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PubMed2006

Shared executive dysfunctions in unaffected relatives of patients with autism and obsessive-compulsive disorder.

BACKGROUND: Executive dysfunctions have been studied as a potential endophenotype associated with the genetic basis of autism. Given that recent findings from clinical and molecular genetic studies suggest that autism and obsessive-compulsive disorder (OCD) could share a common pattern of heritability, we assessed executive functions as a possible common cognitive endophenotype in unaffected family members of individuals with either autism or OCD. METHODS: Five tests assessing executive functions (Tower of London, verbal fluency, design fluency, trail making and association fluency) were proposed to 58 unaffected first-degree relatives (parents and siblings) of probands with autism and 64 unaffected first-degree relatives of OCD patients. Results were compared with those of 47 healthy controls matched for age, sex, and level of education. RESULTS: In the Tower of London test, both groups of unaffected relatives showed significantly lower scores and longer response times compared with controls. No differences were observed between autism and OCD relatives and healthy controls in the four other tasks (verbal fluency, design fluency, trail making test and association fluency). CONCLUSIONS: Our findings show the existence of executive dysfunction in the unaffected first-degree relatives of probands with OCD, similar to those observed in the relatives of patients with autism. These results support and extend previous cognitive studies on probands indicating executive dysfunctions in autism and OCD. Planning and working memory processes could thus represent a common cognitive endophenotype in autism and OCD that could help in the identification of genes conferring vulnerability to these disorders.

Adolescent↗

PubMed2006

The heritability of melatonin secretion and sensitivity to bright nocturnal light in twins.

The super-sensitivity of the neurohormone melatonin to light in patients with bipolar disorder provides evidence of the circadian nature of the disorder. This response has been proposed as an endophenotype for identifying people at risk of the disorder and guiding investigations of molecular genetic targets. However, before this response is used as an endophenotypic marker, the heritable nature of melatonin sensitivity in the normal population must be established. The aim of this study was to investigate the heritability of nocturnal melatonin secretion and sensitivity to light in monozygotic and dizygotic twins with no psychiatric history. This study investigated overall melatonin levels (between 2000 and 2400 h) and suppression by 500 lx of light (between 2400 and 0100 h) in 20 pairs of twins (nine monozygotic, 11 dizygotic). The results indicate that melatonin secretion is highly heritable with secretion in one twin being a significant predictor of secretion in their twin in both monozygotic and dizygotic pairs. In relation to light sensitivity, genetic loading appears to play a significant role with the greatest concordance between monozygotic twins, followed by dizygotic twins and finally low concordance in unrelated individuals. This provides additional support for the usefulness of melatonin sensitivity to light as a potential endophenotypic marker of bipolar affective disorder.

Adolescent↗

PubMed2003

Smooth pursuit and antisaccade performance evidence trait stability in schizophrenia patients and their relatives.

Several forms of eye movement dysfunction (EMD) have been widely regarded as candidate endophenotypes of schizophrenia, ultimately capable of identifying individuals carrying schizophrenia susceptibility genes and elucidating the pathophysiology of schizophrenia. As an indication of their trait-like status, candidate endophenotypes optimally evidence stability over time. However, there have been few published reports of test-retest reliability of several forms of EMD in schizophrenia patients and their relatives. In the current investigation, schizophrenia patients and the first-degree biological relatives of schizophrenia patients (n=15) were administered by an eye movement battery including smooth pursuit, antisaccade and prosaccade tasks, and re-tested after an average of 1.82 years (range=14-24 months). Adequate test-retest reliabilities of smooth pursuit closed-loop gain (Pearson r=0.72), antisaccade error rate (r=0.73), saccade reaction time to correct antisaccade responses (r=0.73), and prosaccade hypometria (r=0.72) were observed. Lower reliabilities were obtained for smooth pursuit open-loop gain (r=0.52) and prosaccade reaction time (r=0.43). The results are supportive of the trait-like characteristics of particular forms of EMD in schizophrenia families and of the candidacy of EMD as an endophenotypic marker of schizophrenia.

Adult↗

PubMed2004

Temporal stability of saccadic task performance in schizophrenia and bipolar patients.

