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1. Transethnic genome-wide scan identifies novel Alzheimer's disease loci

Author

Jun, Gyungah R., Chung, Jaeyoon, Mez, Jesse, Barber, Robert, Beecham, Gary W., Bennett, David A., Buxbaum, Joseph D., Byrd, Goldie S., Carrasquillo, Minerva M., Crane, Paul K., Cruchaga, Carlos, De Jager, Philip, Ertekin-Taner, Nilufer, Evans, Denis, Fallin, M. Danielle, Foroud, Tatiana M., Friedland, Robert P., Goate, Alison M., Graff-Radford, Neill R., Hendrie, Hugh, Hall, Kathleen S., Hamilton-Nelson, Kara L., Inzelberg, Rivka, Kamboh, M. Ilyas, Kauwe, John S.K., Kukull, Walter A., Kunkle, Brian W., Kuwano, Ryozo, Larson, Eric B., Logue, Mark W., Manly, Jennifer J., Martin, Eden R., Montine, Thomas J., Mukherjee, Shubhabrata, Naj, Adam, Reiman, Eric M., Reitz, Christiane, Sherva, Richard, St. George-Hyslop, Peter H., Thornton, Timothy, Younkin, Steven G., Vardarajan, Badri N., Wang, Li-San, Wendlund, Jens R., Winslow, Ashley R., Haines, Jonathan, Mayeux, Richard, Pericak-Vance, Margaret A., Schellenberg, Gerard, Lunetta, Kathryn L., Farrer, Lindsay A., Adams, Perrie M., Albert, Marilyn S., Albin, Roger L., Apostolova, Liana G., Arnold, Steven E., Asthana, Sanjay, Atwood, Craig S., Barmada, Michjael M., Barnes, Lisa L., Beach, Thomas G., Becker, James T., Bigio, Eileen H., Bird, Thomas D., Blacker, Deborah, Boeve, Bradley F., Bowen, James D., Boxer, Adam, Burke, James R., Cairns, Nigel J., Cao, Chuanhai, Carlson, Chris S., Carlsson, Cynthia M., Carney, Regina M., Carroll, Steven L., Chui, Helena C., Clark, David G., Corneveaux, Jason, Cribbs, David H., Crocco, Elizabeth A., De Jager, Philip L., DeCarli, Charles, DeKosky, Steven T., Demirci, F. Yesim, Dick, Malcolm, Dickson, Dennis W., Doody, Rachelle S., Duara, Ranjan, Faber, Kelley M., Fairchild, Thomas J., Fallon, Kenneth B., Farlow, Martin R., Ferris, Steven, Frosch, Matthew P., Galasko, Douglas R., Gearing, Marla, Geschwind, Daniel H., Ghetti, Bernardino, Gilbert, John R., Glass, Jonathan D., Green, Robert C., Growdon, John H., Hakonarson, Hakon, Hamilton, Ronald L., Hardy, John, Harrell, Lindy E., Head, Elizabeth, Honig, Lawrence S., Huebinger, Ryan M., Huentelman, Matthew J., Hulette, Christine M., Hyman, Bradley T., Jarvik, Gail P., Jicha, Gregory A., Jin, Lee-Way, Karydas, Anna, Kaye, Jeffrey A., Kim, Ronald, Koo, Edward H., Kowall, Neil W., Kramer, Joel H., LaFerla, Frank M., Lah, James J., Leverenz, James B., Levey, Allan I., Li, Ge, Lieberman, Andrew P., Lin, Chiao-Feng, Lopez, Oscar L., Lyketsos, Constantine G., Mack, Wendy J., Marson, Daniel C., Martiniuk, Frank, Mash, Deborah C., Masliah, Eliezer, McCormick, Wayne C., McCurry, Susan M., McDavid, Andrew N., McKee, Ann C., Mesulam, Marsel, Miller, Bruce L., Miller, Carol A., Miller, Joshua W., Morris, John C., Murrell, Jill R., Myers, Amanda J., O'Bryant, Sid, Olichney, John M., Pankratz, Vernon S., Parisi, Joseph E., Partch, Amanda, Paulson, Henry L., Perry, William, Peskind, Elaine, Petersen, Ronald C., Pierce, Aimee, Poon, Wayne W., Potter, Huntington, Quinn, Joseph F., Raj, Ashok, Raskind, Murray, Reisberg, Barry, Reisch, Joan S., Ringman, John M., Roberson, Erik D., Rogaeva, Ekaterina, Rosen, Howard J., Rosenberg, Roger N., Royall, Donald R., Sager, Mark A., Sano, Mary, Saykin, Andrew J., Schneider, Julie A., Schneider, Lon S., Seeley, William W., Smith, Amanda G., Sonnen, Joshua A., Spina, Salvatore, Stern, Robert A., Tanzi, Rudolph E., Thornton-Wells, Tricia A., Trojanowski, John Q., Troncoso, Juan C., Tsuang, Debby W., Van Deerlin, Vivianna M., Van Eldik, Linda J., Vinters, Harry V., Vonsattel, Jean Paul, Weintraub, Sandra, Welsh-Bohmer, Kathleen A., Williamson, Jennifer, Wishnek, Sarah, Woltjer, Randall L., Wright, Clinton B., Wu, Chuang-Kuo, Yu, Chang-En, Yu, Lei, and Zhang, Xiaoling

