Genome-wide pleiotropy analysis of neuropathological traits related to Alzheimer's disease

Jaeyoon Chung; Xiaoling Zhang; Mariet Allen; Xue Wang; Yiyi Ma; Gary Beecham; Thomas J. Montine; Steven G. Younkin; Dennis W. Dickson; Todd E. Golde; Nathan D. Price; Nilüfer Ertekin-Taner; Kathryn L. Lunetta; Jesse Mez; Richard Mayeux; Jonathan L. Haines; Margaret A. Pericak-Vance; Gerard Schellenberg; Gyungah R. Jun; Lindsay A. Farrer

doi:10.1186/s13195-018-0349-z

Genome-wide pleiotropy analysis of neuropathological traits related to Alzheimer's disease

Jaeyoon Chung, Xiaoling Zhang, Mariet Allen, Xue Wang, Yiyi Ma, Gary Beecham, Thomas J. Montine, Steven G. Younkin, Dennis W. Dickson, Todd E. Golde, Nathan D. Price, Nilüfer Ertekin-Taner, Kathryn L. Lunetta, Jesse Mez, Richard Mayeux, Jonathan L. Haines, Margaret A. Pericak-Vance, Gerard Schellenberg, Gyungah R. Jun, Lindsay A. Farrer

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Abstract

Background: Simultaneous consideration of two neuropathological traits related to Alzheimer's disease (AD) has not been attempted in a genome-wide association study. Methods: We conducted genome-wide pleiotropy analyses using association summary statistics from the Beecham et al. study (PLoS Genet 10:e1004606, 2014) for AD-related neuropathological traits, including neuritic plaque (NP), neurofibrillary tangle (NFT), and cerebral amyloid angiopathy (CAA). Significant findings were further examined by expression quantitative trait locus and differentially expressed gene analyses in AD vs. control brains using gene expression data. Results: Genome-wide significant pleiotropic associations were observed for the joint model of NP and NFT (NP + NFT) with the single-nucleotide polymorphism (SNP) rs34487851 upstream of C2orf40 (alias ECRG4, P = 2.4 × 10^-8) and for the joint model of NFT and CAA (NFT + CAA) with the HDAC9 SNP rs79524815 (P = 1.1 × 10^-8). Gene-based testing revealed study-wide significant associations (P ≤ 2.0 × 10^-6) for the NFT + CAA outcome with adjacent genes TRAPPC12, TRAPPC12-AS1, and ADI1. Risk alleles of proxy SNPs for rs79524815 were associated with significantly lower expression of HDAC9 in the brain (P = 3.0 × 10^-3), and HDAC9 was significantly downregulated in subjects with AD compared with control subjects in the prefrontal (P = 7.9 × 10^-3) and visual (P = 5.6 × 10^-4) cortices. Conclusions: Our findings suggest that pleiotropy analysis is a useful approach to identifying novel genetic associations with complex diseases and their endophenotypes. Functional studies are needed to determine whether ECRG4 or HDAC9 is plausible as a therapeutic target.

Original language	English (US)
Article number	22
Journal	Alzheimer's Research and Therapy
Volume	10
Issue number	1
DOIs	https://doi.org/10.1186/s13195-018-0349-z
State	Published - Feb 20 2018

Keywords

Alzheimer's disease
ECRG4
Genome-wide association study
HDAC9
Neuropathological traits
Pleiotropy analysis

ASJC Scopus subject areas

Neurology
Clinical Neurology
Cognitive Neuroscience

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10.1186/s13195-018-0349-z

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Chung, J., Zhang, X., Allen, M., Wang, X., Ma, Y., Beecham, G., Montine, T. J., Younkin, S. G., Dickson, D. W., Golde, T. E., Price, N. D., Ertekin-Taner, N., Lunetta, K. L., Mez, J., Mayeux, R., Haines, J. L., Pericak-Vance, M. A., Schellenberg, G., Jun, G. R., & Farrer, L. A. (2018). Genome-wide pleiotropy analysis of neuropathological traits related to Alzheimer's disease. Alzheimer's Research and Therapy, 10(1), Article 22. https://doi.org/10.1186/s13195-018-0349-z

