Analysis of Whole-Exome Sequencing Data for Alzheimer Disease Stratified by APOE Genotype

Yiyi Ma, Gyungah R. Jun, Xiaoling Zhang, Jaeyoon Chung, Adam C. Naj, Yuning Chen, Celine Bellenguez, Kara Hamilton-Nelson, Eden R. Martin, Brian W. Kunkle, Joshua C. Bis, Stéphanie Debette, Anita L. Destefano, Myriam Fornage, Gaël Nicolas, Cornelia Van Duijn, David A. Bennett, Philip L. De Jager, Richard Mayeux, Jonathan L. Haines & 6 others Margaret A. Pericak-Vance, Sudha Seshadri, Jean Charles Lambert, Gerard D. Schellenberg, Kathryn L. Lunetta, Lindsay A. Farrer

Research output: Contribution to journalArticle

Abstract

Importance: Previous genome-wide association studies of common variants identified associations for Alzheimer disease (AD) loci evident only among individuals with particular APOE alleles. Objective: To identify APOE genotype-dependent associations with infrequent and rare variants using whole-exome sequencing. Design, Setting, and Participants: The discovery stage included 10441 non-Hispanic white participants in the Alzheimer Disease Sequencing Project. Replication was sought in 2 independent, whole-exome sequencing data sets (1766 patients with AD, 2906 without AD [controls]) and a chip-based genotype imputation data set (8728 patients with AD, 9808 controls). Bioinformatics and functional analyses were conducted using clinical, cognitive, neuropathologic, whole-exome sequencing, and gene expression data obtained from a longitudinal cohort sample including 402 patients with AD and 647 controls. Data were analyzed between March 2017 and September 2018. Main Outcomes and Measures: Score, Firth, and sequence kernel association tests were used to test the association of AD risk with individual variants and genes in subgroups of APOE ϵ4 carriers and noncarriers. Results with P ≤ 1 × 10-5 were further evaluated in the replication data sets and combined by meta-analysis. Results: Among 3145 patients with AD and 4213 controls lacking ϵ4 (mean [SD] age, 83.4 [7.6] years; 4363 [59.3.%] women), novel genome-wide significant associations were obtained in the discovery sample with rs536940594 in AC099552 (odds ratio [OR], 88.0; 95% CI, 9.08-852.0; P = 2.22 × 10-7) and rs138412600 in GPAA1 (OR, 1.78; 95% CI, 1.44-2.2; meta-P = 7.81 × 10-8). GPAA1 was also associated with expression in the brain of GPAA1 (β = -0.08; P =.03) and its repressive transcription factor, FOXG1 (β = 0.13; P =.003), and global cognition function (β = -0.53; P =.009). Significant gene-wide associations (threshold P ≤ 6.35 × 10-7) were observed for OR8G5 (P = 4.67 × 10-7), IGHV3-7 (P = 9.75 × 10-16), and SLC24A3 (P = 2.67 × 10-12) in 2377 patients with AD and 706 controls with ϵ4 (mean [SD] age, 75.2 [9.6] years; 1668 [54.1%] women). Conclusions and Relevance: The study identified multiple possible novel associations for AD with individual and aggregated rare variants in groups of individuals with and without APOE ϵ4 alleles that reinforce known and suggest additional pathways leading to AD.

Original languageEnglish (US)
JournalJAMA Neurology
DOIs
StateAccepted/In press - Jan 1 2019

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Exome
Alzheimer Disease
Genotype
Alleles
Odds Ratio
Genome-Wide Association Study
Computational Biology
Cognition
Genes
Meta-Analysis
Transcription Factors

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Ma, Y., Jun, G. R., Zhang, X., Chung, J., Naj, A. C., Chen, Y., ... Farrer, L. A. (Accepted/In press). Analysis of Whole-Exome Sequencing Data for Alzheimer Disease Stratified by APOE Genotype. JAMA Neurology. https://doi.org/10.1001/jamaneurol.2019.1456

