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PubMed2002

Genetic analysis of IQ, processing speed and stimulus-response incongruency effects.

Psychometric IQ (WAIS-III), onset and peak latency of the lateralized readiness potential (LRP), decision time, and accuracy were assessed during an Eriksen Flanker task in a young (149 families) and in an older (122 families) cohort of twins and their siblings. Stimulus-response incongruency effects were found on all measures of processing speed and accuracy. The effects on the percentages of wrong button presses and too slow (>1,000 ms) responses were larger in the older than in the younger age cohort. Significant heritability was found for processing speed (33-48%), accuracy (41%), and stimulus-response incongruency effects (3-32%). Verbal and performance IQ correlated significantly with stimulus-response incongruency effects on accuracy (-0.22 to -0.39), and this correlation was completely mediated by an underlying set of common genes. It is concluded that measures of the ability to perform well under conditions of stimulus-response incongruency are viable endophenotypes of cognitive ability.

Adult↗

PubMed2001

Contingent negative variation in subjects at risk for migraine without aura.

Migraine is a complex disease with a significant genetic background. One possible strategy to investigate the genetics of migraine is the evaluation of functional vulnerability markers or biological elementary endophenotypes in individuals with the greatest probability of developing the disorder (high-risk design). In this study the contingent negative variation (CNV) was recorded in 35 high-risk subjects with a positive family history of migraine without aura (FHP), 35 low-risk individuals without a positive family history (FHN), and 35 migraineurs (migraine without aura). FHP subjects and migraine patients differed significantly from FHN individuals with regard to amplitude and habituation slope of the early CNV component (initial CNV or iCNV). FHP participants demonstrated the same iCNV abnormalities and distribution among iCNV characteristics as migraineurs. The amplitude of the iCNV correlated significantly with the relative number of subjects suffering from migraine among first- and second-degree relatives. The higher the density of affected individuals in the family, the more pronounced were the CNV abnormalities in relatives. This study provides evidence that the familial factor contributes to the abnormal amplitude, and to a lesser degree, habituation of the iCNV, and that the iCNV may be used as a functional-genetic vulnerability marker in further research of migraine genetics.

Adolescent↗

PubMed2003

Phenomenology of tics and natural history of tic disorders.

Tic symptoms, the hallmark of Tourette's syndrome (TS), may simply be fragments of innate behavior. As such, the sensory urges that precede tics may illuminate some of the normal internal cues that are intimately involved in the assembly of behavioral sequences. The occurrence of tics in time appears to have fractal characteristics that may help to explain the waxing and waning course of tic disorders. Longitudinal studies are currently underway that should permit a close examination of the natural fluctuations in tic severity using valid and reliable clinician-rated scales of tic severity. The natural history of tics typically shows a marked decline during the course of adolescence. However, TS can also be associated with social, emotional, and academic difficulties in early adulthood. Comorbid attention deficit/hyperactivity disorder and obsessive-compulsive disorder are likely to influence the long-term adaptive outcomes of individuals with TS. Future progress may also be expected as endophenotypes, and possibly genetic markers, are identified that are associated with specific comorbid conditions and etiologically distinct forms of TS.

Age Factors↗

PubMed2003

Genetics of obsessive-compulsive disorders: new findings and challenges.

A review of the current state of research in the genetics of obsessive-compulsive disorder (OCD) is presented. OCD is a neuropsychiatric condition that affects 1-2% of the population and often has an early age at onset of symptoms. OCD has been shown to be familial, and a major gene effect has been reported. However, phenotypic and genetic heterogeneity of OCD poses multiple challenges for locating susceptibility genes. Strategies such as the use of phenotypic subtyping (using tic disorders or other anxiety disorders) and endophenotyping based on brain mechanisms underlying OCD (functional brain imaging and neuropsychological measures) may open ways to understand the genetic components of OCD. Using child probands and extended families for linkage an association studies is another venue to obtain greater informative families for genetic studies. A better understanding of environmental triggers, OCD subtypes and OCD pathophysiology will lead to locating genes that confer risk to OCD.

Brain↗

PubMed2006

[Schizophrenia: on the genetic trail].

