Neurodegenerative disease risk associated with gene expression in peripheral monocytes across ancestries

It is hypothesised that peripheral immune states responding to regional environmental triggers contribute to central neurodegeneration. Region-specific genetic selection pressures require this hypothesis to be assessed in an ancestry-specific manner. Here, we utilise genome-wide association studies and expression quantitative trait loci from African, East Asian and European ancestries to show that genes causally-implicated in neurodegeneration are preferentially expressed in innate rather than adaptive immune cells.

Using colocalisation and Mendelian randomisation analyses, we show that in addition to known colocalising signals in microglia, genetic variants associated with neurodegenerative disease risk also regulate the expression of these genes in peripheral monocytes across ancestries. This research was funded in part by Aligning Science Across Parkinson’s [ASAP-000509 and ASAP-000463] through the Michael J. Fox Foundation for Parkinson’s Research (MJFF).

This work utilized the computational resources of the NIH HPC Biowulf cluster (http://hpc.nih.gov). This work was supported in part by the Intramural Research Program of the National Institutes of Health including: the Center for Alzheimer’s and Related Dementias, within the Intramural Research Program of the National Institute on Aging and the National Institute of Neurological Disorders and Stroke.AZW was supported through the award of a Clinical Research Fellowship funded by the Wolfson Foundation and Eisai Ltd. SG was supported by Wellcome (100172/Z/12/2) and is currently an MRC Senior Clinical Fellow (MR/T008199/1).

MR was supported by the UK Medical Research Council (MRC) through her award of Tenure-track Clinician Scientist Fellowship (MR/N008324/1). Department of Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London, UK Aaron Z. Gustavsson, Sonia Gandhi & Mina Ryten The Francis Crick Institute, 1 Midland Road, London, UK Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Queen Square, London, UK Aaron Z.

Wood & Sonia Gandhi Center for Alzheimer’s and Related Dementias, National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD, USA Aaron Z. Wood, Sonia Gandhi & Mina Ryten Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, 11 Mandalay Road, Singapore, Singapore Montreal Heart Institute, Montreal, QC, Canada Department of Medicine & Department of Neurosciences, Universite de Montreal, Montreal, QC, Canada MRC Biostatistics Unit, University of Cambridge, Cambridge, UK Dementia Research Institute, Department of Clinical Neuroscience, University of Cambridge, Cambridge, UK Correspondence to Aaron Z. RHR is currently employed by CoSyne Therapeutics (Lead Computational Biologist).

All work performed for this publication was performed in her own time, and not as a part of her duties as an employee. All other authors declare no competing interests. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.