Genetic landscape of adult executive function reveals a cell-type-specific developmental origin, 2026, Rahman et al

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Genetic landscape of adult executive function reveals a cell-type-specific developmental origin

Spoiler: Authors

Rahman, Md Shafiqur; Frkatović-Hodžić, Azra; van den Ameele, Jelle; Hill, Steven M.; Kingston, Nathalie; Bradley, John R.; Tom, Brian D. M.; Chinnery, Patrick F.

Abstract
Executive function is an essential cognitive domain for typical human behavior which is disrupted in neurodevelopmental and neurodegenerative disorders, but little is known about its underlying molecular basis. To address this, we perform genome-wide association studies (GWAS) using three different measures of executive function in UK Biobank ( N = 84,238) and NIHR BioResource’s Genes and Cognition ( N = 9932) study participants, followed by a meta-analysis.

The trail-making alphanumeric (TMA) measure is the most heritable phenotype (h²=7-26%), associated with 18 independent loci that exhibit a similar direction of effect in both cohorts. Across these loci, in-silico follow-up implicates 178 genes, of which NT5DC2 and RP11-579E24.2 are independently replicated prior to meta-analysis. TMA is linked to pan-cerebral differences in brain structure, with brain-enriched genes showing a biphasic expression profile from early development through to later life.

Our data implicate specific cell types, histone modifications and butyrophilin immunoglobulin family proteins as potential targets for promoting cognitive resilience.

Web | DOI | PMC | PDF | Nature Communications

 

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Not really sure what to make of this and was unsure about posting but its from a decent institution and has some interesting comments on the neurological/cognitive role of butyrophillins which we see crop up. Maybe could have gone in misc research or a catch all thread?

 

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This was the relevant paragraphs from their STRING network analysis

The second cluster of associated genes-BTN3A2, BTN3A3 and BTN2A1-belongs to ‘Butyrophilin (BTN) family interaction’ pathway (Supplementary Fig 4), which has previously been linked to general intelligence46, and forms a PPI network (p = 7.93 × 10−05, Fig. 5d (iv)).

Butyrophilins (BTNs) are type 1 membrane proteins belonging to the immunoglobulin (Ig) superfamily and found to reduce the expression of cytokines such as IL-2/6 and IFN-γ47,48. In an earlier study, we identified IFN-γ induced microglial involvement in the regulation of general cognitive ability.

Taken together, a role of BTN family genes in upstream process of the regulation of microglia induced inflammation is possible, paving the way of using anti-BTN antibodies as a therapeutic approach to influence executive function.

So it seems based upon a mix of that network analysis and a previous study (see below)

 

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Dynamics of cognitive variability with age and its genetic underpinning in NIHR BioResource Genes and Cognition cohort participants, 2024, Rahman et al

Spoiler: Authors

Rahman, Md Shafiqur; Harrison, Emma; Biggs, Heather; Seikus, Chloe; Elliott, Paul; Breen, Gerome; Kingston, Nathalie; Bradley, John R.; Hill, Steven M.; Tom, Brian D. M.; Chinnery, Patrick F.

Abstract
A leading explanation for translational failure in neurodegenerative disease is that new drugs are evaluated late in the disease course when clinical features have become irreversible.

Here, to address this gap, we cognitively profiled 21,051 people aged 17–85 years as part of the Genes and Cognition cohort within the National Institute for Health and Care Research BioResource across England. We describe the cohort, present cognitive trajectories and show the potential utility.

Surprisingly, when studied at scale, the APOE genotype had negligible impact on cognitive performance. Different cognitive domains had distinct genetic architectures, with one indicating brain region-specific activation of microglia and another with glycogen metabolism. Thus, the molecular and cellular mechanisms underpinning cognition are distinct from dementia risk loci, presenting different targets to slow down age-related cognitive decline.

Participants can now be recalled stratified by genotype and cognitive phenotype for natural history and interventional studies of neurodegenerative and other disorders.

Web | DOI | PMC | PDF | Nature Medicine