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Todd D. Gould - One of the best experts on this subject based on the ideXlab platform.
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lithium s antisuicidal efficacy elucidation of neurobiological targets using Endophenotype strategies
Annual Review of Pharmacology and Toxicology, 2009Co-Authors: Colleen E Kovacsics, Irving I Gottesman, Todd D. GouldAbstract:Lithium used as a drug treatment for major mental disorders such as bipolar disorder and depression is effective in reducing the risk of both attempted and completed suicide. However, the mechanisms underlying lithium's antisuicidal actions are not yet known, limiting the development of novel lithium-mimetic compounds that may help reduce suicide risk with fewer undesirable side effects. Suicide is a complex behavior, complicated to study in humans, and impossible to fully reproduce in animal models. The Endophenotype approach, by which quantitative measures of neurobiological function are used to assess and subclassify psychiatric illness, may present a path to new discoveries. Aggression and impulsivity are candidate Endophenotypes strongly associated with suicide; we review the evidence supporting aggression and impulsivity as suicide Endophenotypes, as well as the effects of lithium on these constructs in both humans and rodents. Examining the mechanisms that contribute to lithium's antiaggressive and...
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psychiatric Endophenotypes and the development of valid animal models
Genes Brain and Behavior, 2006Co-Authors: Todd D. Gould, Irving I GottesmanAbstract:Endophenotypes are quantifiable components in the genes-to-behaviors pathways, distinct from psychiatric symptoms, which make genetic and biological studies of etiologies for disease categories more manageable. The Endophenotype concept has emerged as a strategic tool in neuropsychiatric research. This emergence is due to many factors, including the modest reproducibility of results from studies directed toward etiologies and appreciation for the complex relationships between genes and behavior. Disease heterogeneity is often guaranteed, rather than simplified, through the current diagnostic system; inherent benefits of Endophenotypes include more specific disease concepts and process definitions. Endophenotypes can be neurophysiological, biochemical, endocrine, neuroanatomical, cognitive or neuropsychological. Heritability and stability (state independence) represent key components of any useful Endophenotype. Importantly, they characterize an approach that reduces the complexity of symptoms and multifaceted behaviors, resulting in units of analysis that are more amenable to being modeled in animals. We discuss the benefits of more direct interpretation of clinical Endophenotypes by basic behavioral scientists. With the advent of important findings regarding the genes that predispose to psychiatric illness, we are at an important crossroads where, without anthropomorphizing, animal models may provide homologous components of psychiatric illness, rather than simply equating to similar (loosely analogized) behaviors, validators of the efficacy of current medications or models of symptoms. We conclude that there exists a need for increased collaboration between clinicians and basic scientists, the result of which should be to improve diagnosis, classification and treatment on one end and to increase the construct relevance of model organisms on the other.
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the Endophenotype concept in psychiatry etymology and strategic intentions
American Journal of Psychiatry, 2003Co-Authors: Irving I Gottesman, Todd D. GouldAbstract:Endophenotypes, measurable components unseen by the unaided eye along the pathway between disease and distal genotype, have emerged as an important concept in the study of complex neuropsychiatric diseases. An Endophenotype may be neurophysiological, biochemical, endocrinological, neuroanatomical, cognitive, or neuropsychological (including configured self-report data) in nature. Endophenotypes represent simpler clues to genetic underpinnings than the disease syndrome itself, promoting the view that psychiatric diagnoses can be decomposed or deconstructed, which can result in more straightforward-and successful-genetic analysis. However, to be most useful, Endophenotypes for psychiatric disorders must meet certain criteria, including association with a candidate gene or gene region, heritability that is inferred from relative risk for the disorder in relatives, and disease association parameters. In addition to furthering genetic analysis, Endophenotypes can clarify classification and diagnosis and foster the development of animal models. The authors discuss the etymology and strategy behind the use of Endophenotypes in neuropsychiatric research and, more generally, in research on other diseases with complex genetics.
