Abstract
Our understanding of brain iron regulation and its disruption in disease is limited. Excess iron affects motor circuitry, contributing to Parkinson's disease (PD) risk. The molecular mechanisms regulating central iron levels, beyond a few well-known genes controlling peripheral iron, remain unclear. We generated scores based on the archetypal brain iron accumulation observed in magnetic resonance imaging scans of individuals with excessive dietary iron absorption and hemochromatosis risk. Genome-wide analysis revealed that this score is highly heritable, identifying loci associated with iron homeostasis, and driven by peripheral iron levels. Our score predicted gait abnormalities and showed a U-shaped relationship with PD risk, identifying individuals with threefold increased risk. These results establish a hormetic relationship between brain iron and PD risk, where central iron levels are strongly determined by genetics via peripheral iron. This framework combining forward and reverse genetics is a powerful study design to understand genomic drivers underlying high dimensional phenotypes.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | eadp4431 |
| Tidsskrift | Science Advances |
| Vol/bind | 10 |
| Udgave nummer | 47 |
| ISSN | 2375-2548 |
| DOI | |
| Status | Udgivet - 2024 |
Bibliografisk note
Funding Information:UK Biobank acknowledgment: UKB's research resource is a major contributor in the advancement of modern medicine and treatment, enabling better understanding of the prevention, diagnosis, and treatment of a wide range of serious and life-threatening illnesses-including cancer, heart diseases, and stroke. UKB is supported by its founding funders the Wellcome Trust and UK Medical Research Council, as well as the Department of Health, Scottish Government, the Northwest Regional Development Agency, British Heart Foundation, and Cancer Research UK. The organization has over 150 dedicated members of staff, based in multiple locations across the UK. ABCD acknowledgment: Data used in the preparation of this article were obtained from the ABCD Study (https://abcdstudy. org), held in the NDA. This is a multisite, longitudinal study designed to recruit more than 10, 000 children age 9 to 10 and follow them over 10 years into early adulthood. The ABCD Study is supported by the National Institutes of Health and additional federal partners under award numbers: U01DA041022, U01DA041028, U01DA041048, U01DA041089, U01DA041106, U01DA041117, U01DA041120, U01DA041134, U01DA041148, U01DA041156, U01DA041174, U24DA041123, and U24DA041147 A full list of supporters is available at https://abcdstudy.org/federal-partners/. A listing of participating sites and a complete listing of the study investigators can be found at https://abcdstudy.org/principal-investigators. html. ABCD Study consortium investigators designed and implemented the study and/or provided data but did not necessarily participate in analysis or writing of this report. This manuscript reflects the views of the authors and may not reflect the opinions or views of the NIH or ABCD Study consortium investigators. The ABCD data repository grows and changes over time. The ABCD data used in this came from [NDA Digital Object Identifier (10.15154/1523041)]. URLs: PLINK (https://cog-genomics. org/plink/2.0/), FUMA (https://fuma.ctglab.nl), LDSC and sLDSC (https://github.com/bulik/ldsc), and annotations for sLDSC tissue-specific analysis (https://alkesgroup. broadinstitute.org/LDSCORE/). Funding: 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). A.D. is supported by the following grants from the National Institutes of Health (NIH): U24DA041123, R01AG076838, U24DA055330, and OT2HL161847. J.R.I. was supported by NIH R01AA028411. Author contributions: Conceptualization: R.L., C.C.F., M.B., J.A., O.A., T.L.J., L.S., W.K.T., A.J.S., and A.D. Methodology: R.L., C.C.F., A.D., O.F., W.K.T., L.S., and A.J.S. Data curation: R.L., D.J.H., T.L.J., O.A., and A.D. Validation: R.L., C.C.F., and A.J.S. Formal analysis: R.L., C.C.F., L.S., O.F., and A.D. Software: R.L., C.C.F., D.J.H., J.R.I., A.D., and O.F. Investigation: T.L.J., A.J.S., and A.D. Visualization: R.L., C.C.F., and L.S. Supervision: C.C.F., T.L.J., L.S., W.K.T., A.D., and A.J.S. Resources: C.C.F., T.L.J., and A.D. Project administration: C.C.F., T.L.J., O.A., and A.D. Funding acquisition: C.C.F., T.L.J., and A.D. Writing- original draft: R.L., C.C.F., J.A., L.S., and A.J.S. Writing-review and editing: R.L., C.C.F., N.Z., J.A., D.J.H., D.M.S., L.S., W.K.T., A.J.S., O.A., and O.F. Competing interests: O.A. has received speaker's honorarium from Lundbeck and is a consultant to HealthLytix. A.D. is Founding Director, holds equity in CorTechs Labs Inc. (DBA Cortechs.ai), and serves on its Board of Directors and the Scientific Advisory Board. He is an unpaid consultant for Oslo University Hospital. The terms of these arrangements have been reviewed and approved by the University of California, San Diego in accordance with its conflict-of-interest policies. The other authors declare that they have no competing interests. Data and materials availability: UKB data were accessed under accession number 27412. Summary statistics from GWAS of Hemochromatosis Brain PVS are available at figshare (https://doi.org/10.6084/m9.figshare.26122102.v1). Researchers can apply for access to UKB data at https://ukbiobank.ac.uk/enable-your-research/apply-for-access. The ABCD data used in this came from [NDA Digital Object Identifier (10.15154/1523041)]. These data are available to approved researchers (find more information at https://abcdstudy.org). All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. We have created a Python command line program to generate PVS's for T2-weighted images registered in Montreal Neurological Institute space using classification weights presented in this analysis-(https://zenodo.org/doi/10.5281/zenodo.12535194) https://github.com/robloughnan/pvs.