BACKGROUND: Identifying endophenotypes of schizophrenia will assist in the identification of individuals who are at heightened risk for the disorder. Investigators have proposed antisaccade task deficits as an endophenotypic marker of schizophrenia. However, the diagnostic specificity and the temporal stability of the task deficit are unresolved issues. To date, there are few published reports of test-retest stability of antisaccade task performance in psychiatric patients. METHOD: Twenty-three schizophrenia out-patients and 10 bipolar out-patients were administered two saccadic (antisaccade and refixation) tasks at two separate assessments, with an average test retest interval of 33 months. RESULTS: The schizophrenia patients displayed high test-retest reliabilities of antisaccade task accuracy, despite changes in medication and clinical status. Additionally, the schizophrenia group's saccadic reaction times for antisaccade correct responses and task errors were moderately stable over time. In contrast, the bipolar patients did not show temporal stability in their antisaccade task accuracy or in their response latencies to either correct or incorrect antisaccade responses. CONCLUSIONS: The results are supportive of the trait-like characteristics of antisaccade task deficits in schizophrenia patients. These findings also suggest that antisaccade task deficits may serve as an endophenotypic marker of schizophrenia.

Adult↗

PubMed2003

The recognition of facial affect in autistic and schizophrenic subjects and their first-degree relatives.

BACKGROUND: Autism and schizophrenia are considered to be substantially influenced by genetic factors. The endophenotype of both disorders probably also includes deficits in affect perception. The objective of this study was to examine the capacity to detect facially expressed emotion in autistic and schizophrenic subjects, their parents and siblings. METHOD: Thirty-five subjects with autism and 102 of their relatives, 21 schizophrenic subjects and 46 relatives from simplex (one child affected) and multiplex (more than one child affected) families, as well as an unaffected control sample consisting of 22 probands completed a 50-item computer-based test to assess the ability to recognize basic emotions. RESULTS: The autistic subjects showed a poorer performance on the facial recognition test than did the schizophrenic and the unaffected individuals. In addition, there was a tendency for subjects from multiplex families with autistic loading to score lower on the test than individuals from simplex families with autistic loading. Schizophrenic subjects and their relatives as well as siblings and parents of autistic subjects did not differ from the sample of unaffected subjects in their ability to judge facial affect. CONCLUSIONS: Findings corroborate the assumption that emotion detection deficits are part of the endophenotype of autism. In families with autistic children, the extent of facial recognition deficits probably indexes an elevation in familial burden. It seems unlikely that problems in emotion perception form a consistent part of the endophenotype of schizophrenia or the broader phenotype in relatives of patients with psychosis or autism.

Adolescent↗

PubMed2006

Performance deficit of alpha7 nicotinic receptor knockout mice in a delayed matching-to-place task suggests a mild impairment of working/episodic-like memory.

Patients with schizophrenia exhibit deficits in a range of cognitive functions, particularly working and episodic memory, which are thought to be core features of the disorder. Memory dysfunction in schizophrenia is familial and thus a promising endophenotype for genetic studies. Both human and animal studies suggest a role for the neural nicotinic acid receptor family in cognition and specifically the alpha7-receptor subunit in schizophrenia and its endophenotypes. Consequently, we tested mice lacking the alpha7 subunit of the neural nicotinic receptor (B6.129S7-Chrna7(tm1Bay)/J) in the delayed matching-to-place (DMP) task of the Morris water maze, a measure of working/episodic memory akin to human episodic memory. We report that a minor impairment in alpha7 knockout mice was observed in the DMP task, with knockout mice taking longer to find the hidden platform than their wildtype controls. This suggests a role for the alpha7 subunit in working/episodic memory and a potential role for the alpha7 neural nicotinic receptor gene (CHRNA7) in schizophrenia and its endophenotypes.

Acetylcholine↗

PubMed2006

Profiles of executive function in parents and siblings of individuals with autism spectrum disorders.

