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PubMed2005

Brain MRI abnormalities in schizophrenia: same genes or same environment?

BACKGROUND: Structural brain volume abnormalities are among the most extensively studied endophenotypes in schizophrenia. Bivariate genetic model fitting (adjusted to account for selection) was used to quantify the genetic relationship between schizophrenia and brain volumes and to estimate the heritability of these volumes. METHOD: We demonstrated by simulation that the adjusted genetic model produced unbiased estimates for endophenotype heritability and the genetic and environmental correlations. The model was applied to brain volumes (whole brain, hippocampus, third and lateral ventricles) in a sample of 14 monozygotic (MZ) twin pairs concordant for schizophrenia, 10 MZ discordant pairs, 17 MZ control pairs, 22 discordant sibling pairs, three concordant sibling pairs, and 114 healthy control subjects. RESULTS: Whole brain showed a substantial heritability (88%) and lateral ventricles substantial common environmental effects (67%). Whole brain showed a significant genetic correlation with schizophrenia, whereas lateral ventricles showed a significant individual specific correlation with schizophrenia. There were significant familial effects for hippocampus and third ventricle, but the analyses could not resolve whether these were genetic or environmental in origin (around 30%each). CONCLUSIONS: Using genetic model fitting on twin and sibling data we have demonstrated differential sources of covariation between schizophrenia and brain volumes, genetic in the case of whole brain volume and individual specific environment in the case of lateral ventricles.

Adolescent↗

PubMed2005

Normal levels of prepulse inhibition in the euthymic phase of bipolar disorder.

BACKGROUND: Deficits in prepulse inhibition (PPI) of the acoustic startle response have been suggested as a potentially useful endophenotype for schizophrenia spectrum disorders and may explain certain symptoms and cognitive deficits observed in the psychoses. PPI deficits have also been found in mania, but it remains to be confirmed whether this dysfunction is present in the euthymic phase of bipolar disorder. METHOD: Twenty-three adult patients with DSM-IV bipolar disorder were compared to 20 controls on tests of acoustic startle reactivity and PPI of the startle response. Sociodemographic and treatment variables were recorded and symptom scores assessed using the Hamilton Depression Inventory and the Young Mania Rating Scale. RESULTS: Overall, the patient and control groups demonstrated similar levels of startle reactivity and PPI, although there was a trend for the inter-stimulus interval to differentially affect levels of PPI in the two groups. CONCLUSIONS: In contrast to bipolar patients experiencing a manic episode, general levels of PPI were normal in this euthymic sample. Further studies are required to confirm this finding and to determine the mechanisms by which this potential disruption/normalization occurs. It is suggested that an examination of PPI in a high-risk group is required to fully discount dysfunctional PPI as a potentially useful endophenotype for bipolar disorder.

Acoustic Stimulation↗

PubMed2005

Saccadic distractibility is elevated in schizophrenia patients, but not in their unaffected relatives.

BACKGROUND: Saccadic distractibility, as measured by the antisaccade task, has attracted attention as a putative endophenotypic marker for schizophrenia. Some studies have suggested that this measure is elevated in the unaffected relatives of schizophrenia patients. However, recent studies have called this into question and the topic remains controversial. METHOD: Saccadic distractibility was measured in 53 patients with DSM-IV schizophrenia, 80 unaffected first-degree relatives and 41 unaffected controls.Results. Schizophrenia patients performed worse than relatives and controls combined (p<0.00001), but relatives did not differ significantly from controls. Performance in multiply affected families was no worse than that in singly affected families. Relatives with a high presumed genetic risk for schizophrenia performed no worse than other relatives. The performance of the patients did not predict that of their relatives. CONCLUSIONS: These results demonstrate that saccadic distractibility is strongly associated with disease status but not with genetic loading for schizophrenia. We conclude that saccadic distractibility is unlikely to be useful as an endophenotypic marker in schizophrenia.

Adult↗

PubMed2006

Reaction time, inhibition, working memory and 'delay aversion' performance: genetic influences and their interpretation.

