BRAIN IRON AND RISK OF DEMENTIA AND PARKINSON'S DISEASE: A GENETIC ANALYSIS IN THE UK BIOBANK COHORT

Francesco CASANOVA¹, Luke PILLING¹, Qu TIAN², Daniel WILLIAMSON³, Yong QIAN², David ZWEIBAUM², Jun DING², Janice ATKINS¹, David MELTZER¹, Luigi FERRUCCI²

¹Department of Clinical and Biomedical Sciences, University of Exeter, Exeter, United Kingdom
²Translational Gerontology Branch Longitudinal Studies Section, National Institute on Aging, Baltimore, United States
³Department of Medical Imaging, University of Exeter, Exeter, United Kingdom

Introduction

Iron overload is observed in neurodegenerative diseases, especially Alzheimer’s disease (AD) and Parkinson’s disease (PD). Whether brain iron deposition is causal or secondary to the neurodegenerative processes is unclear.

Methods

We analysed UK Biobank participants of European genetic ancestry (N=451,231), including 39,533 with brain MRI data. We performed genome-wide association studies (GWAS) on brain iron estimated by R2* and quantitative susceptibility mapping (QSM) in subcortical regions of accumbens, amygdala, caudate, hippocampus, pallidum, putamen, substantia nigra and thalamus. We used Mendelian randomisation to examine the causal effect of brain iron on AD, non-AD, PD and grey matter volumes as well as exploring if genetic liability to AD and PD was associated with increased R2* and QSM.

Results

In GWAS, we replicated 83% of previously reported genetic loci for R2* and QSM and identified additional 174 loci for R2* or QSM across all brain regions.

Genetically predicted higher R2* and QSM in putamen and thalamus were associated with increased risk of non-AD dementia (Odds Ratio(OR)-QSM~putamen 1.15(1.05;1.25), p=0.001) and lower corresponding grey matter volumes but was not associated with AD risk (p>0.05). Genetic liability to AD was associated with QSM in the amygdala only.

Genetically predicted higher iron in the caudate, putamen, and substantia nigra were associated with an increased risk of PD (OR-QSM~substantia-nigra 1.21(1.07;1.37), p=0.003). Genetic liability to PD was not associated with R2* or QSM.

Conclusion

We found genetic evidence of a likely causal effect of higher iron deposition in specific subcortical brain regions for non-Alzheimer’s dementia and Parkinson’s disease.