Translational Psychiatry (Jul 2022)
Polygenic resilience scores capture protective genetic effects for Alzheimer’s disease
- Jiahui Hou,
- Jonathan L. Hess,
- Nicola Armstrong,
- Joshua C. Bis,
- Benjamin Grenier-Boley,
- Ida K. Karlsson,
- Ganna Leonenko,
- Katya Numbers,
- Eleanor K. O’Brien,
- Alexey Shadrin,
- Anbupalam Thalamuthu,
- Qiong Yang,
- Ole A. Andreassen,
- Henry Brodaty,
- Margaret Gatz,
- Nicole A. Kochan,
- Jean-Charles Lambert,
- Simon M. Laws,
- Colin L. Masters,
- Karen A. Mather,
- Nancy L. Pedersen,
- Danielle Posthuma,
- Perminder S. Sachdev,
- Julie Williams,
- the Alzheimer’s Disease Neuroimaging Initiative,
- Chun Chieh Fan,
- Stephen V. Faraone,
- Christine Fennema-Notestine,
- Shu-Ju Lin,
- Valentina Escott-Price,
- Peter Holmans,
- Sudha Seshadri,
- Ming T. Tsuang,
- William S. Kremen,
- Stephen J. Glatt
Affiliations
- Jiahui Hou
- Psychiatric Genetic Epidemiology & Neurobiology Laboratory (PsychGENe Lab), SUNY Upstate Medical University
- Jonathan L. Hess
- Psychiatric Genetic Epidemiology & Neurobiology Laboratory (PsychGENe Lab), SUNY Upstate Medical University
- Nicola Armstrong
- Mathematics and Statistics, Curtin University
- Joshua C. Bis
- Department of Medicine, Cardiovascular Health Research Unit, University of Washington
- Benjamin Grenier-Boley
- U1167-RID-AGE - Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Univ. Lille, Inserm, CHU Lille, Institut Pasteur Lille
- Ida K. Karlsson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet
- Ganna Leonenko
- Dementia Research Institute, School of Medicine, Cardiff University
- Katya Numbers
- Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, Faculty of Medicine, University of New South Wales
- Eleanor K. O’Brien
- Centre for Precision Health, Edith Cowan University
- Alexey Shadrin
- NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo
- Anbupalam Thalamuthu
- Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, Faculty of Medicine, University of New South Wales
- Qiong Yang
- Department of Biostatistics, School of Public Health, Boston University
- Ole A. Andreassen
- NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo
- Henry Brodaty
- Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, Faculty of Medicine, University of New South Wales
- Margaret Gatz
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet
- Nicole A. Kochan
- Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, Faculty of Medicine, University of New South Wales
- Jean-Charles Lambert
- U1167-RID-AGE - Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Univ. Lille, Inserm, CHU Lille, Institut Pasteur Lille
- Simon M. Laws
- Centre for Precision Health, Edith Cowan University
- Colin L. Masters
- The Florey Institute, The University of Melbourne
- Karen A. Mather
- Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, Faculty of Medicine, University of New South Wales
- Nancy L. Pedersen
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet
- Danielle Posthuma
- Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit
- Perminder S. Sachdev
- Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, Faculty of Medicine, University of New South Wales
- Julie Williams
- Division of Psychological Medicine and Clinical Neurology and Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University
- the Alzheimer’s Disease Neuroimaging Initiative
- Chun Chieh Fan
- Department of Cognitive Science, University of California San Diego
- Stephen V. Faraone
- Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University
- Christine Fennema-Notestine
- Departments of Psychiatry and Radiology, University of California San Diego
- Shu-Ju Lin
- Department of Psychiatry, University of California San Diego
- Valentina Escott-Price
- Dementia Research Institute, School of Medicine, Cardiff University
- Peter Holmans
- Division of Psychological Medicine and Clinical Neurology and Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University
- Sudha Seshadri
- Department of Neurology, School of Medicine, Boston University
- Ming T. Tsuang
- Department of Psychiatry, University of California San Diego
- William S. Kremen
- Department of Psychiatry, University of California San Diego
- Stephen J. Glatt
- Psychiatric Genetic Epidemiology & Neurobiology Laboratory (PsychGENe Lab), SUNY Upstate Medical University
- DOI
- https://doi.org/10.1038/s41398-022-02055-0
- Journal volume & issue
-
Vol. 12,
no. 1
pp. 1 – 11
Abstract
Abstract Polygenic risk scores (PRSs) can boost risk prediction in late-onset Alzheimer’s disease (LOAD) beyond apolipoprotein E (APOE) but have not been leveraged to identify genetic resilience factors. Here, we sought to identify resilience-conferring common genetic variants in (1) unaffected individuals having high PRSs for LOAD, and (2) unaffected APOE-ε4 carriers also having high PRSs for LOAD. We used genome-wide association study (GWAS) to contrast “resilient” unaffected individuals at the highest genetic risk for LOAD with LOAD cases at comparable risk. From GWAS results, we constructed polygenic resilience scores to aggregate the addictive contributions of risk-orthogonal common variants that promote resilience to LOAD. Replication of resilience scores was undertaken in eight independent studies. We successfully replicated two polygenic resilience scores that reduce genetic risk penetrance for LOAD. We also showed that polygenic resilience scores positively correlate with polygenic risk scores in unaffected individuals, perhaps aiding in staving off disease. Our findings align with the hypothesis that a combination of risk-independent common variants mediates resilience to LOAD by moderating genetic disease risk.