BACKGROUND: For candidate endophenotypes to be useful for psychiatric genetic research, they first of all need to show significant genetic influences. To address the relative lack of previous data, we set to investigate the extent of genetic and environmental influences on performance in a set of theoretically driven cognitive-experimental tasks in a large twin sample. We further aimed to illustrate how test-retest reliability of the measures affects the estimates. METHOD: Four-hundred 7- to 9-year-old twin pairs were assessed individually on tasks measuring reaction time, inhibition, working memory and 'delay aversion' performance. Test-retest reliability data on some of the key measures were available from a previous study. RESULTS: Several key measures of reaction time, inhibition and working-memory performance indicated a moderate degree of genetic influence. Combining data across theoretically related tasks increased the heritability estimates, as illustrated by the heritability estimates of 60% for mean reaction time and 50% for reaction-time variability. Psychometric properties (reliability or ceiling effects) had a substantial influence on the estimates for some measures. CONCLUSIONS: The data support the usefulness of several of the variables for endophenotype studies that aim to link genes to cognitive and motivational processes. Importantly, the data also illustrate specific conditions under which the true extent of genetic influences may be underestimated and hence the usefulness for genetic mapping studies compromised, and suggest ways to address this.

Child↗

PubMed2006

Cognitive functioning in patients with familial bipolar I disorder and their unaffected relatives.

BACKGROUND: Impairments in verbal learning and memory, executive functions and attention are manifest in some euthymic patients with bipolar disorder (BPD). However, evidence is sparse on their putative role as aetiologically important genetic vulnerability markers for the disorder. This population-based study examined the cognitive functions of affected and unaffected individuals in families with BPD. The aim was to discover whether any cognitive function would indicate genetic liability to the disorder and could thus be regarded as endophenotypes of BPD. METHOD: A diagnostic interview and a neuropsychological test battery were administered to 32 familial bipolar I disorder patients, 40 of their unaffected first-degree relatives and 55 controls, all representing population-based samples. RESULTS: Unaffected first-degree relatives showed impairment in psychomotor performance speed and slight impairment in executive function. Bipolar patients were impaired in verbal learning and memory compared with unaffected relatives and controls. They also differed from controls in tasks of executive functions. There were no difference between the groups in simple attention and working memory tasks. CONCLUSIONS: Impaired psychomotor performance speed and executive function may represent endophenotypes of BPD, reflecting possible underlying vulnerability to the disorder. Verbal memory impairments appear to be more related to the fully developed disorder.

Bipolar Disorder↗

PubMed2007

Genetic overlap between bipolar illness and event-related potentials.

BACKGROUND: Electrophysiological endophenotypes are far less explored in bipolar disorder as compared to schizophrenia. No previous twin study of event-related potentials (ERPs) in bipolar illness has been reported. This study uses a twin design and advanced genetic model fitting analyses aiming to (1) assess and quantify the relationship of a range of ERP components with bipolar disorder with psychotic features, and (2) examine the source of the relationship (due to genetic or environmental factors). METHOD: P300, P50 suppression and mismatch negativity (MMN) were recorded in 10 discordant monozygotic (MZ) bipolar twin pairs, six concordant MZ bipolar twin pairs and 78 control twin pairs. Statistical analyses were based on structural equation modelling. RESULTS: Bipolar disorder was significantly associated with smaller P300 amplitude and decreased P50 suppression. Genetic correlations were the main source of the associations, estimated to be -0 x 33 for P300 amplitude and 0 x 46 for P50 ratio. Individual-specific environmental influences were not significant. MMN and P300 latency were not associated with the illness. CONCLUSIONS: The results provide supporting evidence that P300 amplitude and P50 suppression ratio are ERP endophenotypes for bipolar disorder.

Adult↗

PubMed2001

Genetics of brain function and cognition.

There is overwhelming evidence for the existence of substantial genetic influences on individual differences in general and specific cognitive abilities, especially in adults. The actual localization and identification of genes underlying variation in cognitive abilities and intelligence has only just started, however. Successes are currently limited to neurological mutations with rather severe cognitive effects. The current approaches to trace genes responsible for variation in the normal ranges of cognitive ability consist of large scale linkage and association studies. These are hampered by the usual problems of low statistical power to detect quantitative trait loci (QTLs) of small effect. One strategy to boost the power of genomic searches is to employ endophenotypes of cognition derived from the booming field of cognitive neuroscience. This special issue of Behavior Genetics reports on one of the first genome-wide association studies for general IQ. A second paper summarizes candidate genes for cognition, based on animal studies. A series of papers then introduces two additional levels of analysis in the "black box" between genes and cognitive ability: (1) behavioral measures of information-processing speed (inspection time, reaction time, rapid naming) and working memory capacity (performance on on single or dual tasks of verbal and spatio-visual working memory), and (2) electrophyiosological derived measures of brain function (e.g., event-related potentials). The obvious way to assess the reliability and validity of these endophenotypes and their usefulness in the search for cognitive ability genes is through the examination of their genetic architecture in twin family studies. Papers in this special issue show that much of the association between intelligence and speed-of-information processing/brain function is due to a common gene or set of genes, and thereby demonstrate the usefulness of considering these measures in gene-hunting studies for IQ.

