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1. Brain expression genome-wide association study (eGWAS) identifies human disease-associated variants.

Author

Fanggeng Zou, High Seng Chai, Curtis S Younkin, Mariet Allen, Julia Crook, V Shane Pankratz, Minerva M Carrasquillo, Christopher N Rowley, Asha A Nair, Sumit Middha, Sooraj Maharjan, Thuy Nguyen, Li Ma, Kimberly G Malphrus, Ryan Palusak, Sarah Lincoln, Gina Bisceglio, Constantin Georgescu, Naomi Kouri, Christopher P Kolbert, Jin Jen, Jonathan L Haines, Richard Mayeux, Margaret A Pericak-Vance, Lindsay A Farrer, Gerard D Schellenberg, Alzheimer's Disease Genetics Consortium, Ronald C Petersen, Neill R Graff-Radford, Dennis W Dickson, Steven G Younkin, and Nilüfer Ertekin-Taner

Subjects
Genetics, QH426-470
Abstract

Genetic variants that modify brain gene expression may also influence risk for human diseases. We measured expression levels of 24,526 transcripts in brain samples from the cerebellum and temporal cortex of autopsied subjects with Alzheimer's disease (AD, cerebellar n=197, temporal cortex n=202) and with other brain pathologies (non-AD, cerebellar n=177, temporal cortex n=197). We conducted an expression genome-wide association study (eGWAS) using 213,528 cisSNPs within ± 100 kb of the tested transcripts. We identified 2,980 cerebellar cisSNP/transcript level associations (2,596 unique cisSNPs) significant in both ADs and non-ADs (q

Published
2012
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2. Evaluation of memory endophenotypes for association with CLU , CR1, and PICALM variants in black and white subjects

Author

Daniel J. Serie, Thuy Nguyen, Kimberly G. Malphrus, Neill R. Graff-Radford, Gina Bisceglio, Glenn E. Smith, John A. Lucas, Ryan Palusak, Mariet Allen, Li Ma, Rosebud O. Roberts, Robert J. Ivnik, Ronald C. Petersen, V. Shane Pankratz, Nilufer Ertekin-Taner, Kyle J. Jennette, Steven G. Younkin, Minerva M. Carrasquillo, Otto Pedraza, and Julia E. Crook

Subjects
Oncology, Genetics, medicine.medical_specialty, Epidemiology, Health Policy, Wechsler Adult Intelligence Scale, Context (language use), Single-nucleotide polymorphism, medicine.disease, PICALM, Logical address, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Internal medicine, Endophenotype, Multiple comparisons problem, medicine, Neurology (clinical), Geriatrics and Gerontology, Alzheimer's disease, Psychology
Abstract

Background Genetic variants at the CLU , CR1 , and PICALM loci associate with risk for late-onset Alzheimer's disease (LOAD) in genomewide association studies. In this study, our aim was to determine whether the LOAD risk variants at these three loci influence memory endophenotypes in black and white subjects. Methods We pursued an association study between single nucleotide polymorphism genotypes at the CLU , CR1 , and PICALM loci and memory endophenotypes. We assessed black subjects (AA series: 44 with LOAD and 224 control subjects) recruited at Mayo Clinic Florida and whites recruited at Mayo Clinic Minnesota (RS series: 372 with LOAD and 1690 control subjects) and Florida (JS series: 60 with LOAD and 529 control subjects). Single nucleotide polymorphisms at the LOAD risk loci CLU (rs11136000), CR1 (rs6656401, rs3818361), and PICALM (rs3851179) were genotyped and tested for association with Logical Memory immediate recall, Logical Memory delayed recall, Logical Memory percent retention, Visual Reproduction immediate recall, Visual Reproduction delayed recall, and Visual Reproduction percent retention scores from the Wechsler Memory Scale–Revised using multivariable linear regression analysis, adjusting for age at exam, sex, education, and apolipoprotein E e4 dosage. Results We identified nominally significant or suggestive associations between the LOAD-risky CR1 variants and worse Logical Memory immediate recall scores in blacks ( P = .068–.046, β = −2.7 to −1.2). The LOAD-protective CLU variant is associated with better logical memory endophenotypes in white subjects ( P = .099–.027, β = 0.31–0.93). The CR1 associations persisted when the control subjects from the AA series were assessed separately. The CLU associations appeared to be driven by one of the white series (RS) and were also observed when the control subset from RS was analyzed. Conclusion These results suggest for the first time that LOAD risk variants at CR1 may influence memory endophenotypes in blacks. In addition, the CLU LOAD-protective variant may confer enhanced memory in whites. Although these results would not remain significant after stringent corrections for multiple testing, they need to be considered in the context of the LOAD associations with which they have biological consistency. They also provide estimates for effect sizes on memory endophenotypes that could guide future studies. The detection of memory effects for these variants in clinically normal subjects, implies that these LOAD risk loci might modify memory prior to clinical diagnosis of AD.