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The Endophenotype Concept in Psychiatry: Etymology and Strategic Intentions
The American journal of psychiatry, 2003Co-Authors: Irving I Gottesman, Todd D. GouldAbstract:Endophenotypes, measurable components unseen by the unaided eye along the pathway between disease and distal genotype, have emerged as an important concept in the study of complex neuropsychiatric diseases. An Endophenotype may be neurophysiological, biochemical, endocrinological, neuroanatomical, cognitive, or neuropsychological (including configured self-report data) in nature. Endophenotypes represent simpler clues to genetic underpinnings than the disease syndrome itself, promoting the view that psychiatric diagnoses can be decomposed or deconstructed, which can result in more straightforward—and successful—genetic analysis. However, to be most useful, Endophenotypes for psychiatric disorders must meet certain criteria, including association with a candidate gene or gene region, heritability that is inferred from relative risk for the disorder in relatives, and disease association parameters. In addition to furthering genetic analysis, Endophenotypes can clarify classification and diagnosis and foster...
Irving I Gottesman - One of the best experts on this subject based on the ideXlab platform.
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Endophenotypes for Alcohol Use Disorder: An Update on the Field
Current Addiction Reports, 2015Co-Authors: Jessica E. Salvatore, Irving I Gottesman, Danielle M DickAbstract:The Endophenotype concept was first proposed as a strategy to use (purportedly) genetically simpler phenotypes in gene identification studies for psychiatric disorders, and is distinct from the closely related concept of intermediate phenotypes. In the area of alcohol use disorder (AUD) research, two candidate Endophenotypes have produced replicable genetic associations: level of response to alcohol and neurophysiology markers (e.g., event-related oscillations and event-related potentials). Additional candidate Endophenotypes from the cognitive, sensory, and neuroimaging literatures show promise, although more evidence is needed to fully evaluate their potential utility. Translational approaches have helped characterize the underlying neurobiology and genetics of AUD Endophenotypes and identified relevant pharmacological interventions. Future research that capitalizes on the polygenic nature of Endophenotypes and emphasizes Endophenotypes that may change across development will enhance the usefulness of this concept to understand the genetically influenced pathways toward AUD.
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Arguments for the sake of Endophenotypes: Examining common misconceptions about the use of Endophenotypes in psychiatric genetics
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 2014Co-Authors: David C. Glahn, Irving I Gottesman, Emma Knowles, John Blangero, D. Reese Mckay, Emma Sprooten, Henriette Raventós, Laura AlmasyAbstract:Endophenotypes are measurable biomarkers that are correlated with an illness, at least in part, because of shared underlying genetic influences. Endophenotypes may improve our power to detect genes influencing risk of illness by being genetically simpler, closer to the level of gene action, and with larger genetic effect sizes or by providing added statistical power through their ability to quantitatively rank people within diagnostic categories. Furthermore, they also provide insight into the mechanisms underlying illness and will be valuable in developing biologically-based nosologies, through efforts such as RDoC, that seek to explain both the heterogeneity within current diagnostic categories and the overlapping clinical features between them. While neuroimaging, electrophysiological, and cognitive measures are currently most used in psychiatric genetic studies, researchers currently are attempting to identify candidate Endophenotypes that are less genetically complex and potentially closer to the level of gene action, such as transcriptomic and proteomic phenotypes. Sifting through tens of thousands of such measures requires automated, high-throughput ways of assessing and ranking potential Endophenotypes, such as the Endophenotype Ranking Value. However, despite the potential utility of Endophenotypes for gene characterization and discovery, there is considerable resistance to endophenotypic approaches in psychiatry. In this review, we address and clarify some of the common issues associated with the usage of Endophenotypes in the psychiatric genetics community.
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lithium s antisuicidal efficacy elucidation of neurobiological targets using Endophenotype strategies
Annual Review of Pharmacology and Toxicology, 2009Co-Authors: Colleen E Kovacsics, Irving I Gottesman, Todd D. GouldAbstract:Lithium used as a drug treatment for major mental disorders such as bipolar disorder and depression is effective in reducing the risk of both attempted and completed suicide. However, the mechanisms underlying lithium's antisuicidal actions are not yet known, limiting the development of novel lithium-mimetic compounds that may help reduce suicide risk with fewer undesirable side effects. Suicide is a complex behavior, complicated to study in humans, and impossible to fully reproduce in animal models. The Endophenotype approach, by which quantitative measures of neurobiological function are used to assess and subclassify psychiatric illness, may present a path to new discoveries. Aggression and impulsivity are candidate Endophenotypes strongly associated with suicide; we review the evidence supporting aggression and impulsivity as suicide Endophenotypes, as well as the effects of lithium on these constructs in both humans and rodents. Examining the mechanisms that contribute to lithium's antiaggressive and...
