Polygenic resilience scores capture protective genetic effects for Alzheimer’s disease

• DOI: 10.1038/s41398-022-02055-0
• Publication Date: 2022-07-25T13:03:29Z
• Authors: Jiahui Hou; Jonathan L. Hess; Nicola Armstrong; Joshua C. Bis; Benjamin Grenier-...; 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; ; Chun Chieh Fan; Stephen V. Faraone; Christine Fennema...; Shu-Ju Lin; Valentina Escott-...; Peter Holmans; Sudha Seshadri; Ming T. Tsuang; William S. Kremen; Stephen J. Glatt
• Keywords: 0301 basic medicine; Aging; Multifactorial Inheritance; [SDV]Life Sciences [q-bio]; 5202 Biological Psychology; Apolipoprotein E4; 32 Biomedical and Clinical Sciences; Diseases; Neurodegenerative; Alzheimer's Disease; anzsrc-for: 1103 Clinical Sciences; Long-term memory; Risk Factors; Medicine and Health Sciences; 2.1 Biological and endogenous factors; Psychology; Aetiology; 3202 Clinical Sciences; 0303 health sciences; 52 Psychology; Public Health and Health Services; anzsrc-for: 3209 Neurosciences; anzsrc-for: 3202 Clinical Sciences; anzsrc-for: 5202 Biological Psychology; anzsrc-for: 1117 Public Health and Health Services; RC321-571; Clinical Sciences; 610; Neurosciences. Biological psychiatry. Neuropsychiatry; Article; anzsrc-for: 52 Psychology; 03 medical and health sciences; anzsrc-for: 32 Biomedical and Clinical Sciences; Apolipoproteins E; SDG 3 - Good Health and Well-being; Alzheimer Disease; Genetics; Acquired Cognitive Impairment; Humans; Genetic Predisposition to Disease; Clinical genetics; Genetic Testing; Comparative genomics; Prevention; Human Genome; Neurosciences; Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD); anzsrc-for: 1701 Psychology; Alzheimer’s Disease Neuroimaging Initiative; Brain Disorders; 3209 Neurosciences; Dementia; Genome-Wide Association Study

AbstractPolygenic 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.