ABCC9 gene polymorphism is associated with hippocampal sclerosis of aging pathology

Peter T. Nelson; Steven Estus; Erin L. Abner; Ishita Parikh; Manasi Malik; Janna H. Neltner; Eseosa Ighodaro; Wang Xia Wang; Bernard R. Wilfred; Li San Wang; Walter A. Kukull; Kannabiran Nandakumar; Mark L. Farman; Wayne W. Poon; Maria M. Corrada; Claudia H. Kawas; David H. Cribbs; David A. Bennett; Julie A. Schneider; Eric B. Larson; Paul K. Crane; Otto Valladares; Frederick A. Schmitt; Richard J. Kryscio; Gregory A. Jicha; Charles D. Smith; Stephen W. Scheff; Joshua A. Sonnen; Jonathan L. Haines; Margaret A. Pericak-Vance; Richard Mayeux; Lindsay A. Farrer; Linda J. Van Eldik; Craig Horbinski; Robert C. Green; Marla Gearing; Leonard W. Poon; Patricia L. Kramer; Randall L. Woltjer; Thomas J. Montine; Amanda B. Partch; Alexander J. Rajic; Katierose Richmire; Sarah E. Monsell; Gerard D. Schellenberg; David W. Fardo

doi:10.1007/s00401-014-1282-2

ABCC9 gene polymorphism is associated with hippocampal sclerosis of aging pathology

Peter T. Nelson, Steven Estus, Erin L. Abner, Ishita Parikh, Manasi Malik, Janna H. Neltner, Eseosa Ighodaro, Wang Xia Wang, Bernard R. Wilfred, Li San Wang, Walter A. Kukull, Kannabiran Nandakumar, Mark L. Farman, Wayne W. Poon, Maria M. Corrada, Claudia H. Kawas, David H. Cribbs, David A. Bennett, Julie A. Schneider, Eric B. LarsonPaul K. Crane, Otto Valladares, Frederick A. Schmitt, Richard J. Kryscio, Gregory A. Jicha, Charles D. Smith, Stephen W. Scheff, Joshua A. Sonnen, Jonathan L. Haines, Margaret A. Pericak-Vance, Richard Mayeux, Lindsay A. Farrer, Linda J. Van Eldik, Craig Horbinski, Robert C. Green, Marla Gearing, Leonard W. Poon, Patricia L. Kramer, Randall L. Woltjer, Thomas J. Montine, Amanda B. Partch, Alexander J. Rajic, Katierose Richmire, Sarah E. Monsell, Gerard D. Schellenberg, David W. Fardo

Research output: Contribution to journal › Article › peer-review

67 Scopus citations

Abstract

Hippocampal sclerosis of aging (HS-Aging) is a high-morbidity brain disease in the elderly but risk factors are largely unknown. We report the first genome-wide association study (GWAS) with HS-Aging pathology as an endophenotype. In collaboration with the Alzheimer's Disease Genetics Consortium, data were analyzed from large autopsy cohorts: (#1) National Alzheimer's Coordinating Center (NACC); (#2) Rush University Religious Orders Study and Memory and Aging Project; (#3) Group Health Research Institute Adult Changes in Thought study; (#4) University of California at Irvine 90+ Study; and (#5) University of Kentucky Alzheimer's Disease Center. Altogether, 363 HS-Aging cases and 2,303 controls, all pathologically confirmed, provided statistical power to test for risk alleles with large effect size. A two-tier study design included GWAS from cohorts #1-3 (Stage I) to identify promising SNP candidates, followed by focused evaluation of particular SNPs in cohorts #4-5 (Stage II). Polymorphism in the ATP-binding cassette, sub-family C member 9 (ABCC9) gene, also known as sulfonylurea receptor 2, was associated with HS-Aging pathology. In the meta-analyzed Stage I GWAS, ABCC9 polymorphisms yielded the lowest p values, and factoring in the Stage II results, the meta-analyzed risk SNP (rs704178:G) attained genome-wide statistical significance (p = 1.4 × 10^-9), with odds ratio (OR) of 2.13 (recessive mode of inheritance). For SNPs previously linked to hippocampal sclerosis, meta-analyses of Stage I results show OR = 1.16 for rs5848 (GRN) and OR = 1.22 rs1990622 (TMEM106B), with the risk alleles as previously described. Sulfonylureas, a widely prescribed drug class used to treat diabetes, also modify human ABCC9 protein function. A subsample of patients from the NACC database (n = 624) were identified who were older than age 85 at death with known drug history. Controlling for important confounders such as diabetes itself, exposure to a sulfonylurea drug was associated with risk for HS-Aging pathology (p = 0.03). Thus, we describe a novel and targetable dementia risk factor.