Analysis of Whole-Exome Sequencing Data for Alzheimer Disease Stratified by APOE Genotype. / Ma, Yiyi; Jun, Gyungah R.; Zhang, Xiaoling; Chung, Jaeyoon; Naj, Adam C.; Chen, Yuning; Bellenguez, Celine; Hamilton-Nelson, Kara; Martin, Eden R.; Kunkle, Brian W.; Bis, Joshua C.; Debette, Stéphanie; Destefano, Anita L.; Fornage, Myriam; Nicolas, Gaël; Van Duijn, Cornelia; Bennett, David A.; De Jager, Philip L.; Mayeux, Richard; Haines, Jonathan L.; Pericak-Vance, Margaret A.; Seshadri, Sudha; Lambert, Jean Charles; Schellenberg, Gerard D.; Lunetta, Kathryn L.; Farrer, Lindsay A.

In: JAMA Neurology, 01.01.2019.

Research output: Contribution to journalArticle

Ma, Y, Jun, GR, Zhang, X, Chung, J, Naj, AC, Chen, Y, Bellenguez, C, Hamilton-Nelson, K, Martin, ER, Kunkle, BW, Bis, JC, Debette, S, Destefano, AL, Fornage, M, Nicolas, G, Van Duijn, C, Bennett, DA, De Jager, PL, Mayeux, R, Haines, JL, Pericak-Vance, MA, Seshadri, S, Lambert, JC, Schellenberg, GD, Lunetta, KL & Farrer, LA 2019, 'Analysis of Whole-Exome Sequencing Data for Alzheimer Disease Stratified by APOE Genotype', JAMA Neurology. https://doi.org/10.1001/jamaneurol.2019.1456
Ma, Yiyi ; Jun, Gyungah R. ; Zhang, Xiaoling ; Chung, Jaeyoon ; Naj, Adam C. ; Chen, Yuning ; Bellenguez, Celine ; Hamilton-Nelson, Kara ; Martin, Eden R. ; Kunkle, Brian W. ; Bis, Joshua C. ; Debette, Stéphanie ; Destefano, Anita L. ; Fornage, Myriam ; Nicolas, Gaël ; Van Duijn, Cornelia ; Bennett, David A. ; De Jager, Philip L. ; Mayeux, Richard ; Haines, Jonathan L. ; Pericak-Vance, Margaret A. ; Seshadri, Sudha ; Lambert, Jean Charles ; Schellenberg, Gerard D. ; Lunetta, Kathryn L. ; Farrer, Lindsay A. / Analysis of Whole-Exome Sequencing Data for Alzheimer Disease Stratified by APOE Genotype. In: JAMA Neurology. 2019.
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title = "Analysis of Whole-Exome Sequencing Data for Alzheimer Disease Stratified by APOE Genotype",
abstract = "Importance: Previous genome-wide association studies of common variants identified associations for Alzheimer disease (AD) loci evident only among individuals with particular APOE alleles. Objective: To identify APOE genotype-dependent associations with infrequent and rare variants using whole-exome sequencing. Design, Setting, and Participants: The discovery stage included 10441 non-Hispanic white participants in the Alzheimer Disease Sequencing Project. Replication was sought in 2 independent, whole-exome sequencing data sets (1766 patients with AD, 2906 without AD [controls]) and a chip-based genotype imputation data set (8728 patients with AD, 