Published
2013
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3. Comparative Functional Alanine Positional Scanning of the α-Melanocyte Stimulating Hormone and NDP-Melanocyte Stimulating Hormone Demonstrates Differential Structure-Activity Relationships at the Mouse Melanocortin Receptors

Author

Aleksandar Todorovic, Carrie Haskell-Luevano, Zhimin Xiang, Nicholas B. Sorensen, Michael S. Wood, Mark D. Ericson, and Ryan Palusak

Subjects
0301 basic medicine, medicine.medical_specialty, endocrine system, Melanocyte-stimulating hormone, Physiology, Cognitive Neuroscience, Nerve Tissue Proteins, Transfection, Biochemistry, Article, 03 medical and health sciences, Mice, Structure-Activity Relationship, 0302 clinical medicine, Proopiomelanocortin, Internal medicine, medicine, Animals, Humans, ACTH receptor, Melanocyte-Stimulating Hormones, Receptor, Eye Proteins, G protein-coupled receptor, Alanine, biology, integumentary system, Receptors, Melanocortin, digestive, oral, and skin physiology, Cell Biology, General Medicine, beta-Galactosidase, Melanocortin 3 receptor, Melanocortin 4 receptor, 030104 developmental biology, Endocrinology, HEK293 Cells, alpha-MSH, biology.protein, Melanocytes, Melanocortin, Oligopeptides, Protein Processing, Post-Translational, 030217 neurology & neurosurgery, hormones, hormone substitutes, and hormone antagonists
Abstract

The melanocortin system has been implicated in the regulation of various physiological functions including melanogenesis, steroidogenesis, energy homeostasis, and feeding behavior. Five melanocortin receptors have been identified to date and belong to the family of G protein-coupled receptors (GPCR). Post-translational modification of the proopiomelanocortin (POMC) prohormone leads to the biosynthesis of the endogenous melanocortin agonists, including α-melanocyte stimulating hormone (α-MSH), β-MSH, γ-MSH, and adrenocorticotropic hormone (ACTH). All the melanocortin agonists derived from the POMC prohormone contain a His-Phe-Arg-Trp tetrapeptide sequence that has been implicated in eliciting the pharmacological responses at the melanocortin receptors. Herein, an alanine (Ala) positional scan is reported for the endogenous α-MSH ligand and the synthetic, more potent, NDP-MSH peptide (Ac-Ser(1)-Tyr(2)-Ser(3)-Nle(4)-Glu(5)-His(6)-DPhe(7)-Arg(8)-Trp(9)-Gly(10)-Lys(11)-Pro(12)-Val(13)-NH2) at the cloned mouse melanocortin receptors to test the assumption that the structure-activity relationships of one ligand would apply to the other. Several residues outside of the postulated pharmacophore altered potency at the melanocortin receptors, most notably the 1560-, 37-, and 15-fold potency loss when the Glu(5) position of α-MSH was substituted with Ala at the mMC1R, mMC3R, and mMC4R, respectively. Importantly, the altered potencies due to Ala substitutions in α-MSH did not necessarily correlate with equivalent Ala substitutions in NDP-MSH, indicating that structural modifications and corresponding biological activities in one of these melanocortin ligands may not be predictive for the other agonist.