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psychiatric Endophenotypes and the development of valid animal models
Genes Brain and Behavior, 2006Co-Authors: Todd D. Gould, Irving I GottesmanAbstract:Endophenotypes are quantifiable components in the genes-to-behaviors pathways, distinct from psychiatric symptoms, which make genetic and biological studies of etiologies for disease categories more manageable. The Endophenotype concept has emerged as a strategic tool in neuropsychiatric research. This emergence is due to many factors, including the modest reproducibility of results from studies directed toward etiologies and appreciation for the complex relationships between genes and behavior. Disease heterogeneity is often guaranteed, rather than simplified, through the current diagnostic system; inherent benefits of Endophenotypes include more specific disease concepts and process definitions. Endophenotypes can be neurophysiological, biochemical, endocrine, neuroanatomical, cognitive or neuropsychological. Heritability and stability (state independence) represent key components of any useful Endophenotype. Importantly, they characterize an approach that reduces the complexity of symptoms and multifaceted behaviors, resulting in units of analysis that are more amenable to being modeled in animals. We discuss the benefits of more direct interpretation of clinical Endophenotypes by basic behavioral scientists. With the advent of important findings regarding the genes that predispose to psychiatric illness, we are at an important crossroads where, without anthropomorphizing, animal models may provide homologous components of psychiatric illness, rather than simply equating to similar (loosely analogized) behaviors, validators of the efficacy of current medications or models of symptoms. We conclude that there exists a need for increased collaboration between clinicians and basic scientists, the result of which should be to improve diagnosis, classification and treatment on one end and to increase the construct relevance of model organisms on the other.
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the Endophenotype concept in psychiatry etymology and strategic intentions
American Journal of Psychiatry, 2003Co-Authors: Irving I Gottesman, Todd D. GouldAbstract:Endophenotypes, measurable components unseen by the unaided eye along the pathway between disease and distal genotype, have emerged as an important concept in the study of complex neuropsychiatric diseases. An Endophenotype may be neurophysiological, biochemical, endocrinological, neuroanatomical, cognitive, or neuropsychological (including configured self-report data) in nature. Endophenotypes represent simpler clues to genetic underpinnings than the disease syndrome itself, promoting the view that psychiatric diagnoses can be decomposed or deconstructed, which can result in more straightforward-and successful-genetic analysis. However, to be most useful, Endophenotypes for psychiatric disorders must meet certain criteria, including association with a candidate gene or gene region, heritability that is inferred from relative risk for the disorder in relatives, and disease association parameters. In addition to furthering genetic analysis, Endophenotypes can clarify classification and diagnosis and foster the development of animal models. The authors discuss the etymology and strategy behind the use of Endophenotypes in neuropsychiatric research and, more generally, in research on other diseases with complex genetics.
John Blangero - One of the best experts on this subject based on the ideXlab platform.
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assessment of cognition and personality as potential Endophenotypes in the western australian family study of schizophrenia
Schizophrenia Bulletin, 2018Co-Authors: Nina S Mccarthy, Johanna C Badcock, Melanie Clark, Emma Knowles, Gemma Cadby, Phillip E Melton, Vera A Morgan, John BlangeroAbstract:: Phenotypic heterogeneity is a major barrier to understanding the genetic architecture underlying schizophrenia. Incorporating Endophenotypes is one way to reduce heterogeneity and facilitate more powerful genetic analysis. Candidate Endophenotypes require systematic assessment against Endophenotype criteria, and a ranking of their potential utility for genetic analysis. In this study we assess 20 cognitive and personality measures in a sample of 127 families with at least 2 cases of schizophrenia per family (n = 535) plus a set of 30 control families (n = 121) against 4 Endophenotype criteria: (a) be associated with the illness but not be a part of its diagnosis, (b) be heritable, (c) co-segregate with the illness in families, and (d) be found in unaffected relatives at a higher rate than in the general population. The Endophenotype ranking score (Endophenotype ranking variable [ERV]) was used to rank candidate Endophenotypes based on their heritability and genetic correlation with schizophrenia. Finally, we used factor analysis to explore latent factors underlying the cognitive and personality measures. Evidence for personality measures as Endophenotypes was at least equivalent to that of the cognitive measures. Factor analysis indicated that personality and cognitive traits contribute to independent latent dimensions. The results suggest for this first time that a number of cognitive and personality measures are independent and informative Endophenotypes. Use of these Endophenotypes in genetic studies will likely improve power and facilitate novel aetiological insights.
