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PubMed2006

Spatial working memory as a cognitive endophenotype of schizophrenia: assessing risk for pathophysiological dysfunction.

Research suggests that first-degree relatives and individuals with schizophrenia spectrum personality disorders (SSPD) may represent nonpenetrant carriers of the genetic diathesis for schizophrenia. This study examined visuospatial working memory (SWM) as a cognitive endophenotype of schizophrenia by expanding the concept of risk for pathophysiological dysfunction beyond overt psychosis. Risk was thus defined by familial status and the presence or absence of SSPD. SWM was assessed in the following groups, in order of decreasing likelihood of genetic vulnerability: 23 patients with schizophrenia, 17 SSPD relatives of patients with schizophrenia, 23 non-SSPD relatives of patients with schizophrenia, 14 SSPD community members with no family history of psychosis, and 36 non-SSPD community members. SWM performance during a computer task was quantified by A-Prime. Relative risk ratios for SWM deficits were compared among the groups. Compared with community non-SSPD volunteers, relative risk (RR) of SWM deficits was significantly elevated in patients with schizophrenia (RR = 3.76, p = .002) and SSPD family members (RR = 2.97, p = .027), but not in the family non-SSPD (RR = 1.88, p = .241) or community SSPD (RR = 1.03, p = .971) groups. The pattern of SWM performance deficits reflected the proposed model of latent genetic liability, upholding SWM as a viable cognitive endophenotype. The results underscore the importance of including both familial liability and the schizophrenia spectrum when considering risk for schizophrenia and schizophrenia-related traits. This is particularly relevant for research efforts to identify pathophysiological components of the disease.

Adult↗

PubMed2004

Critical evaluation of cognitive dysfunctions as endophenotypes of schizophrenia.

OBJECTIVE: Cognitive dysfunctions are potential endophenotypes of schizophrenia. The aim of this study was to investigate whether recent evidence indeed suggests that cognitive dysfunctions are potent indicators of specific genetic traits that represent susceptibility for schizophrenia. METHOD: Studies including large, well-defined samples and controlled cognitive assessment have been reviewed. RESULTS: Evidence suggests that schizophrenia patients and their unaffected biological relatives are impaired in several cognitive domains, including working memory, executive functions, sustained attention, verbal episodic memory, processing of visual and auditory stimuli, and smooth pursuit eye movements. However, these impairments are present only in a limited proportion of subjects, showing low specificity and sensitivity and high variability. Linkage with specific genes is weak. CONCLUSION: Although some results are promising, at present cognitive dysfunctions cannot be considered as highly sensitive and specific endophenotypes of schizophrenia.

Case-Control Studies↗

PubMed2005

Is impaired set-shifting an endophenotype of anorexia nervosa?

OBJECTIVE: Set-shifting difficulties have been reported in subjects with anorexia nervosa and appear to persist after recovery; therefore, they may be endophenotypic traits. The goals of this study were to investigate whether set-shifting difficulties are familial by examining discordant sister-pairs in comparison with healthy unrelated women and to replicate, with a broader battery, the lack of influence of an acute illness state on neuropsychological performance. METHOD: Forty-seven pairs of sisters discordant for anorexia nervosa and 47 healthy unrelated women who were comparable in age and IQ completed neuropsychological tasks selected to assess set-shifting ability. Analyses of variance with standard errors that are robust against correlations within family clusters were used to compare the groups. Results were adjusted for obsessive-compulsive, anxiety, and depression symptoms. Subjects with acute (N=24) and fully remitted (N=23) anorexia nervosa were compared to assess state versus trait effects. RESULTS: Sisters with and without anorexia nervosa took significantly longer than unrelated healthy women to shift their cognitive set (CatBat task) and demonstrated greater perceptual rigidity (Haptic Illusion task) but did not differ significantly from each other. Women with anorexia nervosa were slower than other groups on Trail Making tasks. Women who had fully recovered from anorexia nervosa made significantly fewer errors than those with acute anorexia nervosa on the Trail Making alphabet task, but these subgroups did not differ on other measures. CONCLUSIONS: Both affected and unaffected sisters had more set-shifting difficulties than unrelated healthy women. This finding, together with the replicated finding that set-shifting difficulties persist after recovery, suggests that set-shifting difficulties are trait characteristics and may inform the search for the endophenotype in anorexia nervosa.

