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Generalized Psychophysiological Interaction (PPI) Analysis of Memory Related Connectivity in Individuals at Genetic Risk for Alzheimer's Disease
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Common and rare genetic variant associations with cognitive performance across development in British birth cohorts

Daniel S Malawsky1, Mahmoud Koko2, Petr Danacek2

  • 1Human Genetics Programme, Wellcome Sanger Institute, Hinxton, UK. dm22@sanger.ac.uk.

Nature Human Behaviour
|July 10, 2026
PubMed

Insights

Genetic influences on cognitive ability change throughout childhood. Polygenic scores for educational attainment strengthen, while rare variant effects diminish, impacting neurodevelopmental condition understanding.

Area of Science:

  • Genetics
  • Neuroscience
  • Developmental Biology

Background:

  • Genetic variants linked to adult cognition also associate with childhood neurodevelopmental disorders.
  • The developmental trajectory of genetic associations with cognition from childhood to adulthood is not well understood.

Purpose of the Study:

  • To investigate how genetic associations with cognitive ability change during childhood.
  • To explore the roles of polygenic scores and rare variant burden in cognitive development.

Main Methods:

  • Utilized data from 6,495 children in the Avon Longitudinal Study of Parents and Children.
  • Employed polygenic indices for educational attainment (PGI_EA) and cognitive performance (PGI_Cog).
  • Analyzed rare variant burden (RVB_pLoF) and conducted trio analyses to assess genetic effects.

Main Results:

  • The association between cognitive ability and polygenic indices (PGI_EA, PGI_Cog) increases with age.
  • Negative associations between cognitive ability and rare variant burden (RVB_pLoF) attenuate with age.
  • Age-related trends are supported by direct genetic effects, with stronger effects at opposite ends of the cognitive spectrum.

Conclusions:

  • Genetic influences on cognition evolve during development, with polygenic effects becoming more prominent and rare variant effects diminishing.
  • These findings offer insights into the variable penetrance of rare variants in neurodevelopmental conditions.
  • Understanding these developmental genetic patterns is crucial for comprehending cognitive trajectories and associated disorders.

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