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

the Alzheimer’s Disease Neuroimaging Initiative

doi:10.1038/s41398-022-02055-0

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

the Alzheimer’s Disease Neuroimaging Initiative

Research output: Contribution to Journal › Article › Academic › peer-review

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.

Original language	English
Article number	296
Pages (from-to)	1-11
Number of pages	11
Journal	Translational Psychiatry
Volume	12
DOIs	https://doi.org/10.1038/s41398-022-02055-0
Publication status	Published - 25 Jul 2022

Bibliographical note

Funding Information:
OAA is a consultant to HealthLytix. SVF in the past year, received income, potential income, travel expenses continuing education support and/or research support from Aardvark, Akili, Genomind, Ironshore, KemPharm/Corium, Noven, Ondosis, Otsuka, Rhodes, Supernus, Takeda, Tris, and Vallon. With his institution, he has US patent US20130217707 A1 for the use of sodium-hydrogen exchange inhibitors in the treatment of ADHD. In previous years, he received support from: Alcobra, Arbor, Aveksham, CogCubed, Eli Lilly, Enzymotec, Impact, Janssen, Lundbeck/Takeda, McNeil, NeuroLifeSciences, Neurovance, Novartis, Pfizer, Shire, and Sunovion. He also receives royalties from books published by Guilford Press: Straight Talk about Your Child’s Mental Health; Oxford University Press: Schizophrenia: The Facts; and Elsevier: ADHD: Non-Pharmacologic Interventions. He is also Program Director of www.adhdinadults.com . He is supported by the European Union’s Horizon 2020 research and innovation programme under grant agreement No 965381; NIMH grants U01AR076092-01A1, 1R21MH1264940, R01MH116037; Oregon Health and Science University, Otsuka Pharmaceuticals, Noven Pharmaceuticals Incorporated, and Supernus Pharmaceutical Company. The remaining authors declare no competing interests.

Funding Information:
We thank all the participants of this study for their contributions. Our effort on this project was supported by the U.S. National Institute on Aging [grant numbers R01AG064955 and R01AG054002]. Additional acknowledgements and detailed acknowledgements of funding sources for the study are provided in Supplementary acknowledgements.

Publisher Copyright:
© 2022, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.

Funding

OAA is a consultant to HealthLytix. SVF in the past year, received income, potential income, travel expenses continuing education support and/or research support from Aardvark, Akili, Genomind, Ironshore, KemPharm/Corium, Noven, Ondosis, Otsuka, Rhodes, Supernus, Takeda, Tris, and Vallon. With his institution, he has US patent US20130217707 A1 for the use of sodium-hydrogen exchange inhibitors in the treatment of ADHD. In previous years, he received support from: Alcobra, Arbor, Aveksham, CogCubed, Eli Lilly, Enzymotec, Impact, Janssen, Lundbeck/Takeda, McNeil, NeuroLifeSciences, Neurovance, Novartis, Pfizer, Shire, and Sunovion. He also receives royalties from books published by Guilford Press: Straight Talk about Your Child’s Mental Health; Oxford University Press: Schizophrenia: The Facts; and Elsevier: ADHD: Non-Pharmacologic Interventions. He is also Program Director of www.adhdinadults.com . He is supported by the European Union’s Horizon 2020 research and innovation programme under grant agreement No 965381; NIMH grants U01AR076092-01A1, 1R21MH1264940, R01MH116037; Oregon Health and Science University, Otsuka Pharmaceuticals, Noven Pharmaceuticals Incorporated, and Supernus Pharmaceutical Company. The remaining authors declare no competing interests. We thank all the participants of this study for their contributions. Our effort on this project was supported by the U.S. National Institute on Aging [grant numbers R01AG064955 and R01AG054002]. Additional acknowledgements and detailed acknowledgements of funding sources for the study are provided in Supplementary acknowledgements.

Funders	Funder number
Noven Pharmaceuticals Incorporated
Supernus Pharmaceutical Company
National Institute of Mental Health	U01AR076092-01A1, 1R21MH1264940, R01MH116037
National Institute on Aging	R01AG064955, R01AG054002
National Heart, Lung, and Blood Institute	R01HL105756
Oregon Health and Science University
Horizon 2020 Framework Programme	965381
Otsuka Pharmaceutical

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41398-022-02055-0

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title = "Polygenic resilience scores capture protective genetic effects for Alzheimer{\textquoteright}s disease",

abstract = "Polygenic risk scores (PRSs) can boost risk prediction in late-onset Alzheimer{\textquoteright}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.",

author = "Jiahui Hou and Hess, {Jonathan L.} and Nicola Armstrong and Bis, {Joshua C.} and Benjamin Grenier-Boley and Karlsson, {Ida K.} and Ganna Leonenko and Katya Numbers and O{\textquoteright}Brien, {Eleanor K.} and Alexey Shadrin and Anbupalam Thalamuthu and Qiong Yang and Andreassen, {Ole A.} and Henry Brodaty and Margaret Gatz and Kochan, {Nicole A.} and Lambert, {Jean Charles} and Laws, {Simon M.} and Masters, {Colin L.} and Mather, {Karen A.} and Pedersen, {Nancy L.} and Danielle Posthuma and Sachdev, {Perminder S.} and Julie Williams and Fan, {Chun Chieh} and Faraone, {Stephen V.} and Christine Fennema-Notestine and Lin, {Shu Ju} and Valentina Escott-Price and Peter Holmans and Sudha Seshadri and Tsuang, {Ming T.} and Kremen, {William S.} and Glatt, {Stephen J.} and {the Alzheimer{\textquoteright}s Disease Neuroimaging Initiative}",

