No Genetic Overlap Between Circulating Iron Levels and Alzheimer’s Disease

Article type: Research Article

Authors: Lupton, Michelle K.^{a; *} | Benyamin, Beben^b | Proitsi, Petroula^c | Nyholt, Dale R.^{a; d} | Ferreira, Manuel A.^a | Montgomery, Grant W.^{a; e} | Heath, Andrew C.^f | Madden, Pamela A.^f | Medland, Sarah E.^a | Gordon, Scott D.^a | GERAD1 Consortium¹ | the Alzheimer’s Disease Neuroimaging Initiative² | Lovestone, Simon^g | Tsolaki, Magda^h | Kloszewska, Iwonaⁱ | Soininen, Hilkka^j | Mecocci, Patrizia^k | Vellas, Bruno^l | Powell, John F.^c | Bush, Ashley I.^m | Wright, Margaret J.^{a; b; n} | Martin, Nicholas G.^a | Whitfield, John B.^a

Affiliations: [a] QIMR Berghofer Medical Research Institute, Brisbane, Australia | [b] Queensland Brain Institute, University of Queensland, Brisbane, Australia | [c] Institute of Psychiatry Psychology and Neuroscience, Kings College London, UK | [d] Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia | [e] Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia | [f] Washington University School of Medicine, StLouis, MO, USA | [g] Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK | [h] Memory and Dementia Centre, 3rd Department of Neurology, Aristotle University of Thessaloniki, Thessaloniki, Greece | [i] Department of Old Age Psychiatry and Psychotic Disorders, Medical University of Lodz, Lodz, Poland | [j] Department of Neurology, University of EasternFinland and Kuopio University Hospital, Kuopio, Finland | [k] Section of Gerontology and Geriatrics, Department of Medicine, University of Perugia, Perugia, Italy | [l] Gerontopole, CHU, UMR INSERM 1027, University ofToulouse, France | [m] Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Australia | [n] Centre for Advanced Imaging, University of Queensland, Brisbane, Australia

Correspondence: [*] Correspondence to: Michelle K. Lupton, PhD, QIMR Berghofer Medical Research Institute. 300 Herston Road, Herston QLD 4030, Australia. Tel.: +61 7 3845 3947; Fax: +61 7 3362 0101; E-mail: [email protected].

Note: [1] Data used in the preparation of this article were obtained from the Genetic and Environmental Risk for Alzheimer’s disease (GERAD1) Consortium. As such, the investigators within the GERAD1 consortia contributed to the design and implementation of GERAD1 and/or provided data but did not participate in analysis or writing of this report (except those who are named authors). Membership of the GERAD1 Consortium is provided in the Acknowledgments section.

Note: [2] Data used in preparing this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (http://adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators may be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf

Abstract: Iron deposition in the brain is a prominent feature of Alzheimer’s disease (AD). Recently, peripheral iron measures have also been shown to be associated with AD status. However, it is not known whether these associations are causal: do elevated or depleted iron levels throughout life have an effect on AD risk? We evaluate the effects of peripheral iron on AD risk using a genetic profile score approach by testing whether variants affecting iron, transferrin, or ferritin levels selected from GWAS meta-analysis of approximately 24,000 individuals are also associated with AD risk in an independent case-control cohort (n∼10,000). Conversely, we test whether AD risk variants from a GWAS meta-analysis of approximately 54,000 account for any variance in iron measures (n∼9,000). We do not identify a genetic relationship, suggesting that peripheral iron is not causal in the initiation of AD pathology.

Keywords: Alzheimer’s disease, apolipoproteins E, dementia, ferritin, genetic profile scores, genome-wide association study, iron, population genetics, transferrin

DOI: 10.3233/JAD-170027

Journal: Journal of Alzheimer's Disease, vol. 59, no. 1, pp. 85-99, 2017