Original language	English
Pages (from-to)	825-843
Number of pages	19
Journal	Acta Neuropathologica
Volume	127
Issue number	6
DOIs	https://doi.org/10.1007/s00401-014-1282-2
State	Published - Jun 2014

Bibliographical note

Funding Information:
Acknowledgments We are deeply grateful to all of the study participants and all the clinical workers, who make this research possible. We thank Ms. Sonya Anderson and Ms. ela Patel for technical support. Thanks also to Drs. Julia Kofler and M. Ilyas Kamboh for collaborative assistance in this project. 1D3 antibody was a generous gift from Dr. Manuela Neumann. Funding included National Institutes of Health (NIH) grants for ADgC (U01 Ag032984), NACC (U01 Ag016976), the National Cell repository for AD (NCrAD; U24 Ag21886), K25 Ag043546, Ul1Tr000117, and the UK-ADC P30 Ag028383 from the National Institute on Aging (NIA). ACT enrollment and clinical data are from NIA U01 Ag 06781 (e lar-son, PI). genetic data for ACT are from Human genome research Institute U01 Hg006375 (e larson, PI). rush religious Order Study and Memory and Aging Project (D Bennett PI) is supported by NIH grants P30Ag10161, r01Ag15819, r01Ag17917, r01Ag42210, and the Translational genomics research Institute. University of California Irvine work was supported by NIH grants for the UCI ADC (P50Ag16573) and 90+ Study (r01Ag21055; C Kawas, PI). For additional acknowledgment and funding support, please see Supplemental material.

Funding

Acknowledgments We are deeply grateful to all of the study participants and all the clinical workers, who make this research possible. We thank Ms. Sonya Anderson and Ms. ela Patel for technical support. Thanks also to Drs. Julia Kofler and M. Ilyas Kamboh for collaborative assistance in this project. 1D3 antibody was a generous gift from Dr. Manuela Neumann. Funding included National Institutes of Health (NIH) grants for ADgC (U01 Ag032984), NACC (U01 Ag016976), the National Cell repository for AD (NCrAD; U24 Ag21886), K25 Ag043546, Ul1Tr000117, and the UK-ADC P30 Ag028383 from the National Institute on Aging (NIA). ACT enrollment and clinical data are from NIA U01 Ag 06781 (e lar-son, PI). genetic data for ACT are from Human genome research Institute U01 Hg006375 (e larson, PI). rush religious Order Study and Memory and Aging Project (D Bennett PI) is supported by NIH grants P30Ag10161, r01Ag15819, r01Ag17917, r01Ag42210, and the Translational genomics research Institute. University of California Irvine work was supported by NIH grants for the UCI ADC (P50Ag16573) and 90+ Study (r01Ag21055; C Kawas, PI). For additional acknowledgment and funding support, please see Supplemental material.

Funders	Funder number
NCRAD	K25 Ag043546, U24 Ag21886, Ul1Tr000117
National Cell repository
Translational Genomics Research Institute
UCI ADC	P50Ag16573
UK-ADC	P30 Ag028383
National Institutes of Health (NIH)	U01 Ag032984
National Institutes of Health (NIH)
National Institute on Aging	R01AG041797, P30AG028383, P30Ag10161
National Institute on Aging
National Association for Colitis and Crohn's Disease	U01 Ag016976
National Association for Colitis and Crohn's Disease

Keywords

ADGC
CTAGE5
KATP
Neuropathology
Oldest old
Potassium channel

ASJC Scopus subject areas

Pathology and Forensic Medicine
Clinical Neurology
Cellular and Molecular Neuroscience

UN SDGs

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

Access to Document

10.1007/s00401-014-1282-2

Cite this

Nelson, P. T., Estus, S., Abner, E. L., Parikh, I., Malik, M., Neltner, J. H., Ighodaro, E., Wang, W. X., Wilfred, B. R., Wang, L. S., Kukull, W. A., Nandakumar, K., Farman, M. L., Poon, W. W., Corrada, M. M., Kawas, C. H., Cribbs, D. H., Bennett, D. A., Schneider, J. A., ... Fardo, D. W. (2014). ABCC9 gene polymorphism is associated with hippocampal sclerosis of aging pathology. Acta Neuropathologica, 127(6), 825-843. https://doi.org/10.1007/s00401-014-1282-2

