Polygenic risk score penetrance & recurrence risk in familial Alzheimer disease
Abstract Objective To compute penetrance and recurrence risk using a genome‐wide PRS (including and excluding the APOE region) in families with Alzheimer's disease. Methods Genotypes from the National Institute on Aging Late‐Onset Alzheimer's Disease Family‐Based Study and a study of famil...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-05-01
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| Series: | Annals of Clinical and Translational Neurology |
| Online Access: | https://doi.org/10.1002/acn3.51757 |
| _version_ | 1797826104914870272 |
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| author | Min Qiao Annie J. Lee Dolly Reyes‐Dumeyer Giuseppe Tosto Kelley Faber Alison Goate Alan Renton Michael Chao Brad Boeve Carlos Cruchaga Margaret Pericak‐Vance Jonathan L. Haines Roger Rosenberg Debby Tsuang Robert A. Sweet David A. Bennett Robert S. Wilson Tatiana Foroud Richard Mayeux Badri N. Vardarajan |
| author_facet | Min Qiao Annie J. Lee Dolly Reyes‐Dumeyer Giuseppe Tosto Kelley Faber Alison Goate Alan Renton Michael Chao Brad Boeve Carlos Cruchaga Margaret Pericak‐Vance Jonathan L. Haines Roger Rosenberg Debby Tsuang Robert A. Sweet David A. Bennett Robert S. Wilson Tatiana Foroud Richard Mayeux Badri N. Vardarajan |
| author_sort | Min Qiao |
| collection | DOAJ |
| description | Abstract Objective To compute penetrance and recurrence risk using a genome‐wide PRS (including and excluding the APOE region) in families with Alzheimer's disease. Methods Genotypes from the National Institute on Aging Late‐Onset Alzheimer's Disease Family‐Based Study and a study of familial Alzheimer's disease in Caribbean Hispanics were used to compute PRS with and without variants in the 2 MB region flanking APOE. PRS was calculated in using clumping/thresholding and Bayesian methods and was assessed for association with Alzheimer's disease and age at onset. Penetrance and recurrence risk for carriers in highest and lowest PRS quintiles were compared separately within APOE‐ε4 carriers and non‐carriers. Results PRS excluding the APOE region was strongly associated with clinical and neuropathological diagnosis of AD. PRS association with AD was similar in participants who did not carry an APOE‐ε4 allele (OR = 1.74 [1.53–1.91]) compared with APOE‐ε4 carriers (1.53 [1.4–1.68]). Compared to the lowest quintile, the highest PRS quintile had a 10% higher penetrance at age 70 (p = 0.0006) and a 20% higher penetrance at age 80 (p < 10e‐05). Stratifying by APOE‐ε4 allele, PRS in the highest quintile was significantly more penetrant than the lowest quintile, both, within APOE‐ε4 carriers (14.5% higher at age 80, p = 0.002) and non‐carriers (26% higher at 80, p < 10e‐05). Recurrence risk for siblings conferred by a co‐sibling in the highest PRS quintile increased from 4% between the ages of 65–74 years to 39% at age 85 and older. Interpretation PRS can be used to estimate penetrance and recurrence risk in familial Alzheimer's disease among carriers and non‐carries of APOE‐ε4. |
| first_indexed | 2024-03-13T11:03:46Z |
| format | Article |
| id | doaj.art-ca34451dd2fe4c19b1a16a4280fe7a72 |
| institution | Directory Open Access Journal |
| issn | 2328-9503 |
| language | English |
| last_indexed | 2024-03-13T11:03:46Z |
| publishDate | 2023-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Annals of Clinical and Translational Neurology |
| spelling | doaj.art-ca34451dd2fe4c19b1a16a4280fe7a722023-05-16T15:39:13ZengWileyAnnals of Clinical and Translational Neurology2328-95032023-05-0110574475610.1002/acn3.51757Polygenic risk score penetrance & recurrence risk in familial Alzheimer diseaseMin Qiao0Annie J. Lee1Dolly Reyes‐Dumeyer2Giuseppe Tosto3Kelley Faber4Alison Goate5Alan Renton6Michael Chao7Brad Boeve8Carlos Cruchaga9Margaret Pericak‐Vance10Jonathan L. Haines11Roger Rosenberg12Debby Tsuang13Robert A. Sweet14David A. Bennett15Robert S. Wilson16Tatiana Foroud17Richard Mayeux18Badri N. Vardarajan19Department of Neurology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain and the Gertrude H. Sergievsky Center Columbia University and the New York Presbyterian Hospital New York New York USADepartment of Neurology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain and the Gertrude H. Sergievsky Center Columbia University and the New York Presbyterian Hospital New York New York USADepartment of Neurology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain and the Gertrude H. Sergievsky Center Columbia University and the New York Presbyterian Hospital New York New York USADepartment of Neurology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain and the Gertrude H. Sergievsky Center Columbia University and the New York Presbyterian Hospital New York New York USADepartment of Medical and Molecular Genetics, National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD) Indiana