Delineation of a cognitive endophenotype for autism is useful both for exploring the genetic mechanisms underlying the disorder and for identifying which cognitive traits may be primary to it. This study investigated whether first-degree relatives of individuals with autism spectrum disorders (ASDs) demonstrate a specific profile of performance on a range of components of executive function (EF), to determine whether EF deficits represent possible endophenotypes for autism. Parents and siblings of ASD and control probands were tested on EF tasks measuring planning, set-shifting, inhibition and generativity. ASD parents showed poorer performance than control parents on a test of ideational fluency or generativity, and ASD fathers demonstrated a weakness in set-shifting to a previously irrelevant dimension. ASD siblings revealed a mild reduction in ideational fluency and a weakness in non-verbal generativity when compared with control siblings. Neither ASD parents nor siblings displayed significant difficulties with planning or inhibition. These results indicated that the broad autism phenotype may not be characterized primarily by impairments in planning and cognitive flexibility, as had been previously proposed. Weaknesses in generativity emerged as stronger potential endophenotypes in this study, suggesting that this aspect of EF should play a central role in cognitive theories of autism. However, discrepancies in the EF profile demonstrated by parents and siblings suggest that factors related to age or parental responsibility may affect the precise pattern of deficits observed.

Adult↗

PubMed2005

[Hereditary factors in attention deficit hyperactivity disorder].

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by concentration problems, hyperactivity and impulsivity. Disturbances in dopamine and/or noradrenalin neurotransmission are probably the underlying pathophysiological mechanisms of ADHD. Around 80% of variants of the phenotype can be ascribed to hereditary factors. There are various chromosomal loci containing ADHD genes. They partially overlap the loci found in linkage studies on dyslexia and autism. It seems likely that a number of genetic variants, each with a small effect size, in combination with gene-environment interactions predispose to ADHD. There is a high degree of phenotypical heterogeneity among people with ADHD. Finding endophenotypes may improve the power of genetic studies. Endophenotypes are specific expressions of the underlying pathophysiology, intermediate between gene and phenotype. Neuro-imaging studies in children with ADHD have indicated abnormalities in frontostriatal, temporal and cerebellar volume. Unaffected brothers and sisters show the same cerebral abnormalities, but not the cerebellar abnormalities. These brain abnormalities together with specific neuropsychological features could be ADHD endophenotypes.

Attention Deficit Disorder with Hyperactivity↗

PubMed2005

Association of DISC1/TRAX haplotypes with schizophrenia, reduced prefrontal gray matter, and impaired short- and long-term memory.

CONTEXT: Chromosome 1q42 is among several genomic regions showing replicated evidence of linkage with schizophrenia, but the specific susceptibility mechanisms underlying this relationship remain to be identified. OBJECTIVE: To examine a series of haplotype blocks of single-nucleotide polymorphic markers from a segment of 1q42 spanning the disrupted-in-schizophrenia 1 (DISC1) and translin-associated factor X (TRAX) genes for association with schizophrenia and several endophenotypic traits thought to be involved in disease pathogenesis. DESIGN: Population-based twin cohort study. SETTING: Finland. PARTICIPANTS: Two hundred thirty-six subjects, consisting of 7 twin pairs concordant for schizophrenia (6 monozygotic [MZ] and 1 dizygotic [DZ]), 52 pairs discordant for schizophrenia (20 MZ and 32 DZ), and 59 demographically balanced normal pairs (28 MZ and 31 DZ), were drawn from a twin cohort consisting of all of the same-sex twins born in Finland from 1940 through 1957. MAIN OUTCOME MEASURES: Psychiatric diagnosis, performance on neurocognitive tests of short- and long-term memory, and gray matter volume measurements taken from high-resolution magnetic resonance images. RESULTS: A common haplotype incorporating 3 single-nucleotide polymorphic markers near the translocation break point of DISC1 (odds ratio, 2.6 [P = .02]) and a rare haplotype incorporating 4 markers from the DISC1 and TRAX genes (odds ratio, 13.0 [P = .001]) were significantly overrepresented among individuals with schizophrenia. These haplotypes were also associated with several quantitative endophenotypic traits previously observed to covary with schizophrenia and genetic liability to schizophrenia, including impairments in short- and long-term memory functioning and reduced gray matter density in the prefrontal cortex, as demonstrated using a population-based brain atlas method, with a trend toward association with reduced hippocampal volume. CONCLUSIONS: Specific alleles of the DISC1 and TRAX genes on 1q42 appear to contribute to genetic risk for schizophrenia through disruptive effects on the structure and function of the prefrontal cortex, medial temporal lobe, and other brain regions. These effects are consistent with their production of proteins that play roles in neuritic outgrowth, neuronal migration, synaptogenesis, and glutamatergic neurotransmission.

