The effects of genetic and modifiable risk factors on brain regions vulnerable to ageing and disease

Jordi Manuello, Joosung Min, Paul McCarthy, Fidel Alfaro-Almagro, Soojin Lee, Stephen Smith, Lloyd T. Elliott, Anderson M. Winkler and Gwenaëlle Douaud ()
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Jordi Manuello: University of Oxford
Joosung Min: Simon Fraser University
Paul McCarthy: University of Oxford
Fidel Alfaro-Almagro: University of Oxford
Soojin Lee: University of Oxford
Lloyd T. Elliott: Simon Fraser University
Anderson M. Winkler: National Institutes of Health
Gwenaëlle Douaud: University of Oxford

Nature Communications, 2024, vol. 15, issue 1, 1-11

Abstract: Abstract We have previously identified a network of higher-order brain regions particularly vulnerable to the ageing process, schizophrenia and Alzheimer’s disease. However, it remains unknown what the genetic influences on this fragile brain network are, and whether it can be altered by the most common modifiable risk factors for dementia. Here, in ~40,000 UK Biobank participants, we first show significant genome-wide associations between this brain network and seven genetic clusters implicated in cardiovascular deaths, schizophrenia, Alzheimer’s and Parkinson’s disease, and with the two antigens of the XG blood group located in the pseudoautosomal region of the sex chromosomes. We further reveal that the most deleterious modifiable risk factors for this vulnerable brain network are diabetes, nitrogen dioxide – a proxy for traffic-related air pollution – and alcohol intake frequency. The extent of these associations was uncovered by examining these modifiable risk factors in a single model to assess the unique contribution of each on the vulnerable brain network, above and beyond the dominating effects of age and sex. These results provide a comprehensive picture of the role played by genetic and modifiable risk factors on these fragile parts of the brain.

Date: 2024
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DOI: 10.1038/s41467-024-46344-2

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