Published
2016

4. O3‐11‐03: Genetic association of variants with late‐onset Alzheimer's disease risk and brain gene expression

Author

Sumit Middha, Sarah Lincoln, Steven G. Younkin, Neill R. Graff-Radford, Thuy Nguyen, Fanggeng Zou, Lindsay A. Farrer, Ronald C. Petersen, High Seng Chai, Mariet Allen, Jin Jen, Nilufer Ertekin-Taner, Dennis W. Dickson, Christopher P. Kolbert, Julia E. Crook, Ryan Palusak, Christopher Rowley, Jonathan L. Haines, Margaret A. Pericak-Vance, Sooraj Maharjan, Kimberly G. Malphrus, Gina Bisceglio, Vernon S. Pankratz, Curtis S. Younkin, Gerard D. Schellenberg, Li Ma, Minerva M. Carrasquillo, Richard Mayeux, Constantin Georgescu, and Asha Nair

Subjects
Genetics, Epidemiology, Health Policy, Late onset, Genome-wide association study, Biology, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Gene expression, Disease risk, Neurology (clinical), Geriatrics and Gerontology, Common disease-common variant, Genetic association
Published
2012
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5. P1‐201: Identification of human disease‐associated variants in a brain expression genome‐wide association study (eGWAS)

Author

Nilufer Ertekin-Taner, Christopher Rowley, Sarah Lincoln, Jin Jen, Vernon S. Pankratz, Li Ma, Thuy Nguyen, Constantin Georgescu, Neill R. Graff-Radford, Asha Nair, Mariet Allen, Sooraj Maharjan, Kimberly G. Malphrus, Naomi Kouri, Curtis S. Younkin, Gina Bisceglio, Sumit Middha, Minerva M. Carrasquillo, Christopher P. Kolbert, Julia E. Crook, Fanggeng Zou, Dennis W. Dickson, Steven G. Younkin, Ryan Palusak, Ronald C. Petersen, and High Seng Chai

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Brain expression, Human disease, Developmental Neuroscience, Epidemiology, Health Policy, Identification (biology), Genome-wide association study, Neurology (clinical), Computational biology, Geriatrics and Gerontology, Biology
Published
2012
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6. O5‐03‐03: Genetic association of progressive supranuclear palsy (PSP) risk loci variants with brain gene expression and neuropathology endophenotypes

Author

Christopher P. Kolbert, Julia E. Crook, Ronald C. Petersen, Thuy Nguyen, Vernon S. Pankratz, Sarah Lincoln, Gina Bisceglio, High Seng Chai, Fanggeng Zou, Curtis S. Younkin, Li Ma, Mariet Allen, Sooraj Maharjan, Jin Jen, Gerard D. Schellenberg, Melissa E. Murray, Daniel J. Serie, Constantin Georgescu, Asha Nair, Ryan Palusak, Nilufer Ertekin-Taner, Kimberly G. Malphrus, Neill R. Graff-Radford, Dennis W. Dickson, Minerva M. Carrasquillo, Christopher Rowley, Naomi Kouri, Steven G. Younkin, and Sumit Middha

Subjects
Genetics, Epidemiology, Health Policy, Neuropathology, Biology, medicine.disease, Progressive supranuclear palsy, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Endophenotype, Gene expression, medicine, Neurology (clinical), Geriatrics and Gerontology, Genetic association
Published
2012
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7. Novel late-onset Alzheimer disease loci variants associate with brain gene expression