@article{b7184ef675f5417389e123ed9198e549,

title = "ABCC9 gene polymorphism is associated with hippocampal sclerosis of aging pathology",

abstract = "Hippocampal sclerosis of aging (HS-Aging) is a high-morbidity brain disease in the elderly but risk factors are largely unknown. We report the first genome-wide association study (GWAS) with HS-Aging pathology as an endophenotype. In collaboration with the Alzheimer's Disease Genetics Consortium, data were analyzed from large autopsy cohorts: (#1) National Alzheimer's Coordinating Center (NACC); (#2) Rush University Religious Orders Study and Memory and Aging Project; (#3) Group Health Research Institute Adult Changes in Thought study; (#4) University of California at Irvine 90+ Study; and (#5) University of Kentucky Alzheimer's Disease Center. Altogether, 363 HS-Aging cases and 2,303 controls, all pathologically confirmed, provided statistical power to test for risk alleles with large effect size. A two-tier study design included GWAS from cohorts #1-3 (Stage I) to identify promising SNP candidates, followed by focused evaluation of particular SNPs in cohorts #4-5 (Stage II). Polymorphism in the ATP-binding cassette, sub-family C member 9 (ABCC9) gene, also known as sulfonylurea receptor 2, was associated with HS-Aging pathology. In the meta-analyzed Stage I GWAS, ABCC9 polymorphisms yielded the lowest p values, and factoring in the Stage II results, the meta-analyzed risk SNP (rs704178:G) attained genome-wide statistical significance (p = 1.4 × 10-9), with odds ratio (OR) of 2.13 (recessive mode of inheritance). For SNPs previously linked to hippocampal sclerosis, meta-analyses of Stage I results show OR = 1.16 for rs5848 (GRN) and OR = 1.22 rs1990622 (TMEM106B), with the risk alleles as previously described. Sulfonylureas, a widely prescribed drug class used to treat diabetes, also modify human ABCC9 protein function. A subsample of patients from the NACC database (n = 624) were identified who were older than age 85 at death with known drug history. Controlling for important confounders such as diabetes itself, exposure to a sulfonylurea drug was associated with risk for HS-Aging pathology (p = 0.03). Thus, we describe a novel and targetable dementia risk factor.",

keywords = "ADGC, CTAGE5, KATP, Neuropathology, Oldest old, Potassium channel",

author = "Nelson, {Peter T.} and Steven Estus and Abner, {Erin L.} and Ishita Parikh and Manasi Malik and Neltner, {Janna H.} and Eseosa Ighodaro and Wang, {Wang Xia} and Wilfred, {Bernard R.} and Wang, {Li San} and Kukull, {Walter A.} and Kannabiran Nandakumar and Farman, {Mark L.} and Poon, {Wayne W.} and Corrada, {Maria M.} and Kawas, {Claudia H.} and Cribbs, {David H.} and Bennett, {David A.} and Schneider, {Julie A.} and Larson, {Eric B.} and Crane, {Paul K.} and Otto Valladares and Schmitt, {Frederick A.} and Kryscio, {Richard J.} and Jicha, {Gregory A.} and Smith, {Charles D.} and Scheff, {Stephen W.} and Sonnen, {Joshua A.} and Haines, {Jonathan L.} and Pericak-Vance, {Margaret A.} and Richard Mayeux and Farrer, {Lindsay A.} and {Van Eldik}, {Linda J.} and Craig Horbinski and Green, {Robert C.} and Marla Gearing and Poon, {Leonard W.} and Kramer, {Patricia L.} and Woltjer, {Randall L.} and Montine, {Thomas J.} and Partch, {Amanda B.} and Rajic, {Alexander J.} and Katierose Richmire and Monsell, {Sarah E.} and Schellenberg, {Gerard D.} and Fardo, {David W.}",

note = "Funding Information: Acknowledgments We are deeply grateful to all of the study participants and all the clinical workers, who make this research possible. We thank Ms. Sonya Anderson and Ms. ela Patel for technical support. Thanks also to Drs. Julia Kofler and M. Ilyas Kamboh for collaborative assistance in this project. 1D3 antibody was a generous gift from Dr. Manuela Neumann. Funding included National Institutes of Health (NIH) grants for ADgC (U01 Ag032984), NACC (U01 Ag016976), the National Cell repository for AD (NCrAD; U24 Ag21886), K25 Ag043546, Ul1Tr000117, and the UK-ADC P30 Ag028383 from the National Institute on Aging (NIA). ACT enrollment and clinical data are from NIA U01 Ag 06781 (e lar-son, PI). genetic data for ACT are from Human genome research Institute U01 Hg006375 (e larson, PI). rush religious Order Study and Memory and Aging Project (D Bennett PI) is supported by NIH grants P30Ag10161, r01Ag15819, r01Ag17917, r01Ag42210, and the Translational genomics research Institute. University of California Irvine work was supported by NIH grants for the UCI ADC (P50Ag16573) and 90+ Study (r01Ag21055; C Kawas, PI). For additional acknowledgment and funding support, please see Supplemental material.",