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Endophenotypes
Psychiatric Genetics, 2018Co-Authors: David C. Glahn, Laura Almasy, John BlangeroAbstract:Endophenotypes are traits that, while genetically related to an illness, are not used for diagnoses (e.g., a symptom). It is unlikely that specific genes directly code for any of our current psychiatric diagnoses. Rather, genes influence neurobiological processes that either increase or decrease risk for mental illness. One use of an Endophenotype is to help characterize a genetic locus or gene previously identified as conferring risk for a particular illness. In this context, Endophenotypes help to bridge the gap between a behavioral syndrome and molecular genetic variation. Alternately, Endophenotypes can be used for novel locus or gene discovery, particularly when used in multivariate analyses. In this chapter, we define Endophenotypes and describe different ways they have been applied to aid our understanding of the genetic architecture of psychiatric disorders.
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Arguments for the sake of Endophenotypes: Examining common misconceptions about the use of Endophenotypes in psychiatric genetics
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 2014Co-Authors: David C. Glahn, Irving I Gottesman, Emma Knowles, John Blangero, D. Reese Mckay, Emma Sprooten, Henriette Raventós, Laura AlmasyAbstract:Endophenotypes are measurable biomarkers that are correlated with an illness, at least in part, because of shared underlying genetic influences. Endophenotypes may improve our power to detect genes influencing risk of illness by being genetically simpler, closer to the level of gene action, and with larger genetic effect sizes or by providing added statistical power through their ability to quantitatively rank people within diagnostic categories. Furthermore, they also provide insight into the mechanisms underlying illness and will be valuable in developing biologically-based nosologies, through efforts such as RDoC, that seek to explain both the heterogeneity within current diagnostic categories and the overlapping clinical features between them. While neuroimaging, electrophysiological, and cognitive measures are currently most used in psychiatric genetic studies, researchers currently are attempting to identify candidate Endophenotypes that are less genetically complex and potentially closer to the level of gene action, such as transcriptomic and proteomic phenotypes. Sifting through tens of thousands of such measures requires automated, high-throughput ways of assessing and ranking potential Endophenotypes, such as the Endophenotype Ranking Value. However, despite the potential utility of Endophenotypes for gene characterization and discovery, there is considerable resistance to endophenotypic approaches in psychiatry. In this review, we address and clarify some of the common issues associated with the usage of Endophenotypes in the psychiatric genetics community.
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Why Endophenotype development requires families
Chinese Science Bulletin, 2011Co-Authors: David C. Glahn, John BlangeroAbstract:Endophenotypes are heritable quantitative traits that are associated with disease liability, can be measured in both affected and unaffected individuals, and provide much greater power to localize and identify risk genes for mental illness than does affection status alone. Traditionally, endophenotypic markers for psychiatric illnesses include in vivo neuroanatomic and functional magnetic resonance imaging measurements and indices of neurocognitive abilities. However, neurocognitive and neuroimaging measures are by no means the only classes of Endophenotypes that could be useful for identifying genes for mental illness. Given the advantages of Endophenotype-based strategies for elucidating the genetic underpinnings of psychiatric disorders, it would seem prudent to develop a wide range of putative Endophenotypes. In order for a measure to be considered a valid Endophenotype, it must meet a number of criteria. Specifically, the trait must (1) have moderate to high heritability, (2) be associated with the illness, (3) be independent of clinical state, and (4) impairment must co-segregate with the illness within a family, with non-affected family members showing impairment relative to the general population. While each of these criteria is critical, the heritability and co-segregation requirements are really what differentiate an Endophenotype from a simple biomarker. At this time, one requires an experimental design that includes families to demonstrate both heritability and co-segregation. The assertion that novel Endophenotypes can not be fully established without family data does not preclude work in unrelated individuals, rather that unrelated samples will only be able to nominate potential candidate Endophenotypes that subsequently need to be confirmed in family-based experiments.
David L Braff - One of the best experts on this subject based on the ideXlab platform.
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Endophenotypes, Epigenetics, Polygenicity and More: Irv Gottesman's Dynamic Legacy.