Subjects
0301 basic medicine, Apolipoprotein E, Epidemiology, Apolipoprotein E4, Clinical Neurology, Genomics, Genome-wide association study, Locus (genetics), Single-nucleotide polymorphism, Biology, Peroxisomal Bifunctional Enzyme, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, Receptors, GABA, Developmental Neuroscience, Alzheimer Disease, SNP, Humans, Genetic Predisposition to Disease, Allele, Adaptor Proteins, Signal Transducing, Genetics, Membrane Glycoproteins, Health Policy, GTPase-Activating Proteins, Genetic architecture, NFI Transcription Factors, Psychiatry and Mental health, 030104 developmental biology, Neurology (clinical), Geriatrics and Gerontology, Genome-Wide Association Study, Heparin-binding EGF-like Growth Factor, Molecular Chaperones
Abstract

Introduction Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood. Methods We conducted a transethnic genome-wide association study (GWAS) for late-onset AD in Stage 1 sample including whites of European Ancestry, African-Americans, Japanese, and Israeli-Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset. Results Genome-wide significant (GWS) associations in single-nucleotide polymorphism (SNP)–based tests ( P −8 ) were identified for SNPs in PFDN1/HBEGF , USP6NL/ECHDC3 , and BZRAP1-AS1 and for the interaction of the (apolipoprotein E) APOE e4 allele with NFIC SNP. We also obtained GWS evidence ( P −6 ) for gene-based association in the total sample with a novel locus, TPBG ( P = 1.8 × 10 −6 ). Discussion Our findings highlight the value of transethnic studies for identifying novel AD susceptibility loci.

Published
2017
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2. Novel late-onset Alzheimer disease loci variants associate with brain gene expression