Brain↗

PubMed2004

Conducting genetic epidemiology studies of autism spectrum disorders: issues in matching.

The objective of this review is to clarify the role of matching in family genetic studies of autism as a way of defining endophenotypes for linkage analysis. The concept of a confounding variable is reviewed and the importance of considering these in family studies of three endophenotypes in autism are considered: cognitive/language impairments, psychiatric disorders, and autistic-like traits. The importance of matching in infant sibling studies of autism is also addressed. Matching as a way of dealing with confounding variables has an important impact on understanding the extent to which these phenotypes are associated with the genes that confer susceptibility to autism and to the early detection of the disorder. Matching continues to be an important issue in the planning and conduct of family-genetic studies of the autism spectrum disorders, particularly as the search for autism susceptibility genes enters the next generation of studies.

Autistic Disorder↗

PubMed2006

Smooth pursuit eye movement and schizotypy in the community.

Deficits in smooth pursuit eye movements are well documented in schizophrenia and schizotypic psychopathology. The status of eye tracking dysfunction (ETD) as an endophenotype for schizophrenia liability is relatively robust. However, the relation of ETD to schizophrenia-related deviance in the general population has not been confirmed. This study examined smooth pursuit eye tracking and schizotypal personality features in the general population. Smooth pursuit eye movement and schizotypal features were measured in 300 adult community subjects. The sample included both sexes, subjects with a wide age and educational range, and subjects with no prior history of psychosis. Primary outcome measures were peak gain (eye velocity/target velocity), catch-up saccade rate, and schizotypal feature scores. Total schizotypal features were significantly associated with decreased peak gain and were associated at the trend level with increased catch-up saccade rate. These associations were essentially unchanged after controlling for age, sex, and intellectual level effects. These data confirm a hypothesized association between schizotypal features and poorer eye tracking performance (principally, peak gain) in the general population as well as support the conceptualization of ETD as an endophenotype for schizophrenia liability.

Adolescent↗

PubMedDate not supplied

Psychopharmacology of male rat sexual behavior: modeling human sexual dysfunctions?

Most of our current understanding of the neurobiology, neuroanatomy and psychopharmacology of sexual behavior and ejaculatory function has been derived from preclinical studies in the rat. When a large population of male rats is tested on sexual activity during a number of successive tests, over time individual rats display a very stable sexual behavior that is either slow, normal or fast as characterized by the number of ejaculations performed. These sexual endophenotypes are postulated as rat counterparts of premature (fast rats) or retarded ejaculation (slow rats). Psychopharmacology in these endophenotypes helps to delineate the underlying mechanisms and pathology. This is illustrated by the effects of serotonergic antidepressants and serotonergic compounds on sexual and ejaculatory behavior of rats. These preclinical studies and models contribute to a better understanding of the neurobiology of ejaculation and boost the development of novel drug targets to treat ejaculatory disorders such as premature and retarded ejaculation.

Animals↗

PubMed2001

Altered IMPA2 gene expression and calcium homeostasis in bipolar disorder.

Reduced inositol monophosphatase (IMPase) activity and elevated basal intracellular calcium levels ([Ca(2+)](B)) have been reported in B lymphoblast cell lines (BLCLs) from bipolar I affective disorder (BD-I) patients, which may reflect cellular endophenotypes of this disorder. As the PI cycle couples to intracellular Ca(2+) mobilization, these two putative endophenotypes may be related. Using an RT-PCR assay, mRNA levels were estimated for IMPA1 and 2 genes encoding human IMPase 1 and 2, respectively, in BLCLs phenotyped on [Ca(2+)](B), from patients with a DSM-IV diagnosis of BD-I (n = 12 per phenotype) and from age- and sex-matched healthy subjects (n = 12). IMPA2 mRNA levels were significantly lower in BLCLs from male BD-I patients with high [Ca(2+)](B) (n = 6) compared with healthy male subjects (n = 5) (-52%, P = 0.013), male BD-I patients with normal BLCL [Ca(2+)](B) (n = 8) (-42%, P = 0.003) and female BD-I patients with high [Ca(2+)](B) (n = 6) (-59%, P = 0.0004). A significant negative correlation was observed between IMPA2 mRNA levels and [Ca(2+)](B) in BLCLs from male (P = 0.046), but not female BD-I patients. Sex-dependent differences were also evident in postmortem temporal cortex IMPA2 mRNA levels which, in contrast to BLCLs, were significantly higher in male BD-I subjects compared with male controls (P = 0.025, n = 4/group). Collectively, these observations suggest a potential sex-dependent link between abnormalities in IMPA2 expression and calcium homeostasis in the pathophysiology of BD.