Adult↗

PubMed2005

A comparison of univariate, bivariate, and trivariate whole-genome linkage screens of genetically correlated electrophysiological endophenotypes.

We used a maximum-likelihood based multipoint linkage approach implemented in SOLAR to examine simultaneously linkage for three electrophysiological endophenotypes from the Collaborative Study of the Genetics of Alcoholism: TTTH1, TTTH2, and TTTH3. These endophenotypes have been identified as markers of alcohol dependence susceptibility. Data were from 905 individuals in 143 families. Measured covariates considered included sex, age at electrophysiology data collection, habitual smoking status, and the maximum number of drinks consumed in a 24-hour period. Comparisons were made among genome-wide univariate, bivariate, and trivariate linkage analyses using genotypes based on microsatellite markers supplied by the Center for Inherited Disease Research, and genotypes based on single-nucleotide polymorphism markers provided by Illumina. All LODs were corrected to a standard equivalent to 1 degree of freedom. Using the trivariate approach and the microsatellite-based genotypes, we estimated a maximum multipoint linkage signal of LOD = 2.66 on chromosome 7q at 157 cM. Analyses using the Illumina SNP genotypes produced similar results, yielding a maximum multipoint LOD of 2.95 on 7q at 174 cM. These regions of interest correspond to those identified in the univariate and bivariate linkage screens. Our results suggest that trivariate multipoint linkage analyses have utility in the further characterization of chromosomal regions potentially containing genes influencing the phenotypes being examined. Based on a comparison of the number of LOD scores achieving statistical significance, our results suggest that the microsatellite- and Illumina SNP-based genotypes have similar utility for detecting genomic regions of interest.

Chromosome Mapping↗

PubMed2001

Endophenotypes as quantitative risk factors for psychiatric disease: rationale and study design.

Genetic influences on psychiatric disorders are well established. However, localization of the genes responsible for these effects has proved extremely difficult. One emerging strategy that may circumvent some of these difficulties is the use of quantitative risk factors, or endophenotypes, which are correlated with disease and may be closer to underlying genetic liability and to gene action than are diagnostic phenotypes. Genetic studies of quantitative endophenotypes require different sampling and analysis strategies than studies of disease state. The rationale for using quantitative risk factors as indicators of disease liability and the optimal study design for localizing genes influencing such risk factors are discussed.

Genetic Linkage↗

PubMed2006

[Attention deficit hyperactivity disorder: its aetiological factors and endophenotypes].

INTRODUCTION: Attention deficit hyperactivity disorder (ADHD) is one of the most frequent reasons for patients' visits in everyday practice. The academic and social distortion it produces in those affected by this condition have turned it into a subject that is receiving growing attention from researchers and the progress being made in the neurosciences means that it is being investigated from a wide range of approaches. Genetic aspects, as well as anatomical and neurobiological markers, are some of the new lines of research that are being used together with a more precise neuropsychological approach to obtain a more comprehensive understanding of ADHD. Such knowledge now involves genetic factors, centres of cognitive disorder and the search for endophenotypes that account for the complexity of its semiology. DEVELOPMENT: The primary cognitive deficits in ADHD appear to be the underlying problem in the disorder, special attention also being given to both the executive functions and the distortion of the capacity to inhibit responses. Furthermore, anatomical factors have been related to the type and severity of the symptomatology of the disorder, although the dispersion of the results and the genetic findings that focus their attention on anomalous alleles for dopamine transporting and receptor genes suggest that the disorder is more complex. CONCLUSIONS: The different aetiological factors that have been associated to the disorder and the variability in the semiology of ADHD place us before a situation in disarray; the determination of endophenotypes, however, could enable us carry out a better systematisation of a disorder that is currently still a long way from being fully understood.