Data from genetic epidemiology studies demonstrate the existence of hereditary factors in the genesis of schizophrenia. Most authors now think that a multigenic multifactorial model will explain the transmission of this disease. Several genes may be involved, either additively (their effects added together, each gene having its own contribution), or epistatically (expression of one gene effective only if another gene is also expressed). Other risk factors - environmental, biological, and neurodevelopmental - may also play a role. There is likely to be a threshold effect above which the sum total of these factors makes the disease clinically detectable. New study strategies have therefore sought to characterize candidate regions or genes based on various biochemical or neurodevelopmental hypotheses. This research collides, however, with the heterogeneity of symptoms as well as the diversity of the disease development. Other avenues of research therefore look towards the study of endophenotypes or 'markers of vulnerability' and towards the identification of genetically homogeneous subgroups of patients and families, among whom susceptibility genes may be detected. Current genetic studies agree about the complexity of the transmission of this disease with its heterogeneous polygenic characteristics.

Chromosome Aberrations↗

PubMed1998

Closing in on genes for manic-depressive illness and schizophrenia.

Advances in the human genetic map, and in genetic analysis of linkage and association in complex inheritance traits, have led to genetic progress in the major psychoses. For chromosome 6 in schizophrenia, and chromosomes 18 and 21 in manic-depressive illness, there are reports of linkage in several independent data sets. These are small effect genes, best detected with affected-relative-pair linkage methods. Association with candidate genes is an alternative strategy to uncovering susceptibility genes for these illnesses, but convincing associations remain to be demonstrated. New clinical and laboratory investigation methods are being developed. Testing every gene in the human genome for association with illness has recently been proposed (Risch and Merikangas 1996). This would require further progress in characterizing the genome and in automated large-scale genotyping. The best type of pedigree sampling for common disease studies, whether for linkage or association, is not yet established. An endophenotype hybrid strategy can combine genetic linkage, association, and pathophysiologic studies. As clinical molecular investigation methods advance, identification of disease susceptibility mutations and delineation of their pathophysiological roles may be expected.

Bipolar Disorder↗

PubMed1999

Atrophic and static (neurodevelopmental) schizophrenic psychoses: premorbid functioning, symptoms and neuroleptic response.

The question of whether schizophrenic-like disorders are neurodevelopmental or degenerative in origin has been argued since the time of Kraepelin. The authors provide evidence for the existence of two etiologically distinct endophenotypes of the psychoses contained within the rubric of familial non-affective psychosis (schizophrenia), one atrophic and the other neurodevelopmental. The atrophic psychosis, identified by progressive ventricular enlargement throughout adult illness, evidences progressive impairment of interests, relationships, and withdrawal from latency through adolescence, with emergence of trait-like negative symptoms which are only marginally responsive to conventional neuroleptics. This psychosis also exhibits delayed response of positive symptoms during neuroleptic treatment, and may also proceed to a praecox dementia in later life. In contrast, a putative neurodevelopmental psychosis, associated with static ventricles during the course of adult illness, also demonstrates preadolescent impairments, but impairments which do not progress to marked negative symptoms. Conventional neuroleptics appear to have little effect (except sedation) on positive symptoms, but appear to induce negative symptomatology and partial disengagement from the burden of persistent psychotic thought processes in such static ventricle psychoses. Thus, separate patterns of illnesses with different prodromal features, different treatment response patterns, and different patterns of residual (negative) symptoms appear to characterize patients with psychosis who have expanding as opposed to stable cerebral-ventricles at doses of neuroleptic at 10 mg haloperidol equivalents/day.

Adult↗

PubMed2002

Executive/attentional cognitive functions in schizophrenic patients and their parents: a preliminary study.

The aim of this study was to determine whether executive/attentional cognitive performances could be considered as markers of vulnerability to schizophrenia. The Stroop Color Word and fluency tests were significantly impaired in schizophrenic patients and their parents compared to controls matched on age and sex while performances on Nelson's Modified Card Sorting Test and the Trail Making Test did not differ. The impairments on the Stroop and fluency could be considered as endophenotypic markers of schizophrenia.

Adult↗

PubMed2002

Eye movement and neuropsychological studies in first-degree relatives of schizophrenic patients.