year = "2014",

month = jun,

doi = "10.1007/s00401-014-1282-2",

language = "English",

volume = "127",

pages = "825--843",

number = "6",

}

Nelson, PT , Estus, S , Abner, EL, Parikh, I, Malik, M, Neltner, JH, Ighodaro, E, Wang, WX, Wilfred, BR, Wang, LS, Kukull, WA, Nandakumar, K, Farman, ML, Poon, WW, Corrada, MM, Kawas, CH, Cribbs, DH, Bennett, DA, Schneider, JA, Larson, EB, Crane, PK, Valladares, O, Schmitt, FA , Kryscio, RJ , Jicha, GA, Smith, CD, Scheff, SW, Sonnen, JA, Haines, JL, Pericak-Vance, MA, Mayeux, R, Farrer, LA, Van Eldik, LJ, Horbinski, C, Green, RC, Gearing, M, Poon, LW, Kramer, PL, Woltjer, RL, Montine, TJ, Partch, AB, Rajic, AJ, Richmire, K, Monsell, SE, Schellenberg, GD & Fardo, DW 2014, 'ABCC9 gene polymorphism is associated with hippocampal sclerosis of aging pathology', Acta Neuropathologica, vol. 127, no. 6, pp. 825-843. https://doi.org/10.1007/s00401-014-1282-2

TY - JOUR

T1 - ABCC9 gene polymorphism is associated with hippocampal sclerosis of aging pathology

AU - Nelson, Peter T.

AU - Estus, Steven

AU - Abner, Erin L.

AU - Parikh, Ishita

AU - Malik, Manasi

AU - Neltner, Janna H.

AU - Ighodaro, Eseosa

AU - Wang, Wang Xia

AU - Wilfred, Bernard R.

AU - Wang, Li San

AU - Kukull, Walter A.

AU - Nandakumar, Kannabiran

AU - Farman, Mark L.

AU - Poon, Wayne W.

AU - Corrada, Maria M.

AU - Kawas, Claudia H.

AU - Cribbs, David H.

AU - Bennett, David A.

AU - Schneider, Julie A.

AU - Larson, Eric B.

AU - Crane, Paul K.

AU - Valladares, Otto

AU - Schmitt, Frederick A.

AU - Kryscio, Richard J.

AU - Jicha, Gregory A.

AU - Smith, Charles D.

AU - Scheff, Stephen W.

AU - Sonnen, Joshua A.

AU - Haines, Jonathan L.

AU - Pericak-Vance, Margaret A.

AU - Mayeux, Richard

AU - Farrer, Lindsay A.

AU - Van Eldik, Linda J.

AU - Horbinski, Craig

AU - Green, Robert C.

AU - Gearing, Marla

AU - Poon, Leonard W.

AU - Kramer, Patricia L.

AU - Woltjer, Randall L.

AU - Montine, Thomas J.

AU - Partch, Amanda B.

AU - Rajic, Alexander J.

AU - Richmire, Katierose

AU - Monsell, Sarah E.

AU - Schellenberg, Gerard D.

AU - Fardo, David W.

N1 - Funding Information: Acknowledgments We are deeply grateful to all of the study participants and all the clinical workers, who make this research possible. We thank Ms. Sonya Anderson and Ms. ela Patel for technical support. Thanks also to Drs. Julia Kofler and M. Ilyas Kamboh for collaborative assistance in this project. 1D3 antibody was a generous gift from Dr. Manuela Neumann. Funding included National Institutes of Health (NIH) grants for ADgC (U01 Ag032984), NACC (U01 Ag016976), the National Cell repository for AD (NCrAD; U24 Ag21886), K25 Ag043546, Ul1Tr000117, and the UK-ADC P30 Ag028383 from the National Institute on Aging (NIA). ACT enrollment and clinical data are from NIA U01 Ag 06781 (e lar-son, PI). genetic data for ACT are from Human genome research Institute U01 Hg006375 (e larson, PI). rush religious Order Study and Memory and Aging Project (D Bennett PI) is supported by NIH grants P30Ag10161, r01Ag15819, r01Ag17917, r01Ag42210, and the Translational genomics research Institute. University of California Irvine work was supported by NIH grants for the UCI ADC (P50Ag16573) and 90+ Study (r01Ag21055; C Kawas, PI). For additional acknowledgment and funding support, please see Supplemental material.

