Polygenic architecture of a novel MRI endophenotype: the “hemochromatosis brain”

Iron is an important element required for the body to function properly; however, hemochromatosis, an excess of iron in healthy tissue, can lead to cell damage. C282Y is a genetic variant prevalent in European populations, which is known to increase iron levels in the body and is responsible for most hemochromatosis cases. Recent work from our group analyzing brain Magnetic Resonance (MR) images established, in a large sample of older adults, that individuals who were homozygous for C282Y showed evidence consistent with substantial iron deposition localized to brain regions related to the motor system. These individuals also had nearly two-fold increased risk for developing movement disorders, like Parkinson’s Disease (PD). Here, we describe the broader polygenic architecture of this novel endophenotype - the “hemochromatosis brain.” This multivariate MRI phenotype captures average brain-wide differences of C282Y homozygote individuals and may reflect consequences of iron deposition localized to motor circuits. To do this we trained a classifier in a sample of 960 individuals from the UKBiobank to distinguish C282Y homozygotes from other genotypes using phenotypes derived from MR images sensitive to iron. This classifier was then applied to an independent set of 35,283 individuals for which MRI were available in the UKBiobank. This generated, for each individual, a PolyVoxel Score (PVS) that captures variation in MRI phenotypes associated previously with C282Y homozygosity and may reflect the degree of brain-specific iron deposition or other disease mechanisms. In this independent set we showed the PVS significantly predicted risk for PD (OR=1.37, p=0.0089). Studying the genetics of the “hemochromatosis brain” we conducted a GWAS on the PVS to show it to be highly heritable ![Graphic][1] with 43 genome-wide significant loci. Many of these signals are proximal to genes known to be involved in iron homeostasis (TF, rs6794370, p=2.43×10−81; HFE rs1800562, p=6.93×10−75; TMPRSS6, rs2413450, p=2.52×10−50). Discovered genomic variants overlapped with previous GWAS studies of iron/red blood cells, non-iron blood markers and brain and cognitive traits. Cell type enrichment implicated glial cells to be the principal cell class related to the PVS GWAS signal, in line with previous work finding that these cells to have the highest iron concentrations in the brain. Finally, tissue-specific analysis identified the substantia nigra and hippocampus to have enriched epigenetic markers to our GWAS findings. We have made available a python program to generate the PVS from MRI scans. In conclusion, we have shown that the multivariate MRI phenotype associated with C282Y homozygosity is, in fact, highly heritable, polygenic, and represents a novel brain endophenotype of PD. Our unique approach of combining classical forward and reverse genetics approaches to define and describe potentially disease mediating endophenotypes could be applied more broadly to other clinically relevant disorders. ### Competing Interest Statement Dr. Andreassen has received speaker's honorarium from Lundbeck, and is a consultant to HealthLytix. Dr. Dale is a Founder of and holds equity in CorTechs Labs, Inc, and serves on its Scientific Advisory Board. He is a member of the Scientific Advisory Board of Human Longevity, Inc. and receives funding through research agreements with General Electric Healthcare and Medtronic, Inc. The terms of these arrangements have been reviewed and approved by UCSD in accordance with its conflict of interest policies. The other authors declare no competing interests. ### Funding Statement This work was supported by grants R01MH122688 and RF1MH120025 funded by the National Institute for Mental Health (NIMH) in addition to Lundbeck Foundation fellowship (R335-2019-2318). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study used ONLY openly available human data that were originally located at: https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes UK Biobank data was accessed under accession number 27412. Summary statistics from GWAS of ‘Hemochromatosis Brain’ PVS are available as a supplementary file. Researchers are able to apply for access to UK Biobank data at https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access. [1]: /embed/inline-graphic-1.gif