Attention Deficit Disorder with Hyperactivity↗

PubMed2024

Biobank-wide association scan identifies risk factors for late-onset Alzheimer's disease and endophenotypes.

Rich data from large biobanks, coupled with increasingly accessible association statistics from genome-wide association studies (GWAS), provide great opportunities to dissect the complex relationships among human traits and diseases. We introduce BADGERS, a powerful method to perform polygenic score-based biobank-wide association scans. Compared to traditional approaches, BADGERS uses GWAS summary statistics as input and does not require multiple traits to be measured in the same cohort. We applied BADGERS to two independent datasets for late-onset Alzheimer's disease (AD; n=61,212). Among 1738 traits in the UK biobank, we identified 48 significant associations for AD. Family history, high cholesterol, and numerous traits related to intelligence and education showed strong and independent associations with AD. Furthermore, we identified 41 significant associations for a variety of AD endophenotypes. While family history and high cholesterol were strongly associated with AD subgroups and pathologies, only intelligence and education-related traits predicted pre-clinical cognitive phenotypes. These results provide novel insights into the distinct biological processes underlying various risk factors for AD.

Alzheimer Disease↗

PubMed2004

Association of genetic risks for schizophrenia and bipolar disorder with specific and generic brain structural endophenotypes.

CONTEXT: For more than a century, it has been uncertain whether or not the major diagnostic categories of psychosis--schizophrenia and bipolar disorder--are distinct disease entities with specific genetic causes and neuroanatomical substrates. OBJECTIVE: To investigate the relationship between genetic risk and structural variation throughout the entire brain in patients and their unaffected relatives sampled from multiply affected families with schizophrenia or bipolar disorder. DESIGN: Analysis of the association between genetic risk and variation in tissue volume on magnetic resonance images. SETTING: Psychiatric research center. PARTICIPANTS: Subjects comprised 25 patients with schizophrenia, 36 of their unaffected first-degree relatives, 37 patients with bipolar 1 disorder who experienced psychotic symptoms during illness exacerbation, and 50 of their unaffected first-degree relatives. MAIN OUTCOME MEASURES: We used computational morphometric techniques to map significant associations between a continuous measure of genetic liability for each subject and variation in gray or white matter volume. RESULTS: Genetic risk for schizophrenia was specifically associated with distributed gray matter volume deficits in the bilateral fronto-striato-thalamic and left lateral temporal regions, whereas genetic risk for bipolar disorder was specifically associated with gray matter deficits only in the right anterior cingulate gyrus and ventral striatum. A generic association between genetic risk for both disorders and white matter volume reduction in the left frontal and temporoparietal regions was consistent with left frontotemporal disconnectivity as a genetically controlled brain structural abnormality common to both psychotic disorders. CONCLUSIONS: Genetic risks for schizophrenia and bipolar disorder are associated with specific gray matter but generic white matter endophenotypes. Thus, Emil Kraepelin's pivotal distinction was neither wholly right nor wholly wrong: the 2 major psychoses show both distinctive and similar patterns of brain structural abnormality related to variable genetic risk.

Adolescent↗

PubMed2002

Investigation of Notch3 as a candidate gene for bipolar disorder using brain hyperintensities as an endophenotype.

The purpose of the study was to consider MRI hyperintensities as a potential endophenotype for bipolar disorder (BPD) and to investigate Notch3 (CADASIL) as a candidate gene for BPD. MRI scans were performed on 21 members of a family with a high incidence of BPD. Two-point and multipoint linkage analyses were performed and two exons of Notch3 were investigated with SSCP. Fifteen of 21 family members had MRI hyperintensities, including all bipolar patients and six family members with no affective illness. Two-point linkage analysis yielded negative results for all models. Multipoint linkage analysis yielded negative results except for Model 1a, in which a maximal LOD score was -1.24. A mutation screen of Exons 3 and 4 was negative. Notch3 does not appear to be a candidate gene for BPD in this family.