PY - 2014/6

Y1 - 2014/6

N2 - Hippocampal sclerosis of aging (HS-Aging) is a high-morbidity brain disease in the elderly but risk factors are largely unknown. We report the first genome-wide association study (GWAS) with HS-Aging pathology as an endophenotype. In collaboration with the Alzheimer's Disease Genetics Consortium, data were analyzed from large autopsy cohorts: (#1) National Alzheimer's Coordinating Center (NACC); (#2) Rush University Religious Orders Study and Memory and Aging Project; (#3) Group Health Research Institute Adult Changes in Thought study; (#4) University of California at Irvine 90+ Study; and (#5) University of Kentucky Alzheimer's Disease Center. Altogether, 363 HS-Aging cases and 2,303 controls, all pathologically confirmed, provided statistical power to test for risk alleles with large effect size. A two-tier study design included GWAS from cohorts #1-3 (Stage I) to identify promising SNP candidates, followed by focused evaluation of particular SNPs in cohorts #4-5 (Stage II). Polymorphism in the ATP-binding cassette, sub-family C member 9 (ABCC9) gene, also known as sulfonylurea receptor 2, was associated with HS-Aging pathology. In the meta-analyzed Stage I GWAS, ABCC9 polymorphisms yielded the lowest p values, and factoring in the Stage II results, the meta-analyzed risk SNP (rs704178:G) attained genome-wide statistical significance (p = 1.4 × 10-9), with odds ratio (OR) of 2.13 (recessive mode of inheritance). For SNPs previously linked to hippocampal sclerosis, meta-analyses of Stage I results show OR = 1.16 for rs5848 (GRN) and OR = 1.22 rs1990622 (TMEM106B), with the risk alleles as previously described. Sulfonylureas, a widely prescribed drug class used to treat diabetes, also modify human ABCC9 protein function. A subsample of patients from the NACC database (n = 624) were identified who were older than age 85 at death with known drug history. Controlling for important confounders such as diabetes itself, exposure to a sulfonylurea drug was associated with risk for HS-Aging pathology (p = 0.03). Thus, we describe a novel and targetable dementia risk factor.

AB - Hippocampal sclerosis of aging (HS-Aging) is a high-morbidity brain disease in the elderly but risk factors are largely unknown. We report the first genome-wide association study (GWAS) with HS-Aging pathology as an endophenotype. In collaboration with the Alzheimer's Disease Genetics Consortium, data were analyzed from large autopsy cohorts: (#1) National Alzheimer's Coordinating Center (NACC); (#2) Rush University Religious Orders Study and Memory and Aging Project; (#3) Group Health Research Institute Adult Changes in Thought study; (#4) University of California at Irvine 90+ Study; and (#5) University of Kentucky Alzheimer's Disease Center. Altogether, 363 HS-Aging cases and 2,303 controls, all pathologically confirmed, provided statistical power to test for risk alleles with large effect size. A two-tier study design included GWAS from cohorts #1-3 (Stage I) to identify promising SNP candidates, followed by focused evaluation of particular SNPs in cohorts #4-5 (Stage II). Polymorphism in the ATP-binding cassette, sub-family C member 9 (ABCC9) gene, also known as sulfonylurea receptor 2, was associated with HS-Aging pathology. In the meta-analyzed Stage I GWAS, ABCC9 polymorphisms yielded the lowest p values, and factoring in the Stage II results, the meta-analyzed risk SNP (rs704178:G) attained genome-wide statistical significance (p = 1.4 × 10-9), with odds ratio (OR) of 2.13 (recessive mode of inheritance). For SNPs previously linked to hippocampal sclerosis, meta-analyses of Stage I results show OR = 1.16 for rs5848 (GRN) and OR = 1.22 rs1990622 (TMEM106B), with the risk alleles as previously described. Sulfonylureas, a widely prescribed drug class used to treat diabetes, also modify human ABCC9 protein function. A subsample of patients from the NACC database (n = 624) were identified who were older than age 85 at death with known drug history. Controlling for important confounders such as diabetes itself, exposure to a sulfonylurea drug was associated with risk for HS-Aging pathology (p = 0.03). Thus, we describe a novel and targetable dementia risk factor.

KW - ADGC

KW - CTAGE5

KW - KATP

KW - Neuropathology

KW - Oldest old

KW - Potassium channel

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M3 - Article

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AN - SCOPUS:84901614207

SN - 0001-6322

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SP - 825

EP - 843

JO - Acta Neuropathologica

JF - Acta Neuropathologica

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ER -

ABCC9 gene polymorphism is associated with hippocampal sclerosis of aging pathology

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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