Author

Mariet, Allen, Fanggeng, Zou, High Seng, Chai, Curtis S, Younkin, Julia, Crook, V Shane, Pankratz, Minerva M, Carrasquillo, Christopher N, Rowley, Asha A, Nair, Sumit, Middha, Sooraj, Maharjan, Thuy, Nguyen, Li, Ma, Kimberly G, Malphrus, Ryan, Palusak, Sarah, Lincoln, Gina, Bisceglio, Constantin, Georgescu, Debra, Schultz, Fariborz, Rakhshan, Christopher P, Kolbert, Jin, Jen, Jonathan L, Haines, Richard, Mayeux, Margaret A, Pericak-Vance, Lindsay A, Farrer, Gerard D, Schellenberg, Ronald C, Petersen, Neill R, Graff-Radford, Dennis W, Dickson, Steven G, Younkin, Nilüfer, Ertekin-Taner, Liana G, Apostolova, Steven E, Arnold, Clinton T, Baldwin, Robert, Barber, Michael M, Barmada, Thomas, Beach, Gary W, Beecham, Duane, Beekly, David A, Bennett, Eileen H, Bigio, Thomas D, Bird, Deborah, Blacker, Bradley F, Boeve, James D, Bowen, Adam, Boxer, James R, Burke, Jacqueline, Buros, Joseph D, Buxbaum, Nigel J, Cairns, Laura B, Cantwell, Chuanhai, Cao, Chris S, Carlson, Regina M, Carney, Steven L, Carroll, Helena C, Chui, David G, Clark, Jason, Corneveaux, Carl W, Cotman, Paul K, Crane, Carlos, Cruchaga, Jeffrey L, Cummings, Philip L, De Jager, Charles, DeCarli, Steven T, DeKosky, F Yesim, Demirci, Ramon, Diaz-Arrastia, Malcolm, Dick, Beth A, Dombroski, Ranjan, Duara, William D, Ellis, Denis, Evans, Kelley M, Faber, Kenneth B, Fallon, Martin R, Farlow, Steven, Ferris, Tatiana M, Foroud, Matthew, Frosch, Douglas R, Galasko, Paul J, Gallins, Mary, Ganguli, Marla, Gearing, Daniel H, Geschwind, Bernardino, Ghetti, John R, Gilbert, Sid, Gilman, Bruno, Giordani, Jonathan D, Glass, Alison M, Goate, Robert C, Green, John H, Growdon, Hakon, Hakonarson, Ronald L, Hamilton, John, Hardy, Lindy E, Harrell, Elizabeth, Head, Lawrence S, Honig, Matthew J, Huentelman, Christine M, Hulette, Bradley T, Hyman, Gail P, Jarvik, Gregory A, Jicha, Lee-Way, Jin, Gyungah, Jun, M Ilyas, Kamboh, Jason, Karlawish, Anna, Karydas, John S K, Kauwe, Jeffrey A, Kaye, Nancy, Kennedy, Ronald, Kim, Edward H, Koo, Neil W, Kowall, Patricia, Kramer, Walter A, Kukull, James J, Lah, Eric B, Larson, Allan I, Levey, Andrew P, Lieberman, Oscar L, Lopez, Kathryn L, Lunetta, Wendy J, Mack, Daniel C, Marson, Eden R, Martin, Frank, Martiniuk, Deborah C, Mash, Eliezer, Masliah, Wayne C, McCormick, Susan M, McCurry, Andrew N, McDavid, Ann C, McKee, Marsel, Mesulam, Bruce L, Miller, Carol A, Miller, Joshua W, Miller, Thomas J, Montine, John C, Morris, Amanda J, Myers, Adam C, Naj, Petra, Nowotny, Joseph E, Parisi, Daniel P, Perl, Elaine, Peskind, Wayne W, Poon, Huntington, Potter, Joseph F, Quinn, Ashok, Raj, Ruchita A, Rajbhandary, Murray, Raskind, Eric M, Reiman, Barry, Reisberg, Christiane, Reitz, John M, Ringman, Erik D, Roberson, Ekaterina, Rogaeva, Roger N, Rosenberg, Mary, Sano, Andrew J, Saykin, Julie A, Schneider, Lon S, Schneider, William, Seeley, Michael L, Shelanski, Michael A, Slifer, Charles D, Smith, Joshua A, Sonnen, Salvatore, Spina, Peter, St George-Hyslop, Robert A, Stern, Rudolph E, Tanzi, John Q, Trojanowski, Juan C, Troncoso, Debby W, Tsuang, Vivianna M, Van Deerlin, Badri Narayan, Vardarajan, Harry V, Vinters, Jean Paul, Vonsattel, Li-San, Wang, Sandra, Weintraub, Kathleen A, Welsh-Bohmer, Jennifer, Williamson, and Randall L, Woltjer

