands and their unaffected parents compared to controls. Whole blood 5-HT concentration showed a strong correlation within families (p < 0.001). The only parameter that appeared to discriminate affected and unaffected subjects was 5-HT2A receptor-binding characteristics, with increased receptor number and affinity in parents and no change in OCD probands. The presence of peripheral serotonergic abnormalities in OCD patients and their unaffected parents supports a familial origin of these disturbances. These alterations may serve as endophenotypic markers in OCD, and could contribute to the study of the biological mechanisms and genetic underpinnings of the disorder.

Adolescent↗

PubMed2005

Cognitive deficits in unaffected first-degree relatives of schizophrenia patients: a meta-analytic review of putative endophenotypes.

Cognitive deficits may index genetic liability for schizophrenia and are candidate endophenotypes for the illness. In order to compare the degree of sensitivity among cognitive tasks to group differences between healthy relatives and controls and the influence of moderator variables, this review reports mean effect sizes for 43 cognitive test scores from 58 studies of cognitive performance in the unaffected adult relatives of schizophrenia patients. Results indicate reliable relative-control differences, in the small to medium effect size range, over a diverse array of tasks, with the largest effect sizes seen in complex versions of continuous performance tasks, auditory verbal learning, design copy tests, and category fluency. Three study design features were found to have significant effects on overall effect size magnitude: groups unmatched on education, groups unmatched on age, and asymmetric psychiatric exclusion criteria. After excluding studies with the latter 2 design features, reliable performance differences were still observed over a smaller subset of cognitive test variables, with the largest effect sizes seen in Trails B (d = 0.50) and performance measures from both simple (d = 0.56) and complex (d = 0.60-0.66) versions of continuous performance tasks. Four of the 6 largest effect sizes reflect tasks with high executive control demands in common, such as working memory demands, set shifting, and inhibition of prepotent responses. Cognitive deficits, particularly those tapping such executive control functions, should continue to prove valuable as endophenotypes of interest in the search for specific genetic factors related to schizophrenia.

Cognition Disorders↗