Adolescent↗

PubMed2001

Human brain mapping in dystonia reveals both endophenotypic traits and adaptive reorganization.

Dystonia has a wide clinical spectrum from early-onset generalized to late-onset sporadic, task-specific forms. The genetic origin of the former has been clearly established. A critical role of repetitive skilled motor tasks has been put forward for the latter, while underlying vulnerability traits are still being searched for. Using magnetoencephalography, we looked for structural abnormalities reflecting a preexisting dysfunction. We studied finger representations of both hands in the primary sensory cortex, as compared in 23 patients with unilateral task-specific dystonia and 20 control subjects. A dramatic disorganization of the nondystonic hand representation was found in all patients, and its amount paralleled the severity of the dystonic limb motor impairment. Abnormalities were also observed in the cortex coding the dystonic limb representation, but they were important only in the most severely affected patients. The abnormal cortical finger representations from the nondystonic limb appear to be endophenotypic traits of dystonia. That finger representations from the dystonic limb were almost normal for the less severely affected patients may be due to intrinsic beneficial remapping in reaction against the primary disorder.

Adaptation, Physiological↗

PubMed2006

Using endophenotypes for pathway clusters to map complex disease genes.

Nature determines the complexity of disease etiology and the likelihood of revealing disease genes. While culprit genes for many monogenic diseases have been successfully unraveled, efforts to map major complex disease genes have not been as productive as hoped. The conceptual framework currently adopted to deal with the heterogeneous nature of complex diseases focuses on using homogeneous internal features of the disease phenotype for mapping. However, phenotypic homogeneity does not equal genotypic homogeneity. In this report, we advocate working with well-measured phenotypes portrayed by amounts of transcripts and activities of gene products or their metabolites, which are pertinent to relatively small pathway clusters. Reliable and controlled measures for oligogenic traits resulting from proper dissection efforts may enhance statistical power. The large amounts of information obtained on gene and protein expression from technological advances can add to the power of gene finding, particularly for diseases with unclear etiology. Data-mining tools for dimension reduction can assist biologists to reveal novel molecular endophenotypes. However, there are still hurdles to overcome, including high cost, relatively poor reproducibility and comparability among platforms, the cross-sectional nature of the information, and the accessibility of human tissues. Concerted efforts are required to carry out large-scale prospective studies that are integrated at the levels of phenotype characterization, high throughput experimental techniques, data analyses, and beyond.

Chromosome Mapping↗

PubMed2005

[Neural correlates of working memory deficits in schizophrenic patients. Ways to establish neurocognitive endophenotypes of psychiatric disorders].

This article briefly reviews some methodological limitations of functional neuroimaging studies in psychiatric patients. We argue that the investigation of the neural substrates of cognitive deficits in psychiatric disorders requires a combination of functional neuroimaging studies in healthy subjects with corresponding behavioral experiments in patients. In order to exemplify this methodological approach we review recent findings regarding the functional neuroanatomy of distinct components of human working memory and provide evidence for selective dysfunctions of cortical networks that underlie specific working memory deficits in schizophrenia. This identification of subgroups of schizophrenic patients according to neurocognitive parameters may facilitate the establishment of behavioral and neurophysiological endophenotypes and the development of a neurobiological classification of psychiatric disorders.

Brain Mapping↗

PubMed2006

In vivo characterization of brain morphometric and metabolic endophenotypes in three inbred strains of mice using magnetic resonance techniques.