Subjects
Male, Candidate gene, Genotype, Apolipoprotein E4, Gene Dosage, Gene Expression, Single-nucleotide polymorphism, Genome-wide association study, Locus (genetics), Biology, Gene dosage, Polymorphism, Single Nucleotide, PICALM, Alzheimer Disease, Risk Factors, Humans, Genetic Predisposition to Disease, Alleles, Genetic association, Aged, Temporal cortex, Genetics, Brain Chemistry, Temporal Lobe, Linear Models, RNA, Female, Neurology (clinical), Autopsy
Abstract

Objective: Recent genome-wide association studies (GWAS) of late-onset Alzheimer disease (LOAD) identified 9 novel risk loci. Discovery of functional variants within genes at these loci is required to confirm their role in Alzheimer disease (AD). Single nucleotide polymorphisms that influence gene expression (eSNPs) constitute an important class of functional variants. We therefore investigated the influence of the novel LOAD risk loci on human brain gene expression. Methods: We measured gene expression levels in the cerebellum and temporal cortex of autopsied AD subjects and those with other brain pathologies (∼400 total subjects). To determine whether any of the novel LOAD risk variants are eSNPs, we tested their cis -association with expression of 6 nearby LOAD candidate genes detectable in human brain ( ABCA7, BIN1, CLU, MS4A4A, MS4A6A, PICALM ) and an additional 13 genes ±100 kb of these SNPs. To identify additional eSNPs that influence brain gene expression levels of the novel candidate LOAD genes, we identified SNPs ±100 kb of their location and tested for cis -associations. Results: CLU rs11136000 ( p = 7.81 × 10 −4 ) and MS4A4A rs2304933/rs2304935 ( p = 1.48 × 10 −4 –1.86 × 10 −4 ) significantly influence temporal cortex expression levels of these genes. The LOAD-protective CLU and risky MS4A4A locus alleles associate with higher brain levels of these genes. There are other cis -variants that significantly influence brain expression of CLU and ABCA7 ( p = 4.01 × 10 −5 –9.09 × 10 −9 ), some of which also associate with AD risk ( p = 2.64 × 10 −2 –6.25 × 10 −5 ). Conclusions: CLU and MS4A4A eSNPs may at least partly explain the LOAD risk association at these loci. CLU and ABCA7 may harbor additional strong eSNPs. These results have implications in the search for functional variants at the novel LOAD risk loci.

Published
2012

8. O3‐01‐08: Evaluation of known Alzheimer's genes for SNPs that influence their brain expression (eSNPs)

Author

Neill R. Graff-Radford, Ronald C. Petersen, High Seng Chai, Fanggeng Zou, Thuy Nguyen, Jin Jen, Mariet Allen, Shane Pankratz, Gina Bisceglio, Curtis S. Younkin, Kimberly G. Malphrus, Christopher Rowley, Li Ma, Nilufer Ertekin-Taner, Constantin Georgescu, Asha Nair, Ryan Palusak, Minerva M. Carrasquillo, Sumit Middha, Steven G. Younkin, Dennis W. Dickson, Christopher P. Kolbert, Julia E. Crook, Sooraj Maharjan, and Sarah Lincoln

Subjects
Genetics, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Brain expression, Developmental Neuroscience, Epidemiology, Health Policy, Single-nucleotide polymorphism, Neurology (clinical), Geriatrics and Gerontology, Biology, Gene
Published
2011
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9. P1‐229: Genome‐Wide Association Study of Brain Gene Expression Levels (eGWAS)

