Adjudicating neurocognitive endophenotypes for schizophrenia

Glahn, David C.; Almasy, Laura; Blangero, John; Burk, Gary M.; Estrada, José Guadalupe Salazar; Peralta, Juan M.; Meyenberg, Naxhielli; Castro, Mariana Pereira; Barrett, Jennifer; Nicolini, Humberto; Raventós, Henriette; Escamilla, Michael

doi:10.1002/ajmg.b.30446

Cited by 96 publications

(104 citation statements)

References 48 publications

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“…Each participant completed a 90-min neuropsychological test battery consisting of standard and computerized measures (23,44). Twenty-two neurocognitive variables were derived from 16 separate neuropsychological tests, including measures of attention, executive processing, working memory, declarative memory, language processing, intelligence, and emotional processing (Table S3).…”

Section: Methodsmentioning

confidence: 99%

Genetic basis of neurocognitive decline and reduced white-matter integrity in normal human brain aging

Glahn

Kent

Sprooten

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Identification of genes associated with brain aging should markedly improve our understanding of the biological processes that govern normal age-related decline. However, challenges to identifying genes that facilitate successful brain aging are considerable, including a lack of established phenotypes and difficulties in modeling the effects of aging per se, rather than genes that influence the underlying trait. In a large cohort of randomly selected pedigrees (n = 1,129 subjects), we documented profound aging effects from young adulthood to old age (18-83 y) on neurocognitive ability and diffusion-based white-matter measures. Despite significant phenotypic correlation between white-matter integrity and tests of processing speed, working memory, declarative memory, and intelligence, no evidence for pleiotropy between these classes of phenotypes was observed. Applying an advanced quantitative gene-by-environment interaction analysis where age is treated as an environmental factor, we demonstrate a heritable basis for neurocognitive deterioration as a function of age. Furthermore, by decomposing gene-by-aging (G × A) interactions, we infer that different genes influence some neurocognitive traits as a function of age, whereas other neurocognitive traits are influenced by the same genes, but to differential levels, from young adulthood to old age. In contrast, increasing white-matter incoherence with age appears to be nongenetic. These results clearly demonstrate that traits sensitive to the genetic influences on brain aging can be identified, a critical first step in delineating the biological mechanisms of successful aging.neurocognition | diffusion tensor imaging | fractional anisotropy | genetic correlation | gene x environment interaction P opulation projections suggest for the first time in human history there will be more individuals over the age of 65 than below the age of 14 by 2050 (1). This milestone reflects the dramatic increase of the average lifespan of people worldwide, rather than a reduction in the total number of children being born. Indeed, 25% of the US population is expected to be over the age of 60 midway through this century (1). The implications of our aging population are substantial, because aging is associated with decreased mental and physical ability coupled with increased health care utilization. Thus, there is considerable interest in delineating the biological mechanisms that influence age-related changes to facilitate successful aging (2), defined as avoidance of disease or disability, maintaining good physical and cognitive function, and engagement in social and productive activities. Because the brain appears to play a pivotal role in aging biology (3), one promising strategy is to define measures of brain structure and function that index concomitant aging outcomes (4). The observation that many measures of brain aging are heritable and can be localized to specific genomic regions (6) indicates that genetic factors play a crucial role in the brain's ability to either prosper or ...

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Section: Methodsmentioning

confidence: 99%

Genetic basis of neurocognitive decline and reduced white-matter integrity in normal human brain aging

Glahn

Kent

Sprooten

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Traditionally, endophenotypic markers for psychiatric illnesses include in vivo neuroanatomic and functional magnetic resonance imaging (MRI) measurements and indices of neurocognitive abilities [7][8][9]. MRI-based measures of brain structure and function are highly heritable, as we have demonstrated in large extended pedigrees [10,11].…”

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confidence: 95%

Why endophenotype development requires families

Glahn

Blangero

2011

Chin. Sci. Bull.

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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.endophenotype, family studies, biomarker, schizophrenia, bipolar disorder

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“…The COGS (Consortium on the Genetics of Schizophrenia) and Glahn et al's endophenotype project [20] focus on examining candidate endophenotypes based on Gottesman's criteria but not clinical outcome. Our research-based clinical programme has the advantage of linking neurocognitive endophenotypes to clinical outcome measures and to examine their relationship.…”

Section: Discussionmentioning

confidence: 99%

A family study of endophenotypes for psychosis within an early intervention programme in Hong Kong: Rationale and preliminary findings

et al. 2011

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The study of endophenotypes may be a viable strategy to tackle the genetic complexity and phenotypic heterogeneity of psychosis, but this research direction is relatively under-developed in China as compared to Western countries. We have recently initiated one of the first family studies of endophenotypes for psychosis in China. Patients entering an established early psychosis intervention service are recruited into this research project for phenotyping, endophenotyping and genotyping. At the endophenotypic level, four domains (neurological soft signs, neurocognition of prospective memory, social cognition of facial emotion recognition, and affective cognition of anticipatory and consummatory pleasure) are studied in the sample of patients with psychosis and their unaffected siblings. This article illustrates the benefit of a research-oriented clinical programme and its findings based on the data collected as of early 2011.

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Adjudicating neurocognitive endophenotypes for schizophrenia

Cited by 96 publications

References 48 publications

Genetic basis of neurocognitive decline and reduced white-matter integrity in normal human brain aging

Genetic basis of neurocognitive decline and reduced white-matter integrity in normal human brain aging

Why endophenotype development requires families

A family study of endophenotypes for psychosis within an early intervention programme in Hong Kong: Rationale and preliminary findings

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