9808 controls). Bioinformatics and functional analyses were conducted using clinical, cognitive, neuropathologic, whole-exome sequencing, and gene expression data obtained from a longitudinal cohort sample including 402 patients with AD and 647 controls. Data were analyzed between March 2017 and September 2018. Main Outcomes and Measures: Score, Firth, and sequence kernel association tests were used to test the association of AD risk with individual variants and genes in subgroups of APOE ϵ4 carriers and noncarriers. Results with P ≤ 1 × 10-5 were further evaluated in the replication data sets and combined by meta-analysis. Results: Among 3145 patients with AD and 4213 controls lacking ϵ4 (mean [SD] age, 83.4 [7.6] years; 4363 [59.3.{\%}] women), novel genome-wide significant associations were obtained in the discovery sample with rs536940594 in AC099552 (odds ratio [OR], 88.0; 95{\%} CI, 9.08-852.0; P = 2.22 × 10-7) and rs138412600 in GPAA1 (OR, 1.78; 95{\%} CI, 1.44-2.2; meta-P = 7.81 × 10-8). GPAA1 was also associated with expression in the brain of GPAA1 (β = -0.08; P =.03) and its repressive transcription factor, FOXG1 (β = 0.13; P =.003), and global cognition function (β = -0.53; P =.009). Significant gene-wide associations (threshold P ≤ 6.35 × 10-7) were observed for OR8G5 (P = 4.67 × 10-7), IGHV3-7 (P = 9.75 × 10-16), and SLC24A3 (P = 2.67 × 10-12) in 2377 patients with AD and 706 controls with ϵ4 (mean [SD] age, 75.2 [9.6] years; 1668 [54.1{\%}] women). Conclusions and Relevance: The study identified multiple possible novel associations for AD with individual and aggregated rare variants in groups of individuals with and without APOE ϵ4 alleles that reinforce known and suggest additional pathways leading to AD.",
author = "Yiyi Ma and Jun, {Gyungah R.} and Xiaoling Zhang and Jaeyoon Chung and Naj, {Adam C.} and Yuning Chen and Celine Bellenguez and Kara Hamilton-Nelson and Martin, {Eden R.} and Kunkle, {Brian W.} and Bis, {Joshua C.} and St{\'e}phanie Debette and Destefano, {Anita L.} and Myriam Fornage and Ga{\"e}l Nicolas and {Van Duijn}, Cornelia and Bennett, {David A.} and {De Jager}, {Philip L.} and Richard Mayeux and Haines, {Jonathan L.} and Pericak-Vance, {Margaret A.} and Sudha Seshadri and Lambert, {Jean Charles} and Schellenberg, {Gerard D.} and Lunetta, {Kathryn L.} and Farrer, {Lindsay A.}",
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month = "1",
day = "1",
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journal = "JAMA Neurology",
issn = "2168-6149",
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TY - JOUR