Author

Kevin Morgan, Harry Campbell, Ozren Polasek, Fanggeng Zou, Shane Pankratz, Caroline Hayward, Clifford R. Jack, Dennis W. Dickson, Sarah Lincoln, Sigrid Botne Sando, Ronald C. Petersen, Ryan Palusak, High Seng Chai, Kimberly G. Malphrus, Neill R. Graff-Radford, Christopher Rowley, Christopher P. Kolbert, Otto Pedraza, Julia E. Crook, Maria Barcikowska, Gina Bisceglio, Thuy Nguyen, Morad Ansari, Jan O. Aasly, Li Ma, Nicholas D. Hastie, Igor Rudan, Sooraj Maharjan, Curtis S. Younkin, Mariet Allen, Zbigniew K. Wszolek, Constantin Georgescu, Nilufer Ertekin-Taner, Asha Nair, Jin Jen, Steven G. Younkin, Alan F. Wright, Minerva M. Carrasquillo, and Sumit Middha

Subjects
Genetics, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Gene expression, Expression quantitative trait loci, Genome-wide association study, Neurology (clinical), Geriatrics and Gerontology, Biology
Published
2011
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10. P1‐252: Evaluation of Cognitive Endophenotypes for Association with CLU, CR1 and PICALM LOAD Risk Genes

Author

Glenn E. Smith, Ronald C. Petersen, Mariet Allen, Rosebud O. Roberts, Neill R. Graff-Radford, Thuy Nguyen, Kimberly G. Malphrus, Kyle J. Jennette, Shane Pankratz, Otto Pedraza, Minerva M. Carrasquillo, Julia E. Crook, David S. Knopman, Ryan Palusak, Nilufer Ertekin-Taner, Robert J. Ivnik, and Steven G. Younkin

Subjects
Genetics, Epidemiology, Health Policy, Cognition, Biology, PICALM, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Endophenotype, Neurology (clinical), Geriatrics and Gerontology, Association (psychology), Gene
Published
2011
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11. P1‐102: Investigating cis‐SNP/mRNA level associations of candidate Alzheimer genes in different brain regions of patients and controls

Author

Richard Miles, Neil Graff-Radford, Minerva M. Carrasquillo, Ryan Palusak, Li Ma, Dennis W. Dickson, Steven G. Younkin, Thuy Nguyen, Ronald C. Petersen, Fanggeng Zou, and Nilufer Ertekin-Taner

Subjects
Genetics, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Mrna level, Epidemiology, Health Policy, SNP, Neurology (clinical), Geriatrics and Gerontology, Biology, Gene
Published
2010
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12. Novel Progressive Supranuclear Palsy (PSP) Risk Loci Variants Associate with Brain Gene Expression Levels (S54.002)

Author

Christopher P. Kolbert, Christopher Rowley, Gina Bisceglio, Steve Younkin, Neil Graff-Radford, Fanggeng Zou, Constantin Georgescu, Asha Nair, Thuy Nguyen, D. Dickson, J. Crook, Sumit Middha, R. C. Petersen, Sooraj Maharjan, Curtis S. Younkin, Nilufer Taner, High Seng Chai, Li Ma, V. Pankratz, Mariet Allen, Jin Jen, Minerva M. Carrasquillo, Ryan Palusak, Kimberly G. Malphrus, Naomi Kouri, and Sarah Lincoln

Subjects
Genetics, Gene expression, medicine, Neurology (clinical), Biology, medicine.disease, Progressive supranuclear palsy
Published
2012
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13. Brain Expression Genome-Wide Association Study (eGWAS) Identifies Human Disease-Associated Variants (P05.069)

