Local genetic correlations exist among neurodegenerative and neuropsychiatric diseases

Regina H Reynolds; Aaron Z Wagen; Frida Lona-Durazo; Sonja W Scholz; Maryam Shoai; John Hardy; Sarah A Gagliano Taliun; Mina Ryten

doi:10.1038/s41531-023-00504-1

Local genetic correlations exist among neurodegenerative and neuropsychiatric diseases

NPJ Parkinsons Dis. 2023 Apr 28;9(1):70. doi: 10.1038/s41531-023-00504-1.

Authors

Regina H Reynolds^#^{1

2}, Aaron Z Wagen^#^{3

4

5}, Frida Lona-Durazo^{6

7}, Sonja W Scholz^{8

9}, Maryam Shoai^{10

11

12}, John Hardy^{10

11

12}, Sarah A Gagliano Taliun^{6

13}, Mina Ryten^{14

15

16}

Affiliations

¹ Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London, UK. regina.reynolds.16@ucl.ac.uk.
² Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA. regina.reynolds.16@ucl.ac.uk.
³ Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London, UK.
⁴ Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, London, UK.
⁵ Neurodegeneration Biology Laboratory, The Francis Crick Institute, London, UK.
⁶ Montréal Heart Institute, Montréal, QC, Canada.
⁷ Faculty of Medicine, Université de Montréal, Montréal, Canada.
⁸ Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
⁹ Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, USA.
¹⁰ Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.
¹¹ Department of Neurodegenerative Diseases, Queen Square Institute of Neurology, University College London, London, UK.
¹² UK Dementia Research Institute, University College London, London, UK.
¹³ Department of Medicine & Department of Neurosciences, Université de Montréal, Montréal, QC, Canada.
¹⁴ Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London, UK. mina.ryten@ucl.ac.uk.
¹⁵ Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA. mina.ryten@ucl.ac.uk.
¹⁶ NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, London, UK. mina.ryten@ucl.ac.uk.

^# Contributed equally.

Abstract

Genetic correlation ([Formula: see text]) between traits can offer valuable insight into underlying shared biological mechanisms. Neurodegenerative diseases overlap neuropathologically and often manifest comorbid neuropsychiatric symptoms. However, global [Formula: see text] analyses show minimal [Formula: see text] among neurodegenerative and neuropsychiatric diseases. Importantly, local [Formula: see text] s can exist in the absence of global relationships. To investigate this possibility, we applied LAVA, a tool for local [Formula: see text] analysis, to genome-wide association studies of 3 neurodegenerative diseases (Alzheimer's disease, Lewy body dementia and Parkinson's disease) and 3 neuropsychiatric disorders (bipolar disorder, major depressive disorder and schizophrenia). We identified several local [Formula: see text] s missed in global analyses, including between (i) all 3 neurodegenerative diseases and schizophrenia and (ii) Alzheimer's and Parkinson's disease. For those local [Formula: see text] s identified in genomic regions containing disease-implicated genes, such as SNCA, CLU and APOE, incorporation of expression quantitative trait loci identified genes that may drive genetic overlaps between diseases. Collectively, we demonstrate that complex genetic relationships exist among neurodegenerative and neuropsychiatric diseases, highlighting putative pleiotropic genomic regions and genes. These findings imply sharing of pathogenic processes and the potential existence of common therapeutic targets.

Grants and funding

MR/N008324/1/MRC_/Medical Research Council/United Kingdom