The aim of the study was to compare the results of oculomotor and neuropsychological tests in first-episode schizophrenic patients, in both their parents and matched healthy controls. Eye movement tests included fixation and a smooth pursuit task and neuropsychological tests which comprised the Trail Making Test (TMT) A and B, the Stroop Test A and B, and the Wisconsin Card Sorting Test (WCST). There was a significant difference between the 21 patients and their 33 healthy parents in the results of both the eye movement tests and the TMT and WCST but not in the Stroop test. On the other hand, a significant difference between parents and their matched control subjects was found in both oculomotor tests, in the Stroop B, and in two indices of the WCST (completed categories, CC and percentage of conceptual level responses, %CONC). A correlation was obtained between patients and their fathers in the intensity of smooth pursuit disturbances and two indices of the WCST (CC and %CONC), but not between patients and their mothers. The results obtained confirm those of other studies pointing to the presence of a significant impairment on oculomotor and neuropsychological tests in first-degree nonpsychotic relatives (parents) of schizophrenic patients, which may be used as an endophenotypic markers of genetic predisposition to schizophrenia.

Adolescent↗

PubMed2003

Cognitive dysfunctions in parents of schizophrenic patients parallel the deficits found in patients.

Schizophrenia is characterized by a global cognitive impairment, with varying degrees of deficit in all ability domains. Since genetic factors are important in the etiology of schizophrenia we investigated whether parents of schizophrenic patients also show cognitive deficits, particularly on those cognitive ability domains that are most severely affected in patients. Both biological parents of 37 patients with schizophrenia (N=74 subjects) and 28 comparable healthy married control couples (N=56 subjects) were included. A comprehensive and standardized cognitive battery was used including tests measuring verbal memory, executive functioning, language, attention, and psychomotor functioning. Parents of patients differed from control couples on those cognitive constructs that are generally considered to be most impaired in schizophrenic patients, i.e. global verbal memory, bilateral motor skill, continuous performance, and word fluency. In addition, parents differed significantly from control couples on some other cognitive constructs on which patients show a smaller but also significant difference compared to healthy controls, i.e. unilateral motor skill and digit span. Results suggest that the cognitive constructs on which patients show relatively most severe impairment may prove suitable as endophenotypic markers in schizophrenia.

Cognition Disorders↗

PubMed2004

Mismatch negativity in schizophrenia: a family study.

BACKGROUND: Mismatch negativity (MMN) is a measure of cortical activity that occurs in response to a change in auditory stimuli. We investigated whether MMN is a potential marker of genetic vulnerability to schizophrenia by comparing MMN in a group of patients with schizophrenia, their unaffected relatives, and controls. METHOD: There are 25 schizophrenic patients, 37 of their unaffected first-degree relatives, and 20 unrelated controls that performed the MMN task. Linear regression with robust standard errors, and accounting for correlations within families, was employed to test for differences in MMN amplitude between the groups. RESULTS: Patients had significantly smaller MMN amplitudes compared to both their unaffected relatives and controls at FZ (P<0.01) and at F3 (P=0.01), whereas relatives and controls did not differ at FZ or at F3. No differences were found between any of the groups at F4. Furthermore, we found no strong evidence that the MMN amplitude is a familial trait. CONCLUSIONS: Our results confirm that the MMN amplitude is reduced in schizophrenia. However, the MMN does not show a significant familial influence and is normal among the unaffected relatives. We conclude that while the MMN is abnormal in patients with schizophrenia, it is a weak or unreliable marker of vulnerability when applied to subclinical populations, and therefore is unlikely to be an endophenotype for the disorder.

Acoustic Stimulation↗

PubMed2003

Genetics and genomics of behavioral and psychiatric disorders.

Psychiatric conditions are to some degree under genetic influences. Despite the application of advanced genetic and molecular biological technologies, the genetic bases of the human behavioral traits and psychiatric diseases remains largely unresolved. Conventional genetic linkage approaches have not yielded definitive results, possibly because of the absence of objective diagnostic tests, the complex nature of human behavior or the incomplete penetrance of psychiatric traits. However, recent studies have revealed some genes of interest using multifaceted approaches to overcome these challenges. The approaches include using families in which specific behaviors segregate as a mendelian trait, utilization of endophenotypes as biological intermediate traits, identification of psychiatric disease phenotypes in genomic disorders, and the establishment of mouse models.