Author

Nilufer Taner, Christopher P. Kolbert, Thuy Nguyen, Fanggeng Zou, Minerva M. Carrasquillo, Jin Jen, Neil Graff-Radford, Naomi Kouri, Sarah Lincoln, R. C. Petersen, Mariet Allen, Sumit Middha, J. Crook, Li Ma, Curtis S. Younkin, V. Pankratz, Steve Younkin, Ryan Palusak, Kimberly G. Malphrus, High Seng Chai, Gina Bisceglio, Constantin Georgescu, Asha Nair, Christopher Rowley, D. Dickson, and Sooraj Maharjan

Subjects
Brain expression, Human disease, Genome-wide association study, Neurology (clinical), Computational biology, Biology
Published
2012
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14. Glutathione S-transferase omega genes in Alzheimer and Parkinson disease risk, age-at-diagnosis and brain gene expression: an association study with mechanistic implications

Author

Thuy Nguyen, Fanggeng Zou, V. Shane Pankratz, Ryan J. Uitti, Constantin Georgescu, Asha Nair, Fariborz Rakhshan, Sigrid Botne Sando, Christopher P. Kolbert, Julia E. Crook, Maria Barcikowska, Mariet Allen, Owen A. Ross, Ronald C. Petersen, High Seng Chai, Christopher Rowley, Jin Jen, Dennis W. Dickson, Jan O. Aasly, Sooraj Maharjan, Neill R. Graff-Radford, Gina Bisceglio, Richard Miles, Curtis S. Younkin, Zbigniew K. Wszolek, Debra A. Schultz, Alexandra I. Ortolaza, Ryan Palusak, Li Ma, Sumit Middha, Minerva M. Carrasquillo, Nilufer Ertekin-Taner, Steven G. Younkin, and Kimberly G. Malphrus

Subjects
Disease risk, Clinical Neurology, Gene Expression, Genome-wide association study, Single-nucleotide polymorphism, Disease, lcsh:Geriatrics, Biology, Polymorphism, Single Nucleotide, lcsh:RC346-429, Association, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Alzheimer Disease, Risk Factors, medicine, Humans, Genetic Predisposition to Disease, Age of Onset, Allele, Molecular Biology, lcsh:Neurology. Diseases of the nervous system, Alleles, Aged, Glutathione Transferase, 030304 developmental biology, Aged, 80 and over, Genetics, GSTO genes, 0303 health sciences, Parkinson Disease, Odds ratio, Middle Aged, medicine.disease, Minor allele frequency, lcsh:RC952-954.6, Immunology, Neurology (clinical), Age of onset, Alzheimer's disease, 030217 neurology & neurosurgery, Follow-Up Studies, Research Article
Abstract

Background Glutathione S-transferase omega-1 and 2 genes (GSTO1, GSTO2), residing within an Alzheimer and Parkinson disease (AD and PD) linkage region, have diverse functions including mitigation of oxidative stress and may underlie the pathophysiology of both diseases. GSTO polymorphisms were previously reported to associate with risk and age-at-onset of these diseases, although inconsistent follow-up study designs make interpretation of results difficult. We assessed two previously reported SNPs, GSTO1 rs4925 and GSTO2 rs156697, in AD (3,493 ADs vs. 4,617 controls) and PD (678 PDs vs. 712 controls) for association with disease risk (case-controls), age-at-diagnosis (cases) and brain gene expression levels (autopsied subjects). Results We found that rs156697 minor allele associates with significantly increased risk (odds ratio = 1.14, p = 0.038) in the older ADs with age-at-diagnosis > 80 years. The minor allele of GSTO1 rs4925 associates with decreased risk in familial PD (odds ratio = 0.78, p = 0.034). There was no other association with disease risk or age-at-diagnosis. The minor alleles of both GSTO SNPs associate with lower brain levels of GSTO2 (p = 4.7 × 10-11-1.9 × 10-27), but not GSTO1. Pathway analysis of significant genes in our brain expression GWAS, identified significant enrichment for glutathione metabolism genes (p = 0.003). Conclusion These results suggest that GSTO locus variants may lower brain GSTO2 levels and consequently confer AD risk in older age. Other glutathione metabolism genes should be assessed for their effects on AD and other chronic, neurologic diseases.

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