C57BL6J, FVB/N and 129/SvJ mice are commonly used as background strains to engineer genetic models of brain pathologies and psychiatric disorders. Magnetic resonance imaging (MRI) and spectroscopy provide alternative approaches to neuroanatomy, histology and neurohistochemistry for investigating the correlation between genes and brain neuroanatomy and neurometabolism in vivo. We used these techniques to non-invasively characterize the cerebral morphologic and metabolic endophenotypes of inbred mouse strains commonly used in neurological and behavioral research. We observed a great variability in the volume of ventricles and of structures involved in cognitive function (cerebellum and hippocampus) among these strains. In addition, distinct metabolic profiles were evidenced with variable levels of N-acetylaspartate, a neuronal marker, and of choline, a compound found in membranes and myelin. Besides, significant differences in high-energy phosphates and phospholipids were detected. Our findings demonstrate the great morphologic and metabolic heterogeneity among C57BL/ 6J, FVB/N and 129/SvJ mice. They emphasize the importance of selecting the appropriate genetic background for over-expressing or silencing a gene and provide some directions for modeling symptoms that characterize psychiatric disorders such as autism, schizophrenia and depression.

Animals↗

PubMed2005

Dysbindin (DTNBP1, 6p22.3) is associated with childhood-onset psychosis and endophenotypes measured by the Premorbid Adjustment Scale (PAS).

Straub et al. (2002) recently identified the 6p22.3 gene dysbindin (DTNBP1) through positional cloning as a schizophrenia susceptibility gene. We studied a rare cohort of 102 children with onset of psychosis before age 13. Standardized ratings of early development, medication response, neuropsychological and cognitive performance, premorbid dysfunction and clinical follow-up were obtained. Fourteen SNPs were genotyped in the gene DTNBP1. Family-based pairwise and haplotype transmission disequilibrium test (TDT) analysis with the clinical phenotype, and quantitative transmission disequilibrium test (QTDT) explored endophenotype relationships. One SNP was associated with diagnosis (TDT p=.01). The QTDT analyses showed several significant relationships. Four adjacent SNPs were associated (p values=.0009-.003) with poor premorbid functioning. These findings support the hypothesis that this and other schizophrenia susceptibility genes contribute to early neurodevelopmental impairment.

Adolescent↗

PubMed2005

Evidence for deficit in tasks of ventral, but not dorsal, prefrontal executive function as an endophenotypic marker for bipolar disorder.

BACKGROUND: Trait functional abnormalities in BD patients have only been reported in the ventral prefrontal cortex (VPFC). We examined whether deficits in VPFC-related inhibitory processes, but not dorsal prefrontal (DPFC) based executive functions, represent an endophenotypic marker for bipolar disorder I (BDI). METHODS: We used the Wisconsin Card Sorting Test (WCST), commonly associated with DPFC function, and the Hayling Sentence Completion Task (HSCT) which engages the VPFC. Performance on these tests of 43 healthy participants was compared to that of 10 remitted BDI patients and 15 of their unaffected offspring. RESULTS: Compared to healthy participants, patients and their offspring made more errors in the HSCT but offspring achieved more categories and made fewer perseverative errors in the WCST. CONCLUSIONS: Impaired response inhibition, predominantly a VPFC related function, may reflect familial predisposition to BDI while deficits in rule attainment, a DPFC based function, may be associated only with the clinical phenotype.

Adult↗

PubMed2005

The cyclothymic temperament in healthy controls and familially at risk individuals for mood disorder: endophenotype for genetic studies?

