Polygenic resilience scores capture protective genetic effects for Alzheimer's disease
Autor: | Hou, Jiahui, Hess, Jonathan L, Armstrong, Nicola, Bis, Joshua C, Grenier-Boley, Benjamin, Karlsson, Ida K, Leonenko, Ganna, Numbers, Katya, O'Brien, Eleanor K, Shadrin, Alexey, Thalamuthu, Anbupalam, Yang, Qiong, Andreassen, Ole A, Brodaty, Henry, Gatz, Margaret, Kochan, Nicole A, Lambert, Jean-Charles, Laws, Simon M, Masters, Colin L, Mather, Karen A, Pedersen, Nancy L, Posthuma, Danielle, Sachdev, Perminder S, Williams, Julie, Alzheimer’s Disease Neuroimaging Initiative, Fan, Chun Chieh, Faraone, Stephen V, Fennema-Notestine, Christine, Lin, Shu-Ju, Escott-Price, Valentina, Holmans, Peter, Seshadri, Sudha, Tsuang, Ming T, Kremen, William S, Glatt, Stephen J |
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Rok vydání: | 2022 |
Předmět: |
Multifactorial Inheritance
Aging Prevention Apolipoprotein E4 Human Genome Clinical Sciences Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) Alzheimer’s Disease Neuroimaging Initiative Neurodegenerative Alzheimer's Disease Brain Disorders Apolipoproteins E Alzheimer Disease Risk Factors Genetics Acquired Cognitive Impairment Public Health and Health Services Humans 2.1 Biological and endogenous factors Psychology Genetic Predisposition to Disease Dementia Genetic Testing Aetiology Genome-Wide Association Study |
Zdroj: | Translational psychiatry, vol 12, iss 1 |
Popis: | 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. |
Databáze: | OpenAIRE |
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