Atrophy↗

PubMed2000

Sustained attention deficits as markers of genetic susceptibility to schizophrenia.

This article reviews recent evidence regarding the potential of the visual sustained attention deficits as measured by the Continuous Performance Test (CPT) as an endophenotype of the genetic susceptibility to schizophrenia. Findings in community subjects indicate that sustained attention develops during the primary school ages, reaches its maximum around early adolescence, and declines with age after adulthood. The assertion that CPT performance deficits, and especially on the more difficult versions, are reliable and valid genetic susceptibility indicators of schizophrenia is supported by the following results: 1) CPT deficits are present in schizophrenic patients, are particularly associated with negative and disorganized symptoms, and deficits on the more difficult CPT versions are not amenable to neuroleptic treatment; 2) subjects with schizotypal personality features also exhibit CPT deficits, which are specifically associated with the negative factor of schizotypy; 3) a substantial proportion of nonpsychotic relatives of schizophrenic patients (19-34%) have CPT deficits, which can also be predicted from their probands' CPT performance. Thus, using a CPT deficits as an endophenotype of schizophrenia would not only provide a valuable measure of genetic risk, but would also greatly enhance our understanding of etiology, and may help identify susceptibility genes for schizophrenia.

Attention Deficit Disorder with Hyperactivity↗

PubMed2002

Spatial working memory deficits in schizophrenia patients and their first degree relatives from Palau, Micronesia.

Spatial working memory deficits associated with dorsolateral prefrontal dysfunction have been found in Caucasian samples of schizophrenia patients and their first-degree relatives. This study evaluated spatial working memory function in affected and unaffected members of multiplex schizophrenia families from the Republic of Palau to determine whether the spatial working memory deficits associated with schizophrenia extend to this non-Caucasian population. Palau is an isolated island nation in Micronesia with an elevated prevalence of schizophrenia and an aggregation of cases in large multigenerational families. Our objective was to evaluate the potential for spatial working memory function to serve as one of multiple endophenotypes in a genetic linkage study of these Palauan schizophrenia families. A spatial delayed response task requiring resistance to distraction and a sensorimotor control task were used to assess spatial working memory in 32 schizophrenia patients, 28 of their healthy first-degree relatives, and 19 normal control subjects. Schizophrenia patients and their relatives were significantly less accurate than normal control subjects on the spatial delayed response task but not on the sensorimotor control task. On both tasks, patients and relatives were slower to respond than the normal controls. There were no age or gender effects on accuracy, and working memory performance in schizophrenia patients was not significantly correlated with medication dosage. In summary, spatial working memory deficits that have been found in Caucasian schizophrenia patients and relatives were confirmed in this isolated Pacific Island family sample. These results suggest that spatial working memory deficits may be a potentially useful addition to the endophenotypic characterization of family members to be used in a comprehensive genome wide linkage analysis of these Palauan families.

Adult↗

PubMed2003

NURR1 promoter polymorphisms: Parkinson's disease, schizophrenia, and personality traits.

We have previously identified mutations in exon three in NURR1 (NR4A2) in two patients with schizophrenia (SZ) and one patient with bipolar disease with psychotic symptoms. In the present study we analyzed the promoter region of NURR1 and identified five polymorphic sites: three were found to be in strong linkage disequilibrium with a previously identified polymorphic site in the sixth intron. One polymorphism of this haplotype and the two other independent polymorphisms were investigated for their possible association with SZ and Parkinson's disease (PD) by comparing their frequencies in a Swedish material consisting of 134 subjects with SZ and 207 matched controls and 108 subjects with PD and 125 matched controls. Exon 1 was also investigated in our Parkinson and control material but no variances were found. The distributions of the two most informative polymorphisms in the promoter were investigated in an American material as well consisting of 141 subjects with SZ and 139 matched controls. Furthermore, the identified markers were screened for association with putative endophenotypes of SZ in the Swedish material. The distribution of sequence variants among the Swedish controls matched for SZ was investigated with regard to personality. No significant genotype or allelic association of the three sequence variants with SZ or PD was found. Several comparisons regarding endophenotypes or personality indicated association at the 5% confidence level, although correction for multiple testing rendered none of these findings significant. We conclude that the identified polymorphic sites in the human NURR1 are unlikely to be involved in conferring susceptibility for SZ or PD in our patient material.