Chung, J, Zhang, X, Allen, M, Wang, X, Ma, Y, Beecham, G, Montine, TJ, Younkin, SG , Dickson, DW, Golde, TE, Price, ND, Ertekin-Taner, N, Lunetta, KL, Mez, J, Mayeux, R, Haines, JL, Pericak-Vance, MA, Schellenberg, G, Jun, GR & Farrer, LA 2018, 'Genome-wide pleiotropy analysis of neuropathological traits related to Alzheimer's disease', Alzheimer's Research and Therapy, vol. 10, no. 1, 22. https://doi.org/10.1186/s13195-018-0349-z

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title = "Genome-wide pleiotropy analysis of neuropathological traits related to Alzheimer's disease",

abstract = "Background: Simultaneous consideration of two neuropathological traits related to Alzheimer's disease (AD) has not been attempted in a genome-wide association study. Methods: We conducted genome-wide pleiotropy analyses using association summary statistics from the Beecham et al. study (PLoS Genet 10:e1004606, 2014) for AD-related neuropathological traits, including neuritic plaque (NP), neurofibrillary tangle (NFT), and cerebral amyloid angiopathy (CAA). Significant findings were further examined by expression quantitative trait locus and differentially expressed gene analyses in AD vs. control brains using gene expression data. Results: Genome-wide significant pleiotropic associations were observed for the joint model of NP and NFT (NP + NFT) with the single-nucleotide polymorphism (SNP) rs34487851 upstream of C2orf40 (alias ECRG4, P = 2.4 × 10-8) and for the joint model of NFT and CAA (NFT + CAA) with the HDAC9 SNP rs79524815 (P = 1.1 × 10-8). Gene-based testing revealed study-wide significant associations (P ≤ 2.0 × 10-6) for the NFT + CAA outcome with adjacent genes TRAPPC12, TRAPPC12-AS1, and ADI1. Risk alleles of proxy SNPs for rs79524815 were associated with significantly lower expression of HDAC9 in the brain (P = 3.0 × 10-3), and HDAC9 was significantly downregulated in subjects with AD compared with control subjects in the prefrontal (P = 7.9 × 10-3) and visual (P = 5.6 × 10-4) cortices. Conclusions: Our findings suggest that pleiotropy analysis is a useful approach to identifying novel genetic associations with complex diseases and their endophenotypes. Functional studies are needed to determine whether ECRG4 or HDAC9 is plausible as a therapeutic target.",

keywords = "Alzheimer's disease, ECRG4, Genome-wide association study, HDAC9, Neuropathological traits, Pleiotropy analysis",

author = "Jaeyoon Chung and Xiaoling Zhang and Mariet Allen and Xue Wang and Yiyi Ma and Gary Beecham and Montine, {Thomas J.} and Younkin, {Steven G.} and Dickson, {Dennis W.} and Golde, {Todd E.} and Price, {Nathan D.} and Nil{\"u}fer Ertekin-Taner and Lunetta, {Kathryn L.} and Jesse Mez and Richard Mayeux and Haines, {Jonathan L.} and Pericak-Vance, {Margaret A.} and Gerard Schellenberg and Jun, {Gyungah R.} and Farrer, {Lindsay A.}",

note = "Publisher Copyright: {\textcopyright} 2018 The Author(s).",

year = "2018",

month = feb,

day = "20",

doi = "10.1186/s13195-018-0349-z",

language = "English (US)",

volume = "10",

journal = "Alzheimer's Research and Therapy",

issn = "1758-9193",

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number = "1",

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TY - JOUR

T1 - Genome-wide pleiotropy analysis of neuropathological traits related to Alzheimer's disease

AU - Chung, Jaeyoon

AU - Zhang, Xiaoling

AU - Allen, Mariet

AU - Wang, Xue

AU - Ma, Yiyi

AU - Beecham, Gary

AU - Montine, Thomas J.

AU - Younkin, Steven G.

AU - Dickson, Dennis W.

AU - Golde, Todd E.

AU - Price, Nathan D.