BACKGROUND: The modern concept of affective disorders focuses increasingly on the study of subthreshold conditions on the border of manic or depressive episodes. Indeed, a spectrum of affective conditions spanning from temperament to clinical episodes has been proposed by the senior author. As bipolar disorder is a familial illness, an examination of cyclothymic temperament (CT) in controls and relatives of bipolar patients is of major relevance. METHODS: We recruited a total sample of 177 healthy symptom-free volunteers. These controls were divided into three groups. The first one is comprised of 100 normal subjects with a negative familial affective history (NFH); the second of 37 individuals, with positive affective family history (PFH); and a third of 40 subjects, with at least one sib or first-degree kin with bipolar disorder type I according to the DSM-IV (BPR). The last two groups defined at risk individuals. We interviewed all subjects with CT, as described by the senior author. RESULTS: We found a statistically significant difference in the rates of CT between the subjects in BPR versus others. CT was also more prevalent in the PFH compared with NFH. Additionally, the simple numeration of the CT traits exhibited gradation in the distribution of individuals inside the NFH, PFH and BPR. Finally, categorically defined CT and CT traits predominated in females. LIMITATION and CONCLUSION: Although not all relatives of bipolar probands were studied, our results exhibit an aggregation of CT in families with affective disorder-and more specifically those with bipolar background. These results allow us to propose the importance of including CT for phenotypic characterization of bipolar disorder. Furthermore, our results support a spectrum concept of bipolar disorder, whereby CT is distributed in ascending order in the well-relatives of those with depressive and bipolar disorders. We submit that this temperament represents a behavioral endophenotype, serving as a link between molecular and behavioral genetics.

Adult↗

PubMed2005

Is the P300 wave an endophenotype for schizophrenia? A meta-analysis and a family study.

INTRODUCTION: We assessed the usefulness of the P300 wave as endophenotype for schizophrenia by means of a meta-analysis of the literature as well as our own family study. METHOD: Meta-analysis: We conducted a systematic search for articles published between 1983 and 2003 that reported P300 measures in non-psychotic relatives of schizophrenic patients and in healthy controls. Meta-regression analyses were performed using a random effects procedure. The pooled standardized effect size (PSES) was calculated as the difference between the means of the two groups divided by the common standard deviation. Local study: We examined the P300 wave with a standard two-tone oddball paradigm in 30 patients with schizophrenia, 40 non-psychotic relatives, and 40 controls using linear mixed models. RESULTS: Meta-analysis: We pooled 472 relatives and 513 controls. The P300 amplitude was significantly reduced in relatives (PSES = 0.61; 95% CI: 0.30 to 0.91; P < 0.001). The P300 latency was significantly delayed in relatives (PSES of -0.50; 95% CI: -0.88 to -0.13; P = 0.009]. Local study: The patients showed a trend for amplitude reductions (P = 0.06) and significant latency delays (P < 0.01). The relatives displayed normal amplitude but had significant latency delays (P = 0.01). The P300 amplitude and especially the P300 latency are promising alternative phenotypes for genetic research into schizophrenia.

Adolescent↗

PubMed2006

A functional endophenotype for sexual orientation in humans.

Sexually arousing visual stimuli activate the human reward system and trigger sexual behavior. Here we performed event-related fMRI during visual processing of sexual core stimuli to pinpoint a neuronal correlate of sexual preference in humans. To dissociate gender of the stimulus from sexual preference, we studied male and female heterosexual and homosexual volunteers while they viewed sexual and nonsexual control stimuli. In contrast to previous work, we used core single-sex stimuli displaying male and female sexually aroused genitals. Since stimuli lacked any additional contextual information, they evoked no activity related to neuronal processing of faces, gestures or social interactions. Our prediction was that the sexual preference of the observer determines the neuronal responsiveness to pure male or female sexual stimuli in the human reward and motor system. Consistent with our prediction, the ventral striatum and the centromedian thalamus, showed a stronger neuronal response to preferred relative to non-preferred stimuli. Likewise, the ventral premotor cortex which is a key structure for imitative (mirror neurons) and tool-related (canonical neurons) actions showed a bilateral sexual preference-specific activation, suggesting that viewing sexually aroused genitals of the preferred sex triggers action representations of sexual behavior. The neuronal response of the ventral striatum, centromedian thalamus and ventral premotor cortex to preferred sexual stimuli was consistent across all groups. We propose that this invariant response pattern in core regions of the human reward and motor system represents a functional endophenotype for sexual orientation independent of the gender of the observer and gender of the stimulus.

Adult↗