Funding Information:
Acknowledgments: UK Biobank acknowledgment: UKB\u2019s research resource is a major contributor in the advancement of modern medicine and treatment, enabling better understanding of the prevention, diagnosis, and treatment of a wide range of serious and life-threatening illnesses\u2014including cancer, heart diseases, and stroke. UKB is supported by its founding funders the Wellcome trust and UK Medical Research council, as well as the department of health, Scottish Government, the Northwest Regional development Agency, British heart Foundation, and cancer Research UK. the organization has over 150 dedicated members of staff, based in multiple locations across the UK. ABcd acknowledgment: data used in the preparation of this article were obtained from the ABcd Study (https://abcdstudy. org), held in the NdA. this is a multisite, longitudinal study designed to recruit more than 10,000 children age 9 to 10 and follow them over 10 years into early adulthood. the ABcd Study is supported by the National institutes of health and additional federal partners under award numbers: U01dA041022, U01dA041028, U01dA041048, U01dA041089, U01dA041106, U01dA041117, U01dA041120, U01dA041134, U01dA041148, U01dA041156, U01dA041174, U24dA041123, and U24dA041147 A full list of supporters is available at https://abcdstudy.org/ federal-partners/. A listing of participating sites and a complete listing of the study investigators can be found at https://abcdstudy.org/principal-investigators.html. ABcd Study consortium investigators designed and implemented the study and/or provided data but did not necessarily participate in analysis or writing of this report. this manuscript reflects the views of the authors and may not reflect the opinions or views of the Nih or ABcd Study consortium investigators. the ABcd data repository grows and changes over time. the ABcd data used in this came from [NdA digital Object identifier (10.15154/1523041)]. URLs: PLiNK (https://cog-genomics.org/plink/2.0/), FUMA (https://fuma.ctglab.nl), LdSc and sLdSc (https:// github.com/bulik/ldsc), and annotations for sLdSc tissue-specific analysis (https://alkesgroup. broadinstitute.org/LdScORe/). Funding: 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). A.d. is supported by the following grants from the National institutes of health (Nih): U24dA041123, R01AG076838, U24dA055330, and Ot2hL161847. J.R.i. was supported by Nih R01AA028411. Author contributions: conceptualization: R.L., c.c.F., M.B., J.A., O.A., t.L.J., L.S., W.K.t., A.J.S., and A.d. Methodology: R.L., c.c.F., A.d., O.F., W.K.t., L.S., and A.J.S. data curation: R.L., d.J.h., t.L.J., O.A., and A.d. validation: R.L., c.c.F., and A.J.S. Formal analysis: R.L., c.c.F., L.S., O.F., and A.d. Software: R.L., c.c.F., d.J.h., J.R.i., A.d., and O.F. investigation: t.L.J., A.J.S., and A.d. visualization: R.L., c.c.F., and L.S. Supervision: c.c.F., t.L.J., L.S., W.K.t., A.d., and A.J.S. Resources: c.c.F., t.L.J., and A.d. Project administration: c.c.F., t.L.J., O.A., and A.d. Funding acquisition: c.c.F., t.L.J., and A.d. Writing\u2014 original draft: R.L., c.c.F., J.A., L.S., and A.J.S. Writing\u2014review and editing: R.L., c.c.F., N.Z., J.A., d.J.h., d.M.S., L.S., W.K.t., A.J.S., O.A., and O.F. Competing interests: O.A. has received speaker\u2019s honorarium from Lundbeck and is a consultant to healthLytix. A.d. is Founding director, holds equity in cortechs Labs inc. (dBA cortechs.ai), and serves on its Board of directors and the Scientific Advisory Board. he is an unpaid consultant for Oslo University hospital. the terms of these arrangements have been reviewed and approved by the University of california, San diego in accordance with its conflict-of-interest policies. the other authors declare that they have no competing interests. Data and materials availability: UKB data were accessed under accession number 27412. Summary statistics from GWAS of hemochromatosis Brain PvS are available at figshare (https://doi.org/10.6084/m9.figshare.26122102.v1). Researchers can apply for access to UKB data at https://ukbiobank.ac.uk/enable-your-research/apply-for-access. the ABcd data used in this came from [NdA digital Object identifier (10.15154/1523041)]. these data are available to approved researchers (find more information at https://abcdstudy.org). All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. We have created a Python command line program to generate PvS\u2019s for t2-weighted images registered in Montreal Neurological institute space using classification weights presented in this analysis\u2014(https://zenodo.org/doi/10.5281/zenodo.12535194) https://github.com/robloughnan/pvs.
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