Animals↗

PubMed2002

Cognition following acute tryptophan depletion: difference between first-degree relatives of bipolar disorder patients and matched healthy control volunteers.

BACKGROUND: Serotonergic circuits have been proposed to mediate cognitive processes, particularly learning and memory. Cognitive impairment is often seen in bipolar disorders in relation to a possible lowered serotonergic turnover. METHODS: We investigated the effects of acute tryptophan depletion (ATD) on cognitive performance in healthy first-degree relatives of bipolar patients (FH) (N= 30) and matched controls (N= 15) in a placebo-controlled, double-blind cross-over design. Performance on planning, memory and attention tasks were assessed at baseline and 5 h after ATD. RESULTS: Following ATD, speed of information processing on the planning task was impaired in the FH group but not in the control group. FH subjects with a bipolar disorder type I relative (FH I) showed impairments in planning and memory, independent of ATD. In all subjects, ATD impaired long-term memory performance and speed of information processing. ATD did not affect short-term memory and focused and divided attention. CONCLUSIONS: The results suggest serotonergic vulnerability affecting frontal lobe areas in FH subjects, indicated by impaired planning. Biological vulnerability in FH I subjects is reflected in impaired planning and memory performance. In conclusion, the cognitive dysfunctions in FH subjects indicate an endophenotype constituting a possible biological marker in bipolar psychopathology. Serotonin appears to be involved in speed of information processing, verbal and visual memory and learning processes.

Administration, Oral↗

PubMed2005

Brain anatomy in non-affected parents of autistic probands: a MRI study.

BACKGROUND: Autism is a neurodevelopmental disorder with an estimated genetic origin of 90%. Previous studies have reported an increase in brain volume of approximately 5% in autistic subjects, especially in children. If this increase in brain volume is genetically determined, biological parents of autistic probands might be expected to show brain enlargement, or at least intracranial enlargement, as well. Identifying structural brain abnormalities under genetic control is of particular importance as these could represent endophenotypes of autism. METHOD: Using quantitative anatomic brain magnetic resonance imaging, volumes of intracranial, total brain, frontal, parietal, temporal and occipital lobe, cerebral and cortical gray and white matter, cerebellum, lateral ventricle, and third ventricle were measured in biological, non-affected parents of autistic probands (19 couples) and in healthy, closely matched control subjects (20 couples). RESULTS: No significant differences were found between the parents of the autistic probands and healthy control couples in any of the brain volumes. Adding gender as a factor in a second analysis did not reveal a significant interaction effect of gender by group. CONCLUSIONS: The present sample of biological, non-affected parents of autistic probands did not show brain enlargements. As the intracranium is not enlarged, it is unlikely that the brain volumes of the parents of autistic probands have originally been enlarged and have been normalized. Thus, increased brain volume in autism might be caused by the interaction of paternal and maternal genes, possibly with an additional effect of environmental factors, or increased brain volumes might reflect phenotypes of autism.

Autistic Disorder↗

PubMed2006

Cognitive function in unaffected twins discordant for affective disorder.

BACKGROUND: Patients may present with cognitive impairment in the euthymic phase of affective disorder, but it is unclear whether the impairment is prevalent before onset of the illness. The aim of the present study was to examine the hypothesis that genetic liability to affective disorder is associated with cognitive impairment. METHOD: In a cross-sectional high-risk case-control study, healthy monozygotic (MZ) and dizygotic (DZ) twins with (High-Risk twins) and without (the control group/Low-Risk twins) a co-twin history of affective disorder were identified through nationwide registers. Cognitive performance of 203 High-Risk and Low-Risk twins was compared. RESULTS: Healthy twins discordant for unipolar disorder showed lower performance on almost all measures of cognitive function: selective and sustained attention, executive function, language processing and working and declarative memory, and also after adjustment for demographic variables, subclinical symptoms and minor psychopathology. Healthy twins discordant for bipolar disorder showed lower performance on tests measuring episodic and working memory, also after adjustment for the above-mentioned covariables. The discrete cognitive impairment found seemed to be related to genetic liability, as the MZ High-Risk twins showed significant impairment on selective and sustained attention, executive function, language processing and working and declarative memory, whereas the DZ High-Risk twins presented with significantly lower scores only on language processing and episodic memory. CONCLUSIONS: The hypothesis that discrete cognitive impairment is present before the onset of the affective disorder and is genetically transmitted was supported. Thus, cognitive function may be a candidate endophenotype for affective disorders.