Schizophrenia bulletin, 2016Co-Authors: David L Braff, Carol A. TammingaAbstract:First, we describe the hallmark contributions of Irv Gottesman's pioneering scholarship for schizophrenia research including concepts of polygenicity, gene × environment interactions, epigenetics and the Endophenotype concept. Gottesman and colleagues' twin studies showed that genes, not social factors, mediate schizophrenia risk. He then showed that schizophrenia is highly polygenic. Next, he introduced the concept of epigenetics into schizophrenia research. Gottesman then introduced the quantitative Endophenotype concept. Endophenotypes are laboratory-based measures that show deficits in schizophrenia patients and lesser deficits in their first degree "unaffected" relatives and are viewed as being more proximal to genes and having a simpler genetic architecture than are "fuzzy" qualitative diagnostic disorders. Endophenotypes offer an exciting path to gene discovery, neural circuits, genetic architecture and new treatment pathways of schizophrenia and related psychotic disorders. Second, we were asked to discuss 2 of many Endophenotype Consortia and related studies, in order to illustrate the impact of Gottesman's work. We describe the Consortium on the Genetics of Schizophrenia (COGS) exploring neurocognitive and neurophysiological Endophenotypes in family and case-control studies. Association, linkage, sequencing and epigenetic studies are described. The Bipolar and Schizophrenia Network for Intermediate Phenotypes (BSNIP) uses an array of Endophenotypes including brain imaging in studies across the psychosis dimension, allowing for dimensional analyses. BSNIP results have led to the concept of biotypes, advancing the field. Irv Gottesman was imaginatively prescient in generating novel insights and predicting many major issues which challenge schizophrenia researchers who still use his concepts to guide current research approaches.
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Genomic substrates of neurophysiological Endophenotypes: Where we've been and where we're going
Psychophysiology, 2014Co-Authors: David L BraffAbstract:This special issue of Psychophysiology is focused on an imaginative and labor-intensive examination of the genomic substrates of heritable neurophysiological Endophenotypes in the Minnesota Center for Twin and Family Research (MCTFR) cohorts. The authors artfully combine the power of family-based behavioral data with the atheoretical genome-wide association study (GWAS) platform to enrich the examination of the genomic substrates of Endophenotypes. Neurophysiological Endophenotype deficits are found in psychiatric patients and are heritable in families of these psychiatric patients, allowing the investigators to combine the explanatory power of Endophenotypes, with their known neural and functional substrates, with the otherwise agnostic identification of genes in the GWAS platform. This amplifies the power of the MCTFR Endophenotype database. These well-considered studies add significantly to our understanding of normal human neurobiology and stimulate the use of these Endophenotypes to expand our knowledge of the role of these measures and their genomic substrates in normal and psychopathology research.
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Paternal age of schizophrenia probands and endophenotypic differences from unaffected siblings
Psychiatry Research-neuroimaging, 2014Co-Authors: James Schmeidler, Rui P. Ferreira, Kristin S Cadenhead, David L Braff, Monica E. Calkins, Laura C Lazzeroni, Robert Freedman, Neal R Swerdlow, Michael F. Green, Tiffany A GreenwoodAbstract:We evaluated the discrepancy of endophenotypic performance between probands with schizophrenia and unaffected siblings by paternal age at proband birth, a possible marker for de novo mutations. Pairs of schizophrenia probands and unaffected siblings (N=220 pairs) were evaluated on 11 neuropsychological or neurophysiological Endophenotypes previously identified as heritable. For each Endophenotype, the sibling-minus-proband differences were transformed to standardized scores. Then for each pair, the average discrepancy was calculated from its standardized scores. We tested the hypothesis that the discrepancy is associated with paternal age, controlling for the number of Endophenotypes shared between proband and his or her sibling, and proband age, which were both associated with paternal age. The non-significant association between the discrepancy and paternal age was in the opposite direction from the hypothesis. Of the 11 Endophenotypes only sensori-motor dexterity was significant, but in the opposite direction. Eight other Endophenotypes were also in the opposite direction, but not significant. The results did not support the hypothesized association of increased differences between sibling/proband pairs with greater paternal age. A possible explanation is that the identification of heritable Endophenotypes was based on samples for which schizophrenia was attributable to inherited rather than de novo/non-inherited causes.
