Polygenic risk scores in familial Alzheimer disease

Giuseppe Tosto, Thomas D. Bird, Debby Tsuang, David A. Bennett, Bradley F. Boeve, Carlos Cruchaga, Kelley Faber, Tatiana Foroud, Martin Farlow, Alison M. Goate, Sarah Bertlesen, Neill R. Graff-Radford, Martin Medrano, Rafael Lantigua, Jennifer Manly, Ruth Ottman, Roger Rosenberg, Daniel J. Schaid, Nicole Schupf, Yaakov SternRobert A. Sweet, Richard Mayeux

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Objective: To investigate the association between a genetic risk score (GRS) and familial late-onset Alzheimer disease (LOAD) and its predictive value in families multiply affected by the disease. Methods: Using data from the National Institute on Aging Genetics Initiative for Late-Onset Alzheimer Disease (National Institute on Aging-Late-Onset Alzheimer's Disease Family Study), mixed regression models tested the association of familial LOAD with a GRS based on single nucleotide polymorphisms (SNPs) previously associated with LOAD. We modeled associations using unweighted and weighted scores with estimates derived from the literature. In secondary models, we adjusted subsequent models for presence of the APOE ϵ4 allele and further tested the interaction between APOE ϵ4 and the GRS. We constructed a similar GRS in a cohort of Caribbean Hispanic families multiply affected by LOAD by selecting the SNP with the strongest p value within the same regions. Results: In the NIA-LOAD families, the GRS was significantly associated with LOAD (odds ratio [OR] 1.29; 95% confidence interval 1.21-1.37). The results did not change after adjusting for APOE ϵ4. In Caribbean Hispanic families, the GRS also significantly predicted LOAD (OR 1.73; 1.57-1.93). Higher scores were associated with lower age at onset in both cohorts. Conclusions: High GRS increases the risk of familial LOAD and lowers the age at onset, regardless of ethnic group.

Original languageEnglish (US)
Pages (from-to)1180-1186
Number of pages7
JournalNeurology
Volume88
Issue number12
DOIs
StatePublished - Mar 21 2017

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Alzheimer Disease
National Institute on Aging (U.S.)
Age of Onset
Hispanic Americans
Single Nucleotide Polymorphism
Odds Ratio
Ethnic Groups
Alleles
Confidence Intervals
Alzheimer disease type 2

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Tosto, G., Bird, T. D., Tsuang, D., Bennett, D. A., Boeve, B. F., Cruchaga, C., ... Mayeux, R. (2017). Polygenic risk scores in familial Alzheimer disease. Neurology, 88(12), 1180-1186. https://doi.org/10.1212/WNL.0000000000003734

Polygenic risk scores in familial Alzheimer disease. / Tosto, Giuseppe; Bird, Thomas D.; Tsuang, Debby; Bennett, David A.; Boeve, Bradley F.; Cruchaga, Carlos; Faber, Kelley; Foroud, Tatiana; Farlow, Martin; Goate, Alison M.; Bertlesen, Sarah; Graff-Radford, Neill R.; Medrano, Martin; Lantigua, Rafael; Manly, Jennifer; Ottman, Ruth; Rosenberg, Roger; Schaid, Daniel J.; Schupf, Nicole; Stern, Yaakov; Sweet, Robert A.; Mayeux, Richard.

In: Neurology, Vol. 88, No. 12, 21.03.2017, p. 1180-1186.