T1 - Analysis of Whole-Exome Sequencing Data for Alzheimer Disease Stratified by APOE Genotype

AU - Ma, Yiyi

AU - Jun, Gyungah R.

AU - Zhang, Xiaoling

AU - Chung, Jaeyoon

AU - Naj, Adam C.

AU - Chen, Yuning

AU - Bellenguez, Celine

AU - Hamilton-Nelson, Kara

AU - Martin, Eden R.

AU - Kunkle, Brian W.

AU - Bis, Joshua C.

AU - Debette, Stéphanie

AU - Destefano, Anita L.

AU - Fornage, Myriam

AU - Nicolas, Gaël

AU - Van Duijn, Cornelia

AU - Bennett, David A.

AU - De Jager, Philip L.

AU - Mayeux, Richard

AU - Haines, Jonathan L.

AU - Pericak-Vance, Margaret A.

AU - Seshadri, Sudha

AU - Lambert, Jean Charles

AU - Schellenberg, Gerard D.

AU - Lunetta, Kathryn L.

AU - Farrer, Lindsay A.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Importance: Previous genome-wide association studies of common variants identified associations for Alzheimer disease (AD) loci evident only among individuals with particular APOE alleles. Objective: To identify APOE genotype-dependent associations with infrequent and rare variants using whole-exome sequencing. Design, Setting, and Participants: The discovery stage included 10441 non-Hispanic white participants in the Alzheimer Disease Sequencing Project. Replication was sought in 2 independent, whole-exome sequencing data sets (1766 patients with AD, 2906 without AD [controls]) and a chip-based genotype imputation data set (8728 patients with AD, 9808 controls). Bioinformatics and functional analyses were conducted using clinical, cognitive, neuropathologic, whole-exome sequencing, and gene expression data obtained from a longitudinal cohort sample including 402 patients with AD and 647 controls. Data were analyzed between March 2017 and September 2018. Main Outcomes and Measures: Score, Firth, and sequence kernel association tests were used to test the association of AD risk with individual variants and genes in subgroups of APOE ϵ4 carriers and noncarriers. Results with P ≤ 1 × 10-5 were further evaluated in the replication data sets and combined by meta-analysis. Results: Among 3145 patients with AD and 4213 controls lacking ϵ4 (mean [SD] age, 83.4 [7.6] years; 4363 [59.3.%] women), novel genome-wide significant associations were obtained in the discovery sample with rs536940594 in AC099552 (odds ratio [OR], 88.0; 95% CI, 9.08-852.0; P = 2.22 × 10-7) and rs138412600 in GPAA1 (OR, 1.78; 95% CI, 1.44-2.2; meta-P = 7.81 × 10-8). GPAA1 was also associated with expression in the brain of GPAA1 (β = -0.08; P =.03) and its repressive transcription factor, FOXG1 (β = 0.13; P =.003), and global cognition function (β = -0.53; P =.009). Significant gene-wide associations (threshold P ≤ 6.35 × 10-7) were observed for OR8G5 (P = 4.67 × 10-7), IGHV3-7 (P = 9.75 × 10-16), and SLC24A3 (P = 2.67 × 10-12) in 2377 patients with AD and 706 controls with ϵ4 (mean [SD] age, 75.2 [9.6] years; 1668 [54.1%] women). Conclusions and Relevance: The study identified multiple possible novel associations for AD with individual and aggregated rare variants in groups of individuals with and without APOE ϵ4 alleles that reinforce known and suggest additional pathways leading to AD.

AB - Importance: Previous genome-wide association studies of common variants identified associations for Alzheimer disease (AD) loci evident only among individuals with particular APOE alleles. Objective: To identify APOE genotype-dependent associations with infrequent and rare variants using whole-exome sequencing. Design, Setting, and Participants: The discovery stage included 10441 non-Hispanic white participants in the Alzheimer Disease Sequencing Project. Replication was sought in 2 independent, whole-exome sequencing data sets (1766 patients with AD, 2906 without AD [controls]) and a chip-based genotype imputation data set (8728 patients with AD, 9808 controls). Bioinformatics and functional analyses were conducted using clinical, cognitive, neuropathologic, whole-exome sequencing, and gene expression data obtained from a longitudinal cohort sample including 402 patients with AD and 647 controls. Data were analyzed between March 2017 and September 2018. Main Outcomes and Measures: Score, Firth, and sequence kernel association tests were used to test the association of AD risk with individual variants and genes in subgroups of APOE ϵ4 carriers and noncarriers. Results with P ≤ 1 × 10-5 were further evaluated in the replication data sets and combined by meta-analysis. Results: Among 3145 patients with AD and 4213 controls lacking ϵ4 (mean [SD] age, 83.4 [7.6] years; 4363 [59.3.%] women), novel genome-wide significant associations were obtained in the discovery sample with rs536940594 in AC099552 (odds ratio [OR], 88.0; 95% CI, 9.08-852.0; P = 2.22 × 10-7) and rs138412600 in GPAA1 (OR, 1.78; 95% CI, 1.44-2.2; meta-P = 7.81 × 10-8). GPAA1 was also associated with expression in the brain of GPAA1 (β = -0.08; P =.03) and its repressive transcription factor, FOXG1 (β = 0.13; P =.003), and global cognition function (β = -0.53; P =.009). Significant gene-wide associations (threshold P ≤ 6.35 × 10-7) were observed for OR8G5 (P = 4.67 × 10-7), IGHV3-7 (P = 9.75 × 10-16), and SLC24A3 (P = 2.67 × 10-12) in 2377 patients with AD and 706 controls with ϵ4 (mean [SD] age, 75.2 [9.6] years; 1668 [54.1%] women). Conclusions and Relevance: The study identified multiple possible novel associations for AD with individual and aggregated rare variants in groups of individuals with and without APOE ϵ4 alleles that reinforce known and suggest additional pathways leading to AD.

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