Adult↗

PubMed2004

[New strategies in schizophrenia: impact of endophentotypes].

Despite the compelling evidence for a strong heritability of schizophrenia, the aetiology and genetic underpinnings of this disabling disease still remain unclear. Reasonable explanations for current problems in identifying candidate genes for schizophrenia are the complexity of its genetic background as well as the heterogeneity of the clinical appearance of this disease. For a higher efficiency in genetic investigations, a new approach came up which defines clinically distinct traits much more precisely: the so called endophenotype concept. Schizophrenic patients suffer from marked cognitive deficits. These deficits are closely related to the neurobiological basis of the disease, exhibit a high negative impact on clinical outcome, and may serve as endophenotypes for genetic studies. Identification of neurocognitive endopenotypes is usually performed in terms of a combination of neuropsychological tests and neurophysiological measurements. Thus, future genetic investigations as well as psychosocial and psychopharmacological therapy strategies will focus on the severity and potential therapeutic modification of cognitive deficits in order to improve psychosocial reintegration of schizophrenic patients in the long-term.

Arousal↗

PubMed2000

Genetics of the risk for alcoholism.

This paper reviews the literature on the importance of genetic influences in the development of alcohol abuse and dependence (alcoholism). The alcohol use disorders are fairly typical of most complex genetic conditions in that multiple genetic influences combine together to explain approximately 40% to 60% of the risk. One useful approach for identifying specific genes related to alcoholism involves identifying a population in which known genetic factors are controlled and using genome scan and/or case-control, association approaches to search for specific genes. Several characteristics, or endophenotypes, have been identified as both genetically influenced and contributing toward the risk for alcoholism, including alcohol-metabolizing enzymes, the low level of response to alcohol, and electrophysiological measures. The potential importance of each of these characteristics is reviewed, and data relating to the search for specific genetic material for each endophenotype are presented. These findings are placed in the perspective of the impact that they are likely to have on both prevention and treatment efforts in the alcohol field.

Alcoholism↗

PubMed2005

The inheritance of intermediate phenotypes for schizophrenia.

PURPOSE OF REVIEW: While schizophrenia is substantially heritable, the mode of inheritance is complex, involving numerous genes of small effect and a non-trivial environmental component. The 'endophenotype' approach is an alternative method for measuring phenotypic variation that may facilitate the identification of susceptibility genes in the context of complexly inherited traits. Here we review recent studies applying this method to measures of brain structure, physiology, and function in samples of schizophrenia patients and their non-ill first-degree relatives (siblings and co-twins). RECENT FINDINGS: The results suggest that there are multiple heritable dimensions of central nervous system pathology in schizophrenia, including disturbances in the structure and functioning of frontal lobe systems involved in working memory and executive processes, temporal lobe systems involved in episodic memory, auditory perception, and language processing, and cortical and sub-cortical systems mediating smooth pursuit eye movements and sensorimotor gating. A number of genetic loci that are suspected to play a role in predisposing to schizophrenia, including the DISC1, COMT, neuregulin, dysbindin, and alpha-7 nicotinic receptor genes, appear to affect quantitative variation on one or more of these indicators. SUMMARY: Future work is encouraged to address whether each of these neural system dysfunctions are under the influence of a partially distinct set of genes, to elucidate the manner in which multiple genes may coalesce in determining schizophrenia-promoting dysfunction in each neurobehavioral domain, and to clarify the degree of overlap in these quantitative trait loci-endophenotype relationships with other forms of psychosis, particularly bipolar disorder.

Journal Article↗

PubMed2003

Two NOTCH4 polymorphisms and their relation to schizophrenia susceptibility and different personality traits.

BACKGROUND: Recently, linkage disequilibrium mapping of the major histocompatibility complex region on the short arm of human chromosome 6 suggested that the NOTCH4 locus is highly associated with schizophrenia. OBJECTIVES AND METHODS: We analysed two polymorphisms in this gene in Swedish schizophrenic patients ( =74) and control subjects ( =135). The NOTCH4 variants were also analysed in schizophrenic patients with regard to subdiagnosis, age at first hospitalization, abuse/dependence of alcohol, solvents, or drugs, previous suicide attempts, extrapyramidal symptoms, treatment with anticholinergic drugs, and response to anti-psychotic drug treatment. Control subjects were scrutinized with regard to personality, another partially heritable trait suggested being of importance in schizophrenia. In addition, two intermediate endophenotypes suggested being of importance in schizophrenia, dopamine D(2) receptor density in striatum and monoamine metabolites in cerebrospinal fluid, respectively, were investigated with regard to the two NOTCH4 variants. RESULTS: There was no significant association between the patients and the controls for the two investigated polymorphisms neither for the parameters analysed in the schizophrenia material. The NOTCH4 SNP2 variant, an A-->G substitution, was associated with the Karolinska Scales of Personality Irritability scale. The NOTCH4 (CTG)(n) variant was associated with the revised NEO personality inventory Extraversion and Activity (E4) scales. However, after correction for multiple testing, no difference remained significant. The results for the endophenotypes and the polymorphisms were non-significant. CONCLUSIONS: The present study does not support that the investigated NOTCH4 variants have a major influence on susceptibility to schizophrenia or related neurobiological traits.