AU - Ertekin-Taner, Nilüfer

AU - Lunetta, Kathryn L.

AU - Mez, Jesse

AU - Mayeux, Richard

AU - Haines, Jonathan L.

AU - Pericak-Vance, Margaret A.

AU - Schellenberg, Gerard

AU - Jun, Gyungah R.

AU - Farrer, Lindsay A.

PY - 2018/2/20

Y1 - 2018/2/20

N2 - Background: Simultaneous consideration of two neuropathological traits related to Alzheimer's disease (AD) has not been attempted in a genome-wide association study. Methods: We conducted genome-wide pleiotropy analyses using association summary statistics from the Beecham et al. study (PLoS Genet 10:e1004606, 2014) for AD-related neuropathological traits, including neuritic plaque (NP), neurofibrillary tangle (NFT), and cerebral amyloid angiopathy (CAA). Significant findings were further examined by expression quantitative trait locus and differentially expressed gene analyses in AD vs. control brains using gene expression data. Results: Genome-wide significant pleiotropic associations were observed for the joint model of NP and NFT (NP + NFT) with the single-nucleotide polymorphism (SNP) rs34487851 upstream of C2orf40 (alias ECRG4, P = 2.4 × 10-8) and for the joint model of NFT and CAA (NFT + CAA) with the HDAC9 SNP rs79524815 (P = 1.1 × 10-8). Gene-based testing revealed study-wide significant associations (P ≤ 2.0 × 10-6) for the NFT + CAA outcome with adjacent genes TRAPPC12, TRAPPC12-AS1, and ADI1. Risk alleles of proxy SNPs for rs79524815 were associated with significantly lower expression of HDAC9 in the brain (P = 3.0 × 10-3), and HDAC9 was significantly downregulated in subjects with AD compared with control subjects in the prefrontal (P = 7.9 × 10-3) and visual (P = 5.6 × 10-4) cortices. Conclusions: Our findings suggest that pleiotropy analysis is a useful approach to identifying novel genetic associations with complex diseases and their endophenotypes. Functional studies are needed to determine whether ECRG4 or HDAC9 is plausible as a therapeutic target.

AB - Background: Simultaneous consideration of two neuropathological traits related to Alzheimer's disease (AD) has not been attempted in a genome-wide association study. Methods: We conducted genome-wide pleiotropy analyses using association summary statistics from the Beecham et al. study (PLoS Genet 10:e1004606, 2014) for AD-related neuropathological traits, including neuritic plaque (NP), neurofibrillary tangle (NFT), and cerebral amyloid angiopathy (CAA). Significant findings were further examined by expression quantitative trait locus and differentially expressed gene analyses in AD vs. control brains using gene expression data. Results: Genome-wide significant pleiotropic associations were observed for the joint model of NP and NFT (NP + NFT) with the single-nucleotide polymorphism (SNP) rs34487851 upstream of C2orf40 (alias ECRG4, P = 2.4 × 10-8) and for the joint model of NFT and CAA (NFT + CAA) with the HDAC9 SNP rs79524815 (P = 1.1 × 10-8). Gene-based testing revealed study-wide significant associations (P ≤ 2.0 × 10-6) for the NFT + CAA outcome with adjacent genes TRAPPC12, TRAPPC12-AS1, and ADI1. Risk alleles of proxy SNPs for rs79524815 were associated with significantly lower expression of HDAC9 in the brain (P = 3.0 × 10-3), and HDAC9 was significantly downregulated in subjects with AD compared with control subjects in the prefrontal (P = 7.9 × 10-3) and visual (P = 5.6 × 10-4) cortices. Conclusions: Our findings suggest that pleiotropy analysis is a useful approach to identifying novel genetic associations with complex diseases and their endophenotypes. Functional studies are needed to determine whether ECRG4 or HDAC9 is plausible as a therapeutic target.

KW - Alzheimer's disease

KW - ECRG4

KW - Genome-wide association study

KW - HDAC9

KW - Neuropathological traits

KW - Pleiotropy analysis

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ER -

Genome-wide pleiotropy analysis of neuropathological traits related to Alzheimer's disease

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