Nomograms of human hippocampal volume shifted by polygenic scores
- University College London, United Kingdom
- University of Southern California, United States
- Sidra Medicine, Qatar
Abstract
Nomograms are important clinical tools applied widely in both developing and aging populations. They are generally constructed as normative models identifying cases as outliers to a distribution of healthy controls. Currently used normative models do not account for genetic heterogeneity. Hippocampal Volume (HV) is a key endophenotype for many brain disorders. Here, we examine the impact of genetic adjustment on HV nomograms and the translational ability to detect dementia patients. Using imaging data from 35,686 healthy subjects aged 44 to 82 from the UK BioBank (UKB), we built HV nomograms using gaussian process regression (GPR), which - compared to a previous method - extended the application age by 20 years, including dementia critical age ranges. Using HV Polygenic Scores (HV-PGS), we built genetically adjusted nomograms from participants stratified into the top and bottom 30% of HV-PGS. This shifted the nomograms in the expected directions by ~100 mm3 (2.3% of the average HV), which equates to 3 years of normal aging for a person aged ~65. Clinical impact of genetically adjusted nomograms was investigated by comparing 818 subjects from the AD neuroimaging (ADNI) database diagnosed as either cognitively normal (CN), having mild cognitive impairment (MCI) or Alzheimer’s disease patients (AD). While no significant change in the survival analysis was found for MCI-to-AD conversion, an average of 68% relative decrease was found in intra-diagnostic-group variance, highlighting the importance of genetic adjustment in untangling phenotypic heterogeneity.
Data availability
The scripts and code used in this study have been made publicly available and can be found at: https://github.com/Mo-Janahi/NOMOGRAMS
Article and author information
Author details
Funding
Medical Research Council (MR/L016311/1)
- Andre Altmann
National Institute of Biomedical Imaging and Bioengineering (P41EB015922)
- Leon Aksman
National Institute on Aging (P30AG066530)
- Leon Aksman
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2022, Janahi et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Nomograms of human hippocampal volume shifted by polygenic scores
eLife 11:e78232.
https://doi.org/10.7554/eLife.78232
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