Adult↗

PubMed2005

Familial cognitive deficits in schizophrenia.

Susceptibility to schizophrenia is considered familial, but the mechanism for transmission has not been found. Since widespread cognitive deficits have been found in patients with schizophrenia, several of these have been proposed as candidate familial endophenotypes that may or may not be predictive of who develops the illness. The current study examines these candidates in individuals from 32 families with at least 2 members having the diagnosis of chronic schizophrenia and normal comparison subjects using an extensive neuropsychological battery. Consistent with previous literature, family members with schizophrenia were significantly impaired on all measures compared with controls. Well relatives demonstrated significantly worse performance on a measure of verbal learning, delayed visual recall, perceptual-motor, and pure motor speed. Expressive and receptive language, but not other functions, were highly correlated within both concordant for schizophrenia and discordant sibling pairs, suggesting that they are familial vulnerability endophenotypes, but not predictive of whom becomes ill. On the other hand, some measures of perceptual-motor, pure motor speed, and frontal/executive functioning were significantly correlated in concordant, but not discordant pairs. These latter correlations suggest that some cognitive measures may be genetically related to the illness.

Adult↗

PubMed2018

Sex-specific genetic predictors of Alzheimer's disease biomarkers.

Cerebrospinal fluid (CSF) levels of amyloid-β 42 (Aβ42) and tau have been evaluated as endophenotypes in Alzheimer's disease (AD) genetic studies. Although there are sex differences in AD risk, sex differences have not been evaluated in genetic studies of AD endophenotypes. We performed sex-stratified and sex interaction genetic analyses of CSF biomarkers to identify sex-specific associations. Data came from a previous genome-wide association study (GWAS) of CSF Aβ42 and tau (1527 males, 1509 females). We evaluated sex interactions at previous loci, performed sex-stratified GWAS to identify sex-specific associations, and evaluated sex interactions at sex-specific GWAS loci. We then evaluated sex-specific associations between prefrontal cortex (PFC) gene expression at relevant loci and autopsy measures of plaques and tangles using data from the Religious Orders Study and Rush Memory and Aging Project. In Aβ42, we observed sex interactions at one previous and one novel locus: rs316341 within SERPINB1 (p = 0.04) and rs13115400 near LINC00290 (p = 0.002). These loci showed stronger associations among females (β = - 0.03, p = 4.25 × 10-8; β = 0.03, p = 3.97 × 10-8) than males (β = - 0.02, p = 0.009; β = 0.01, p = 0.20). Higher levels of expression of SERPINB1, SERPINB6, and SERPINB9 in PFC was associated with higher levels of amyloidosis among females (corrected p values < 0.02) but not males (p > 0.38). In total tau, we observed a sex interaction at a previous locus, rs1393060 proximal to GMNC (p = 0.004), driven by a stronger association among females (β = 0.05, p = 4.57 × 10-10) compared to males (β = 0.02, p = 0.03). There was also a sex-specific association between rs1393060 and tangle density at autopsy (pfemale = 0.047; pmale = 0.96), and higher levels of expression of two genes within this locus were associated with lower tangle density among females (OSTN p = 0.006; CLDN16 p = 0.002) but not males (p ≥ 0.32). Results suggest a female-specific role for SERPINB1 in amyloidosis and for OSTN and CLDN16 in tau pathology. Sex-specific genetic analyses may improve understanding of AD's genetic architecture.

Aged, 80 and over↗

PubMed2006

Heritability and reliability of P300, P50 and duration mismatch negativity.