Biogenic Monoamines↗

PubMed2005

Startle modulation in Caucasian-Americans and Asian-Americans: a prelude to genetic/endophenotypic studies across the 'Pacific Rim'.

OBJECTIVES: Deficient prepulse inhibition (PPI) of startle in schizophrenia patients and unaffected family members may be a useful endophenotype in studies seeking to identify vulnerability genes for schizophrenia. Before expanding such studies to include Pacific Rim populations with distinct genetic origins compared with North American Caucasian populations, we examined PPI and related startle measures in normal North American Caucasian and Asian men. METHODS: One hundred and seventy-four consecutive carefully screened right-handed male 18-35 year olds completed tests of startle and PPI using bilateral electromyography measures of orbicularis oculi. Subjects identified their racial background. RESULTS: Startle in Caucasian subjects was of significantly larger magnitude and shorter latency compared with Asian subjects; the percent PPI was significantly greater in Asian versus Caucasian subjects at 60 and 120 ms prepulse intervals. Group differences in PPI but not reflex latency were eliminated when groups were matched for startle magnitude on pulse alone trials. Caucasian-American and Asian-American groups did not differ significantly in resting blink rate, resting electromyography activity, or startle reflex habituation. CONCLUSIONS: Robust phenotypic differences in acoustic startle magnitude and latency between Caucasian-American and Asian-American populations must be considered in studies using startle and PPI as endophenotypes across these populations.

Adolescent↗

PubMed2007

Animal models of mood disorders: Recent developments.

PURPOSE OF REVIEW: The wide spectrum of disruptions that characterizes depression and bipolar illness highlights the difficulties researchers are posed with as they try to mimic these disorders in the laboratory. Nonetheless, numerous attempts have been made to create rodent models of mood disorders, or at least models of the symptoms of depression and bipolar illness. Despite many advances, however, there are no satisfactory animal models available. The need for improved animal models for identifying new antidepressants and providing insights into the neuropathology underlying the disease is critical. This review focuses on the attempts to improve current paradigms and also illustrates examples where current paradigms are used to uncover novel molecular targets of antidepressants. RECENT FINDINGS: Currently, there is a shift away from traditional animal models to a more focused research dealing with an endophenotype-style approach, genetic models and incorporation of new findings from human neuroimaging and genetic studies. SUMMARY: Endophenotype-based modelling of depression and bipolar illness is opening up more tractable avenues for understanding the neurobiological and genetic bases of these disorders. Further, advances in the clinical dissection of the psychiatric illnesses using molecular genetics, coupled with functional neuroimaging techniques, promises to yield better translational animal models and hence more fruitful therapeutic targets.

Animals↗

PubMed2025

Neuroimaging PheWAS and molecular phenotyping implicate PSMC3 in Alzheimer's Disease.

INTRODUCTION: Neuroimaging genetics have advanced Alzheimer's disease (AD) research, yet frameworks mechanistically connecting genes to neurological outcomes via functional genomics are needed to elucidate genetic associations. To address this challenge, we assessed relationships between AD-associated variants and disease via their impact on gene expression and neuroimaging phenotypes. METHODS: We mapped established AD genes to neuroimaging traits using NeuroimaGene atlas and predicted transcript-driven AD neurological features by comparing gene-derived neuroimaging features to clinical neuroimaging data. Genetic correlation and covariance analyses characterized shared genetic architecture between AD endophenotypes and neuroimaging features and identified neuroimaging features associated with dementia family history. RESULTS: Our analyses implicate PSMC3 expression as a strong contributor to AD pathophysiology and indicate AD endophenotypes, including dementia family history, linked to frontal cortex thickness, volume, and cerebrospinal fluid volume changes. DISCUSSION: Our findings prioritize AD genes whose regulation is associated with vulnerable brain regions, offering a potential mechanistic framework for downstream functional validation.

Alzheimer’s Disease↗