note = "Funding Information: OAA is a consultant to HealthLytix. SVF in the past year, received income, potential income, travel expenses continuing education support and/or research support from Aardvark, Akili, Genomind, Ironshore, KemPharm/Corium, Noven, Ondosis, Otsuka, Rhodes, Supernus, Takeda, Tris, and Vallon. With his institution, he has US patent US20130217707 A1 for the use of sodium-hydrogen exchange inhibitors in the treatment of ADHD. In previous years, he received support from: Alcobra, Arbor, Aveksham, CogCubed, Eli Lilly, Enzymotec, Impact, Janssen, Lundbeck/Takeda, McNeil, NeuroLifeSciences, Neurovance, Novartis, Pfizer, Shire, and Sunovion. He also receives royalties from books published by Guilford Press: Straight Talk about Your Child{\textquoteright}s Mental Health; Oxford University Press: Schizophrenia: The Facts; and Elsevier: ADHD: Non-Pharmacologic Interventions. He is also Program Director of www.adhdinadults.com . He is supported by the European Union{\textquoteright}s Horizon 2020 research and innovation programme under grant agreement No 965381; NIMH grants U01AR076092-01A1, 1R21MH1264940, R01MH116037; Oregon Health and Science University, Otsuka Pharmaceuticals, Noven Pharmaceuticals Incorporated, and Supernus Pharmaceutical Company. The remaining authors declare no competing interests. Funding Information: We thank all the participants of this study for their contributions. Our effort on this project was supported by the U.S. National Institute on Aging [grant numbers R01AG064955 and R01AG054002]. Additional acknowledgements and detailed acknowledgements of funding sources for the study are provided in Supplementary acknowledgements. Publisher Copyright: {\textcopyright} 2022, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.",

year = "2022",

month = jul,

day = "25",

doi = "10.1038/s41398-022-02055-0",

language = "English",

volume = "12",

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journal = "Translational Psychiatry",

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T1 - Polygenic resilience scores capture protective genetic effects for Alzheimer’s disease

AU - Hou, Jiahui

AU - Hess, Jonathan L.

AU - Armstrong, Nicola

AU - Bis, Joshua C.

AU - Grenier-Boley, Benjamin

AU - Karlsson, Ida K.

AU - Leonenko, Ganna

AU - Numbers, Katya

AU - O’Brien, Eleanor K.

AU - Shadrin, Alexey

AU - Thalamuthu, Anbupalam

AU - Yang, Qiong

AU - Andreassen, Ole A.

AU - Brodaty, Henry

AU - Gatz, Margaret

AU - Kochan, Nicole A.

AU - Lambert, Jean Charles

AU - Laws, Simon M.

AU - Masters, Colin L.

AU - Mather, Karen A.

AU - Pedersen, Nancy L.

AU - Posthuma, Danielle

AU - Sachdev, Perminder S.

AU - Williams, Julie

AU - Fan, Chun Chieh

AU - Faraone, Stephen V.

AU - Fennema-Notestine, Christine

AU - Lin, Shu Ju

AU - Escott-Price, Valentina

AU - Holmans, Peter

AU - Seshadri, Sudha

AU - Tsuang, Ming T.

AU - Kremen, William S.

AU - Glatt, Stephen J.

AU - the Alzheimer’s Disease Neuroimaging Initiative

N1 - Funding Information: OAA is a consultant to HealthLytix. SVF in the past year, received income, potential income, travel expenses continuing education support and/or research support from Aardvark, Akili, Genomind, Ironshore, KemPharm/Corium, Noven, Ondosis, Otsuka, Rhodes, Supernus, Takeda, Tris, and Vallon. With his institution, he has US patent US20130217707 A1 for the use of sodium-hydrogen exchange inhibitors in the treatment of ADHD. In previous years, he received support from: Alcobra, Arbor, Aveksham, CogCubed, Eli Lilly, Enzymotec, Impact, Janssen, Lundbeck/Takeda, McNeil, NeuroLifeSciences, Neurovance, Novartis, Pfizer, Shire, and Sunovion. He also receives royalties from books published by Guilford Press: Straight Talk about Your Child’s Mental Health; Oxford University Press: Schizophrenia: The Facts; and Elsevier: ADHD: Non-Pharmacologic Interventions. He is also Program Director of www.adhdinadults.com . He is supported by the European Union’s Horizon 2020 research and innovation programme under grant agreement No 965381; NIMH grants U01AR076092-01A1, 1R21MH1264940, R01MH116037; Oregon Health and Science University, Otsuka Pharmaceuticals, Noven Pharmaceuticals Incorporated, and Supernus Pharmaceutical Company. The remaining authors declare no competing interests. Funding Information: We thank all the participants of this study for their contributions. Our effort on this project was supported by the U.S. National Institute on Aging [grant numbers R01AG064955 and R01AG054002]. Additional acknowledgements and detailed acknowledgements of funding sources for the study are provided in Supplementary acknowledgements. Publisher Copyright: © 2022, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.

PY - 2022/7/25

Y1 - 2022/7/25

N2 - 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.

AB - 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.

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

Abstract

Bibliographical note

Funding

UN SDGs

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