University School of Medicine Indianapolis Indiana USADepartment of Genetics & Genomic Sciences, Ronald M. Loeb Center for Alzheimer's disease Icahn School of Medicine at Mount Sinai New York New York USADepartment of Genetics & Genomic Sciences, Ronald M. Loeb Center for Alzheimer's disease Icahn School of Medicine at Mount Sinai New York New York USADepartment of Genetics & Genomic Sciences, Ronald M. Loeb Center for Alzheimer's disease Icahn School of Medicine at Mount Sinai New York New York USADepartment of Neurology, Mayo Clinic Rochester Minnesota USADepartment of Psychiatry Washington University in St. Louis St. Louis Missouri USAJohn P Hussman Institute for Human Genomics, Dr. John T Macdonald Foundation Department of Human Genetics University of Miami Miller School of Medicine Miami Florida USADepartment of Population & Quantitative Health Sciences and Cleveland Institute for Computational Biology Case Western Reserve University Cleveland Ohio USADepartment of Neurology University of Texas Southwestern Medical Center at Dallas Dallas Texas USAGRECC VA Puget Sound, Department of Psychiatry and Behavioral Sciences University of Washington Seattle WA USADepartments of Psychiatry and Neurology University of Pittsburgh Pittsburgh Pennsylvania USARush Alzheimer's Disease Center Rush University Medical Center Chicago Illinois USARush Alzheimer's Disease Center Rush University Medical Center Chicago Illinois USADepartment of Medical and Molecular Genetics, National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD) Indiana University School of Medicine Indianapolis Indiana USADepartment of Neurology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain and the Gertrude H. Sergievsky Center Columbia University and the New York Presbyterian Hospital New York New York USADepartment of Neurology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain and the Gertrude H. Sergievsky Center Columbia University and the New York Presbyterian Hospital New York New York USAAbstract Objective To compute penetrance and recurrence risk using a genome‐wide PRS (including and excluding the APOE region) in families with Alzheimer's disease. Methods Genotypes from the National Institute on Aging Late‐Onset Alzheimer's Disease Family‐Based Study and a study of familial Alzheimer's disease in Caribbean Hispanics were used to compute PRS with and without variants in the 2 MB region flanking APOE. PRS was calculated in using clumping/thresholding and Bayesian methods and was assessed for association with Alzheimer's disease and age at onset. Penetrance and recurrence risk for carriers in highest and lowest PRS quintiles were compared separately within APOE‐ε4 carriers and non‐carriers. Results PRS excluding the APOE region was strongly associated with clinical and neuropathological diagnosis of AD. PRS association with AD was similar in participants who did not carry an APOE‐ε4 allele (OR = 1.74 [1.53–1.91]) compared with APOE‐ε4 carriers (1.53 [1.4–1.68]). Compared to the lowest quintile, the highest PRS quintile had a 10% higher penetrance at age 70 (p = 0.0006) and a 20% higher penetrance at age 80 (p < 10e‐05). Stratifying by APOE‐ε4 allele, PRS in the highest quintile was significantly more penetrant than the lowest quintile, both, within APOE‐ε4 carriers (14.5% higher at age 80, p = 0.002) and non‐carriers (26% higher at 80, p < 10e‐05). Recurrence risk for siblings conferred by a co‐sibling in the highest PRS quintile increased from 4% between the ages of 65–74 years to 39% at age 85 and older. Interpretation PRS can be used to estimate penetrance and recurrence risk in familial Alzheimer's disease among carriers and non‐carries of APOE‐ε4.https://doi.org/10.1002/acn3.51757 |
| spellingShingle | Min Qiao Annie J. Lee Dolly Reyes‐Dumeyer Giuseppe Tosto Kelley Faber Alison Goate Alan Renton Michael Chao Brad Boeve Carlos Cruchaga Margaret Pericak‐Vance Jonathan L. Haines Roger Rosenberg Debby Tsuang Robert A. Sweet David A. Bennett Robert S. Wilson Tatiana Foroud Richard Mayeux Badri N. Vardarajan Polygenic risk score penetrance & recurrence risk in familial Alzheimer disease Annals of Clinical and Translational Neurology |
| title | Polygenic risk score penetrance & recurrence risk in familial Alzheimer disease |
| title_full | Polygenic risk score penetrance & recurrence risk in familial Alzheimer disease |
| title_fullStr | Polygenic risk score penetrance & recurrence risk in familial Alzheimer disease |
| title_full_unstemmed | Polygenic risk score penetrance & recurrence risk in familial Alzheimer disease |
| title_short | Polygenic risk score penetrance & recurrence risk in familial Alzheimer disease |
| title_sort | polygenic risk score penetrance recurrence risk in familial alzheimer disease |
| url | https://doi.org/10.1002/acn3.51757 |
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