General dimensions of human brain morphometry inferred from genome-wide association data

Anna E. Fürtjes*, Ryan Arathimos, Jonathan R.I. Coleman, James H. Cole, Simon R. Cox, Ian J. Deary, Javier de la Fuente, James W. Madole, Elliot M. Tucker-Drob, Stuart J. Ritchie

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)


Understanding the neurodegenerative mechanisms underlying cognitive decline in the general population may facilitate early detection of adverse health outcomes in late life. This study investigates genetic links between brain morphometry, ageing and cognitive ability. We develop Genomic Principal Components Analysis (Genomic PCA) to model general dimensions of brain-wide morphometry at the level of their underlying genetic architecture. Genomic PCA is applied to genome-wide association data for 83 brain-wide volumes (36,778 UK Biobank participants) and we extract genomic principal components (PCs) to capture global dimensions of genetic covariance across brain regions (unlike ancestral PCs that index genetic similarity between participants). Using linkage disequilibrium score regression, we estimate genetic overlap between those general brain dimensions and cognitive ageing. The first genetic PCs underlying the morphometric organisation of 83 brain-wide regions accounted for substantial genetic variance (R2 = 40%) with the pattern of component loadings corresponding closely to those obtained from phenotypic analyses. Genetically more central regions to overall brain structure - specifically frontal and parietal volumes thought to be part of the central executive network - tended to be somewhat more susceptible towards age (r = −0.27). We demonstrate the moderate genetic overlap between the first PC underlying each of several structural brain networks and general cognitive ability (rg = 0.17–0.21), which was not specific to a particular subset of the canonical networks examined. We provide a multivariate framework integrating covariance across multiple brain regions and the genome, revealing moderate shared genetic etiology between brain-wide morphometry and cognitive ageing.

Original languageEnglish
JournalHuman Brain Mapping
Early online date29 Mar 2023
Publication statusPublished - 1 Jun 2023


  • brain age
  • cognitive ability
  • complex traits
  • genetics
  • statistical modelling
  • structural brain networks
  • structural neuroimageing


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