Nomograms of human hippocampal volume shifted by polygenic scores

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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

The following previously published data sets were used

1. Adams HH
2. et al
(2016) Novel genetic loci underlying human intracranial volume identified through genome-wide association.
EMBL-EBI, GCST003834.

https://www.ebi.ac.uk/gwas/studies/GCST003834
1. Lambert JC
2. et al
(2013) Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease
EMBL-EBI, GCST002245.

https://www.ebi.ac.uk/gwas/studies/GCST002245
1. Hibar DP
2. et al
(2017) Novel genetic loci associated with hippocampal volume
EMBL-EBI, GCST003961.

https://www.ebi.ac.uk/gwas/studies/GCST003961

Article and author information

Author details

Mohammed Janahi

Department of Medical Physics and Biomedical Engineering, University College London, London, United Kingdom

For correspondence
Rmapmja@ucl.ac.uk

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-7442-2298
Leon Aksman

Stevens Neuroimaging and Informatics Institute, University of Southern California, Los Angeles, United States

Competing interests
The authors declare that no competing interests exist.
Jonathan M Schott

Dementia Research Centre, University College London, London, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Younes Mokrab

Human Genetics Department, Sidra Medicine, Doha, Qatar

Competing interests
The authors declare that no competing interests exist.
Andre Altmann

Department of Medical Physics and Biomedical Engineering, University College London, London, United Kingdom

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-9265-2393

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

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.