Adult↗

PubMed2006

Saccadic abnormalities in psychotropic-naive obsessive-compulsive disorder without co-morbidity.

BACKGROUND: Oculomotor studies have found saccadic abnormalities in obsessive-compulsive disorder (OCD), lending support for models postulating a central role for inhibition in OCD. Saccadic abnormalities in OCD may also be potential candidates for a biological marker, important for more endophenotype-oriented research. Saccadic abnormalities have not been examined in psychotropic-naive patients with OCD without co-morbidity. METHOD: We compared the error rates and latencies of 14 carefully selected adult psychotropic-naive patients with OCD with no co-morbid diagnosis and 14 pairwise matched healthy controls on a fixation task, on a prosaccade task and on an antisaccade task. RESULTS: Patients with OCD showed normal error rates on all tasks, but latencies on the antisaccade task were significantly increased. CONCLUSIONS: Our results indicate that patients with OCD have no gross impairment of oculomotor inhibitory capacities, but may have a disturbed capacity to deliberately initiate a saccade to an imagined target.

Adult↗

PubMed2006

Bipolar I and bipolar II disorder: cognition and emotion processing.

BACKGROUND: Cognitive impairment may be part of the endophenotype of bipolar disorder (BP), but little is known about patterns and severity of impairment in BP subgroups and their relation to depression. The same applies to deficits in emotion processing known to be present in BP. METHOD: To explore the relationship between depression and impairment in cognition and emotion processing and the differences between BP subgroups, we assessed 36 (25 BP I and 11 BP II) patients using a cognitive battery and a facial emotion recognition task. RESULTS: BP patients were impaired compared to published norms on memory, naming and executive measures (Binomial Single Proportion tests, p<0.05). Cognitive performance was largely unrelated to depression ratings. Surprise recognition was the only emotion processing impairment in BP patients compared to controls (patients' recognition score 75% v. controls' 89%, p=0.024). Patients with higher depression ratings were more impaired in recognizing expressions of anger (t23=2.21, p=0.037). BP II patients were more impaired than BP I patients in IQ, memory and executive measures (Mann-Whitney tests, p<0.05). Depression severity or exposure to medication or electroconvulsive therapy (ECT) did not explain these differences. CONCLUSIONS: We confirm cognitive impairment and an isolated facial emotion processing deficit in BP patients and suggest that these deficits are largely unrelated to depressive symptoms. Our study also provides evidence that cognitive deficits are more severe and pervasive in BP II patients, suggesting that recurrent depressive episodes, rather than mania, may have a more detrimental and lasting effect on cognition.

Adult↗

PubMed2000

Information processing deficits in relatives of manic depressive patients.

BACKGROUND: The importance of genetic factors in the aetiology of manic-depressive illness (MDI) has been repeatedly confirmed and indicators of vulnerability to the illness in families with affective disorders are needed. Abnormal event-related potentials (ERP) may be markers of genetic vulnerability to mental illness. Long latency and low amplitude of P300 have consistently been reported in schizophrenic patients and their relatives. A few studies have also shown P300 deficits in MDI patients, but no ERP study has been performed on their relatives. METHODS: ERPs were recorded during an auditory oddball task in 19 relatives belonging to families with two or more bipolar patients and in controls with no familial or personal history of affective disorders. The relatives were selected as having no affective disorders on a lifetime basis, but eight had an anxiety disorder. RESULTS: In all relatives, a lower P300 amplitude and a longer P300 latency was found, with much longer reaction time and post-N200 duration till button-press than controls. A lack of P300 amplitude dominance in the right hemisphere was also found in relatives in comparison with controls. There also appeared to be a frontal predominance of ERP abnormalities in relatives. CONCLUSION: We report the first evidence of deficits in reaction time and in P300 amplitude and latency, and a lack of P300 right-sided dominance, in relatives of manic-depressive patients. This pattern may constitute an endophenotypic marker of manic-depressive disorder.

Adult↗