Research output: Contribution to journalArticle

Tosto, G, Bird, TD, Tsuang, D, Bennett, DA, Boeve, BF, Cruchaga, C, Faber, K, Foroud, T, Farlow, M, Goate, AM, Bertlesen, S, Graff-Radford, NR, Medrano, M, Lantigua, R, Manly, J, Ottman, R, Rosenberg, R, Schaid, DJ, Schupf, N, Stern, Y, Sweet, RA & Mayeux, R 2017, 'Polygenic risk scores in familial Alzheimer disease', Neurology, vol. 88, no. 12, pp. 1180-1186. https://doi.org/10.1212/WNL.0000000000003734
Tosto G, Bird TD, Tsuang D, Bennett DA, Boeve BF, Cruchaga C et al. Polygenic risk scores in familial Alzheimer disease. Neurology. 2017 Mar 21;88(12):1180-1186. https://doi.org/10.1212/WNL.0000000000003734
Tosto, Giuseppe ; Bird, Thomas D. ; Tsuang, Debby ; Bennett, David A. ; Boeve, Bradley F. ; Cruchaga, Carlos ; Faber, Kelley ; Foroud, Tatiana ; Farlow, Martin ; Goate, Alison M. ; Bertlesen, Sarah ; Graff-Radford, Neill R. ; Medrano, Martin ; Lantigua, Rafael ; Manly, Jennifer ; Ottman, Ruth ; Rosenberg, Roger ; Schaid, Daniel J. ; Schupf, Nicole ; Stern, Yaakov ; Sweet, Robert A. ; Mayeux, Richard. / Polygenic risk scores in familial Alzheimer disease. In: Neurology. 2017 ; Vol. 88, No. 12. pp. 1180-1186.
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abstract = "Objective: To investigate the association between a genetic risk score (GRS) and familial late-onset Alzheimer disease (LOAD) and its predictive value in families multiply affected by the disease. Methods: Using data from the National Institute on Aging Genetics Initiative for Late-Onset Alzheimer Disease (National Institute on Aging-Late-Onset Alzheimer's Disease Family Study), mixed regression models tested the association of familial LOAD with a GRS based on single nucleotide polymorphisms (SNPs) previously associated with LOAD. We modeled associations using unweighted and weighted scores with estimates derived from the literature. In secondary models, we adjusted subsequent models for presence of the APOE ϵ4 allele and further tested the interaction between APOE ϵ4 and the GRS. We constructed a similar GRS in a cohort of Caribbean Hispanic families multiply affected by LOAD by selecting the SNP with the strongest p value within the same regions. Results: In the NIA-LOAD families, the GRS was significantly associated with LOAD (odds ratio [OR] 1.29; 95{\%} confidence interval 1.21-1.37). The results did not change after adjusting for APOE ϵ4. In Caribbean Hispanic families, the GRS also significantly predicted LOAD (OR 1.73; 1.57-1.93). Higher scores were associated with lower age at onset in both cohorts. Conclusions: High GRS increases the risk of familial LOAD and lowers the age at onset, regardless of ethnic group.",
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AU - Tosto, Giuseppe

AU - Bird, Thomas D.

AU - Tsuang, Debby

AU - Bennett, David A.

AU - Boeve, Bradley F.

AU - Cruchaga, Carlos

AU - Faber, Kelley

AU - Foroud, Tatiana

AU - Farlow, Martin

AU - Goate, Alison M.

AU - Bertlesen, Sarah

AU - Graff-Radford, Neill R.

AU - Medrano, Martin

AU - Lantigua, Rafael

AU - Manly, Jennifer

AU - Ottman, Ruth

AU - Rosenberg, Roger

AU - Schaid, Daniel J.

AU - Schupf, Nicole

AU - Stern, Yaakov

AU - Sweet, Robert A.

AU - Mayeux, Richard

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N2 - Objective: To investigate the association between a genetic risk score (GRS) and familial late-onset Alzheimer disease (LOAD) and its predictive value in families multiply affected by the disease. Methods: Using data from the National Institute on Aging Genetics Initiative for Late-Onset Alzheimer Disease (National Institute on Aging-Late-Onset Alzheimer's Disease Family Study), mixed regression models tested the association of familial LOAD with a GRS based on single nucleotide polymorphisms (SNPs) previously associated with LOAD. We modeled associations using unweighted and weighted scores with estimates derived from the literature. In secondary models, we adjusted subsequent models for presence of the APOE ϵ4 allele and further tested the interaction between APOE ϵ4 and the GRS. We constructed a similar GRS in a cohort of Caribbean Hispanic families multiply affected by LOAD by selecting the SNP with the strongest p value within the same regions. Results: In the NIA-LOAD families, the GRS was significantly associated with LOAD (odds ratio [OR] 1.29; 95% confidence interval 1.21-1.37). The results did not change after adjusting for APOE ϵ4. In Caribbean Hispanic families, the GRS also significantly predicted LOAD (OR 1.73; 1.57-1.93). Higher scores were associated with lower age at onset in both cohorts. Conclusions: High GRS increases the risk of familial LOAD and lowers the age at onset, regardless of ethnic group.

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