BACKGROUND: Event-related potentials (ERPs) have been suggested as possible endophenotypes of schizophrenia. We investigated the test-retest reliabilities and heritabilities of three ERP components in healthy monozygotic and dizygotic twin pairs. METHODS: ERP components (P300, P50 and MMN) were recorded using a 19-channel electroencephalogram (EEG) in 40 healthy monozygotic twin pairs, 19 of them on two separate occasions, and 30 dizygotic twin pairs. Zygosity was determined using DNA genotyping. RESULTS: High reliabilities were found for the P300 amplitude and its latency, MMN amplitude, and P50 suppression ratio components. ICC=0.86 and 0.88 for the P300 amplitude and P300 latency respectively. Reliability of MMN peak amplitude and mean amplitude were 0.67 and 0.66 respectively. P50 T/C ratio reliability was 0.66. Model fitting analyses indicated a substantial heritability or familial component of variance for these ERP measures. Heritability estimates were 63 and 68% for MMN peak amplitude and mean amplitude respectively. For P50 T/C ratio, 68% heritability was estimated. P300 amplitude heritability was estimated at 69%, and while a significant familiality effect was found for P300 latency there was insufficient power to distinguish between shared environment and genetic factors. CONCLUSIONS: The high reliability and heritability of the P300 amplitude, MMN amplitude, and P50 suppression ratio components supports their use as candidate endophenotypes for psychiatric research.

Adult↗

PubMed2006

Genetics of chromosome 15q13-q14 in schizophrenia.

Positive genetic linkage to the 15q13-q14 region has been found in 11 studies, and several association reports support this locus as a candidate region for schizophrenia. The locus is unusual in that it was first linked to an endophenotype found in schizophrenia, the P50 deficit, and subsequently to schizophrenia. There is also biological data showing that a candidate gene in the region, the alpha7 nicotinic receptor CHRNA7, plays a seminal role in the linked endophenotype, and is decreased in expression in the patient population. The 15q13-q14 region is complicated by a partial duplication of the CHRNA7 gene that includes exons 5-10 and considerable sequence downstream. Evidence from multiple studies supports a broad region of genetic linkage around the marker D15S1360.

Chromosome Mapping↗

PubMed2006

P50 auditory evoked potential suppression in bipolar disorder patients with psychotic features and their unaffected relatives.

BACKGROUND: Diminished suppression of the P50 response, a consistent finding in schizophrenia, has also been reported in patients with psychotic bipolar disorder. It is a promising endophenotype for schizophrenia, but its relationship to genetic liability in bipolar disorder is unknown. We therefore assessed whether diminished P50 suppression is associated with familial risk for psychotic bipolar disorder. METHODS: The P50 response was collected in a conditioning (C)--testing (T) paradigm from 42 outpatients with bipolar 1 disorder who had experienced psychotic symptoms and 44 of their unaffected first-degree relatives, all from families multiply affected with bipolar disorder or another non-organic psychotic disorder; 48 healthy control subjects were also studied. The T/C ratio was compared between the groups, with linear regression analyses and robust variance estimators for clustered data. RESULTS: Both patients (estimated mean difference in T/C ratio to control subjects, 32, 95% confidence interval [CI] 15-48, p=.001) and unaffected relatives (20, 95% CI 7-32, p=.002) demonstrated higher T/C ratio, thus indicating diminished P50 suppression compared with control subjects. CONCLUSIONS: To our knowledge, this is the first report of diminished P50 gating in unaffected relatives of psychotic bipolar disorder patients from multiply affected families. Our results suggest that impaired P50 gating is a putative endophenotype for psychotic bipolar disorder and thus might reflect the impact of susceptibility genes across psychosis.

Acoustic Stimulation↗

PubMed2005

Genetic and environmental influences on frontal EEG asymmetry: a twin study.

Research suggests that frontal EEG asymmetry (FA) is a relatively stable trait associated with individual differences in dispositional affect (affective style) and liability to mood disorders. If FA is genetically determined, it can potentially serve as an endophenotype in genetic studies of temperament and mood disorders. The purpose of this study was to assess heritability of FA as well as alpha band EEG power measured at different frontal recording sites. Resting EEG data from a population-based sample of 246 young adult female twins including 73 monozygotic (MZ) and 50 dizygotic (DZ) pairs were analyzed using linear structural equation modeling. FA measured at mid-frontal locations (F3 and F4) showed low but significant heritability, suggesting that 27% of the observed variance can be accounted for by genetic factors. There was no evidence for genetic influences on FA measured at lateral-frontal (F7 and F8) locations. In contrast, alpha band power was highly heritable at all four frontal sites (85-87%). These findings suggest that: (1) genetic influences on FA are very modest and therefore FA has a limited utility as an endophenotype for genetic studies of mood disorders and (2) prefrontal neural circuitry underlying individual differences in affective style is characterized by high developmental plasticity.

Adolescent↗