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is there an association between advanced paternal age and Endophenotype deficit levels in schizophrenia
PLOS ONE, 2014Co-Authors: Debby W Tsuang, Dorcas J Dobie, Kristin S Cadenhead, David L Braff, Tiffany A Greenwood, Monica E. Calkins, Robert Freedman, Michael F. Green, Michelle Esterberg, Raquel E. GurAbstract:The children of older fathers have increased risks of developing schizophrenia spectrum disorders, and among those who develop these disorders, those with older fathers present with more severe clinical symptoms. However, the influence of advanced paternal age on other important domains related to schizophrenia, such as quantitative Endophenotype deficit levels, remains unknown. This study investigated the associations between paternal age and level of endophenotypic impairment in a well-characterized family-based sample from the Consortium on the Genetics of Schizophrenia (COGS). All families included at least one affected subject and one unaffected sibling. Subjects met criteria for schizophrenia (probands; n=293) or were unaffected first-degree siblings of those probands (n=382). Paternal age at the time of subjects’ birth was documented. Subjects completed a comprehensive clinical assessment and a battery of tests that measured 16 Endophenotypes. After controlling for covariates, potential paternal age–Endophenotype associations were analyzed using one model that included probands alone and a second model that included both probands and unaffected siblings. Endophenotype deficits in the Identical Pairs version of the 4-digit Continuous Performance Test and in the Penn Computerized Neurocognitive Battery verbal memory test showed significant associations with paternal age. However, after correcting for multiple comparisons, no Endophenotype was significantly associated with paternal age. These findings suggest that factors other than advanced paternal age at birth may account for endophenotypic deficit levels in schizophrenia.
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group and site differences on the california verbal learning test in persons with schizophrenia and their first degree relatives findings from the consortium on the genetics of schizophrenia cogs
Schizophrenia Research, 2011Co-Authors: William S. Stone, Anthony J Giuliano, Dorcas J Dobie, Kristin S Cadenhead, David L Braff, Monica E. Calkins, Stephen V Faraone, Ming T Tsuang, Robert FreedmanAbstract:Abstract Genetic studies of schizophrenia focus increasingly on putative Endophenotypes because their genetic etiology may be simpler than clinical diagnosis. The Consortium on the Genetics of Schizophrenia (COGS), a multisite family study, aims to identify the genetic basis of several Endophenotypes including verbal declarative memory (VDM), a neurocognitive function that shows robust impairment in schizophrenia. We present data on one type of measure of VDM, the California Verbal Learning Test, Second Edition (CVLT-II), in schizophrenia probands (n = 305), their full biological siblings (n = 449) and parents (n = 232), and in community comparison subjects (CCS; n = 509) across seven sites. Probands performed more poorly on each of five CVLT-II measures compared to related sibling and parent groups and CCS. Siblings and parents performed significantly worse than CCS on one measure (Discriminability), but with smaller effect sizes and less impairment than observed previously. The results raise questions about the homogeneity of VDM as an Endophenotype, about methodological issues related to sampling, and about psychometric issues that impact the utility of the CVLT for detecting VDM deficits in nonpsychotic relatives of persons with schizophrenia.
Nina S Mccarthy - One of the best experts on this subject based on the ideXlab platform.
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assessment of cognition and personality as potential Endophenotypes in the western australian family study of schizophrenia
Schizophrenia Bulletin, 2018Co-Authors: Nina S Mccarthy, Johanna C Badcock, Melanie Clark, Emma Knowles, Gemma Cadby, Phillip E Melton, Vera A Morgan, John BlangeroAbstract:: Phenotypic heterogeneity is a major barrier to understanding the genetic architecture underlying schizophrenia. Incorporating Endophenotypes is one way to reduce heterogeneity and facilitate more powerful genetic analysis. Candidate Endophenotypes require systematic assessment against Endophenotype criteria, and a ranking of their potential utility for genetic analysis. In this study we assess 20 cognitive and personality measures in a sample of 127 families with at least 2 cases of schizophrenia per family (n = 535) plus a set of 30 control families (n = 121) against 4 Endophenotype criteria: (a) be associated with the illness but not be a part of its diagnosis, (b) be heritable, (c) co-segregate with the illness in families, and (d) be found in unaffected relatives at a higher rate than in the general population. The Endophenotype ranking score (Endophenotype ranking variable [ERV]) was used to rank candidate Endophenotypes based on their heritability and genetic correlation with schizophrenia. Finally, we used factor analysis to explore latent factors underlying the cognitive and personality measures. Evidence for personality measures as Endophenotypes was at least equivalent to that of the cognitive measures. Factor analysis indicated that personality and cognitive traits contribute to independent latent dimensions. The results suggest for this first time that a number of cognitive and personality measures are independent and informative Endophenotypes. Use of these Endophenotypes in genetic studies will likely improve power and facilitate novel aetiological insights.