Genome-Wide Association Study of Over 427,000 Individuals Establishes Executive Functioning as a Neurocognitive Basis of Psychiatric Disorders Influenced by GABAergic Processes

As, Hatoum; Cl, Morrison; Ec, Mitchell; M, Lam; Ce, Benca-Bachman; Ae, Reineberg; Palmer, Rohan; Lm, Evans; Mc, Keller; Friedman, Naomi P.

doi:10.1101/674515

Cited by 31 publications

(43 citation statements)

References 43 publications

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“…The four factors were also differentially associated with external criterion variables, suggesting that the factors represent meaningfully distinct dimensions of psychopathology. Further, the direction and magnitude of these correlations is consistent with previous phenotypic (45,46) and genetic studies (32,(47)(48)(49) of the nomological network of higher-order dimensions of psychopathology. Finally, the NDD factor was moderately to highly genetically correlated with the Externalizing and Internalizing factors, suggesting that the genes that predispose to Neurodevelopmental Disorders in early childhood also predispose to Externalizing and Internalizing disorders later in childhood and in adolescence.…”

Section: Discussionsupporting

confidence: 88%

Testing structural models of psychopathology at the genomic level

Waldman

Poore

Luningham

et al. 2018

Preprint

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Genome-wide association studies (GWAS) have revealed hundreds of genetic loci that underlie major psychiatric disorders, and post-GWAS analyses have discovered substantial genetic correlations among these disorders. This suggests these disorders share a common genetic architecture, implying the presence of a higher-order structure of psychopathology at both the genetic and phenotypic levels. Nonetheless, despite recent efforts at elucidating this structure by collaborative consortia such as HiTOP, the exact structure of psychopathology remains unknown. Herein, in one of the largest genetic studies of psychopathology conducted to date, we tested multiple alternative structural models of psychopathology at the genomic level using the genetic correlations among fourteen psychiatric disorders and related psychological traits estimated from GWAS summary statistics. The best-fitting model includes four correlated higher-order factors -Externalizing, Internalizing, Thought Problems, and Neurodevelopmental Disorders. These higher-order factors were validated by examining their correlations with external criterion variables, which showed distinct patterns of genetic correlations with the 4 higher-order factors. Several model modifications were tested to explore the placement of a few disorders -such as bipolar disorder, OCD, and eating disorders -within the broader psychopathology structure. These findings show support for several of the HiTOP higher-order dimensions and suggest a similar structure of psychopathology at the genomic and phenotypic levels. Our results imply that such higher-order psychopathology dimensions might be better targets for genetic and genomic investigations than individual disorders, and might be more predictive of relevant outcomes of considerable public health and societal concern.

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Section: Discussionsupporting

confidence: 88%

Testing structural models of psychopathology at the genomic level

Waldman

Poore

Luningham

et al. 2018

Preprint

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“…Improved working memory performance under increased memory load was associated with higher GABA concentration in the dorsolateral PFC. A recent study (pre-print) (47) attributed a key role to GABAergic genetic contributions to the common EF factor (45), using a large sample in a genome-wide association study (GWAS). This study highlighted the role of the excitatory/inhibitory balance in EF, especially the role of GABA-mediated inhibition.…”

Section: Conceptualization Of Executive Functionmentioning

confidence: 99%

“…Further, genetic influences account for about half of the variability in EF performance (45, 168). The neural substrates of GABA and glutamate present a neural link for the EF (common factor) which has a genetic basis but may be measured with cognitive tasks (47). Lastly, there is empirical support that EF difficulties in relatives of probands with ASD are at a higher rate than the general population (181).…”

Section: Executive Function As a Cognitive Intermediate Phenotypementioning

confidence: 99%

Executive Function in Autism Spectrum Disorder: History, Theoretical Models, Empirical Findings, and Potential as an Endophenotype

2019

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This review presents an outline of executive function (EF) and its application to autism spectrum disorder (ASD). The development of the EF construct, theoretical models of EF, and limitations in the study of EF are outlined. The potential of EF as a cognitive endophenotype for ASD is reviewed, and the Research Domain Criteria (RDoC) framework is discussed for researching EF in ASD given the multifaceted factors that influence EF performance. A number of executive-focused cognitive models have been proposed to explain the symptom clusters observed in ASD. Empirical studies suggest a broad impairment in EF, although there is significant inter-individual variability in EF performance. The observed heterogeneity of EF performance is considered a limiting factor in establishing EF as a cognitive endophenotype in ASD. We propose, however, that this variability in EF performance presents an opportunity for subtyping within the spectrum that can contribute to targeted diagnostic and intervention strategies. Enhanced understanding of the neurobiological basis that underpins EF performance, such as the excitation/inhibition hypothesis, will likely be important. Application of the RDoC framework could provide clarity on the nature of EF impairment in ASD with potential for greater understanding of, and improved interventions for, this disorder.

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“…It has been associated with reproductive traits (age at first calving) in Canchim beef cattle using a GWAS approach [35]. Interesting, in humans, intronic polymorphisms and other genetic variations have been associated neurological disorders such as Alzheimer's, dementia, schizophrenia and personality disorders [36].…”

Section: Intronic Temperament-associated Snpsmentioning

confidence: 99%

Novel genes involved in the genetic architecture of temperament in Brahman cattle

et al. 2020

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Cattle temperament is a complex and economically relevant trait. The objective of this study was to identify genomic regions and genes associated with cattle temperament. From a Brahman cattle population of 1,370 animals evaluated for temperament traits (Exit velocity-EV, Pen Score-PS, Temperament Score-TS), two groups of temperament-contrasting animals were identified based on their EV-average values ±1/2 standard deviation (SD). To be considered in the calm group, the EV of females ranged between 0.16-1.82 m/s (n = 50) and the EV of males ranged between 0.4-1.56 m/s (n = 48). Females were classified as temperamental if their EV ranged between 3.13-7.66 m/s (n = 46) and males were classified as temperamental if their EV ranged between 3.05-10.83 m/s (n = 45). Selected animals were genotyped using a total of 139,376 SNPs (GGP-HD-150K), evaluated for their association with EV. The Genome-Wide Association analysis (GWAS) identified fourteen SNPs:

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Genome-Wide Association Study of Over 427,000 Individuals Establishes Executive Functioning as a Neurocognitive Basis of Psychiatric Disorders Influenced by GABAergic Processes

Cited by 31 publications

References 43 publications

Testing structural models of psychopathology at the genomic level

Testing structural models of psychopathology at the genomic level

Executive Function in Autism Spectrum Disorder: History, Theoretical Models, Empirical Findings, and Potential as an Endophenotype

Novel genes involved in the genetic architecture of temperament in Brahman cattle

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