Author

Allen, Mariet, Zou, Fanggeng, Chai, High Seng, Younkin, Curtis S, Crook, Julia, Pankratz, V Shane, Carrasquillo, Minerva M, Rowley, Christopher N, Nair, Asha A, Middha, Sumit, Maharjan, Sooraj, Nguyen, Thuy, Ma, Li, Malphrus, Kimberly G, Palusak, Ryan, Lincoln, Sarah, Bisceglio, Gina, Georgescu, Constantin, Schultz, Debra, Rakhshan, Fariborz, Kolbert, Christopher P, Jen, Jin, Haines, Jonathan L, Mayeux, Richard, Pericak-Vance, Margaret A, Farrer, Lindsay A, Schellenberg, Gerard D, Petersen, Ronald C, Graff-Radford, Neill R, Dickson, Dennis W, Younkin, Steven G, Ertekin-Taner, Nilüfer, Alzheimer's Disease Genetics Consortium (ADGC), Apostolova, Liana G, Arnold, Steven E, Baldwin, Clinton T, Barber, Robert, Barmada, Michael M, Beach, Thomas, Beecham, Gary W, Beekly, Duane, Bennett, David A, Bigio, Eileen H, Bird, Thomas D, Blacker, Deborah, Boeve, Bradley F, Bowen, James D, Boxer, Adam, Burke, James R, Buros, Jacqueline, Buxbaum, Joseph D, Cairns, Nigel J, Cantwell, Laura B, Cao, Chuanhai, Carlson, Chris S, Carney, Regina M, Carroll, Steven L, Chui, Helena C, Clark, David G, Corneveaux, Jason, Cotman, Carl W, Crane, Paul K, Cruchaga, Carlos, Cummings, Jeffrey L, De Jager, Philip L, DeCarli, Charles, DeKosky, Steven T, Demirci, F Yesim, Diaz-Arrastia, Ramon, Dick, Malcolm, Dombroski, Beth A, Duara, Ranjan, Ellis, William D, Evans, Denis, Faber, Kelley M, Fallon, Kenneth B, Farlow, Martin R, Ferris, Steven, Foroud, Tatiana M, Frosch, Matthew, Galasko, Douglas R, Gallins, Paul J, Ganguli, Mary, Gearing, Marla, Geschwind, Daniel H, Ghetti, Bernardino, Gilbert, John R, Gilman, Sid, Giordani, Bruno, Glass, Jonathan D, Goate, Alison M, Green, Robert C, Growdon, John H, Hakonarson, Hakon, Hamilton, Ronald L, Hardy, John, Harrell, Lindy E, Head, Elizabeth, Honig, Lawrence S, and Huentelman, Matthew J

Subjects
Male, Aging, Genotype, Apolipoprotein E4, Clinical Sciences, Gene Dosage, Gene Expression, Neurodegenerative, Alzheimer's Disease, Alzheimer Disease, Risk Factors, Clinical Research, Acquired Cognitive Impairment, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Polymorphism, Aetiology, Alleles, Aged, Brain Chemistry, Neurology & Neurosurgery, Human Genome, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Single Nucleotide, Temporal Lobe, Brain Disorders, Neurological, Alzheimer's Disease Genetics Consortium, Linear Models, RNA, Female, Dementia, Cognitive Sciences, Autopsy
Abstract

ObjectiveRecent 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.MethodsWe 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.ResultsCLU 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)).ConclusionsCLU 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

3. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

Author

Sims, Rebecca, Van Der Lee, Sven J, Naj, Adam C, Bellenguez, Céline, Badarinarayan, Nandini, Jakobsdottir, Johanna, Kunkle, Brian W, Boland, Anne, Raybould, Rachel, Bis, Joshua C, Martin, Eden R, Grenier-Boley, Benjamin, Heilmann-Heimbach, Stefanie, Chouraki, Vincent, Kuzma, Amanda B, Sleegers, Kristel, Vronskaya, Maria, Ruiz, Agustin, Graham, Robert R, Olaso, Robert, Hoffmann, Per, Grove, Megan L, Vardarajan, Badri N, Hiltunen, Mikko, Nöthen, Markus M, White, Charles C, Hamilton-Nelson, Kara L, Epelbaum, Jacques, Maier, Wolfgang, Choi, Seung-Hoan, Beecham, Gary W, Dulary, Cécile, Herms, Stefan, Smith, Albert V, Funk, Cory C, Derbois, Céline, Forstner, Andreas J, Ahmad, Shahzad, Li, Hongdong, Bacq, Delphine, Harold, Denise, Satizabal, Claudia L, Valladares, Otto, Squassina, Alessio, Thomas, Rhodri, Brody, Jennifer A, Qu, Liming, Sánchez-Juan, Pascual, Morgan, Taniesha, Wolters, Frank J, Zhao, Yi, Garcia, Florentino Sanchez, Denning, Nicola, Fornage, Myriam, Malamon, John, Naranjo, Maria Candida Deniz, Majounie, Elisa, Mosley, Thomas H, Dombroski, Beth, Wallon, David, Lupton, Michelle K, Dupuis, Josée, Whitehead, Patrice, Fratiglioni, Laura, Medway, Christopher, Jian, Xueqiu, Mukherjee, Shubhabrata, Keller, Lina, Brown, Kristelle, Lin, Honghuang, Cantwell, Laura B, Panza, Francesco, McGuinness, Bernadette, Moreno-Grau, Sonia, Burgess, Jeremy D, Solfrizzi, Vincenzo, Proitsi, Petra, Adams, Hieab H, Allen, Mariet, Seripa, Davide, Pastor, Pau, Cupples, L Adrienne, Price, Nathan D, Hannequin, Didier, Frank-García, Ana, Levy, Daniel, Chakrabarty, Paramita, Caffarra, Paolo, Giegling, Ina, Beiser, Alexa S, Giedraitis, Vilmantas, Hampel, Harald, Garcia, Melissa E, Wang, Xue, Lannfelt, Lars, Mecocci, Patrizia, Eiriksdottir, Gudny, Crane, Paul K, Pasquier, Florence, Boccardi, Virginia, Henández, Isabel, Barber, Robert C, Scherer, Martin, Tarraga, Lluis, Adams, Perrie M, Leber, Markus, Chen, Yuning, Albert, Marilyn S, Riedel-Heller, Steffi, Emilsson, Valur, Beekly, Duane, Braae, Anne, Schmidt, Reinhold, Blacker, Deborah, Masullo, Carlo, Schmidt, Helena, Doody, Rachelle S, Spalletta, Gianfranco, Longstreth, WT, Fairchild, Thomas J, Bossù, Paola, Lopez, Oscar L, Frosch, Matthew P, Sacchinelli, Eleonora, Ghetti, Bernardino, Yang, Qiong, Huebinger, Ryan M, Jessen, Frank, Li, Shuo, Kamboh, M Ilyas, Morris, John, Sotolongo-Grau, Oscar, Katz, Mindy J, Corcoran, Chris, Dunstan, Melanie, Braddel, Amy, Thomas, Charlene, Meggy, Alun, Marshall, Rachel, Gerrish, Amy, Chapman, Jade, Aguilar, Miquel, Taylor, Sarah, Hill, Matt, Fairén, Mònica Díez, Hodges, Angela, Vellas, Bruno, Soininen, Hilkka, Kloszewska, Iwona, Daniilidou, Makrina, Uphill, James, Patel, Yogen, Hughes, Joseph T, Lord, Jenny, Turton, James, Hartmann, Annette M, Cecchetti, Roberta, Fenoglio, Chiara, Serpente, Maria, Arcaro, Marina, Caltagirone, Carlo, Orfei, Maria Donata, Ciaramella, Antonio, Pichler, Sabrina, Mayhaus, Manuel, Gu, Wei, Lleó, Alberto, Fortea, Juan, Blesa, Rafael, Barber, Imelda S, Brookes, Keeley, Cupidi, Chiara, Maletta, Raffaele Giovanni, Carrell, David, Sorbi, Sandro, Moebus, Susanne, Urbano, Maria, Pilotto, Alberto, Kornhuber, Johannes, Bosco, Paolo, Todd, Stephen, Craig, David, Johnston, Janet, Gill, Michael, Lawlor, Brian, Lynch, Aoibhinn, Fox, Nick C, Hardy, John, ARUK Consortium, Albin, Roger L, Apostolova, Liana G, Arnold, Steven E, Asthana, Sanjay, Atwood, Craig S, Baldwin, Clinton T, Barnes, Lisa L, Barral, Sandra, Beach, Thomas G, Becker, James T, Bigio, Eileen H, Bird, Thomas D, Boeve, Bradley F, Bowen, James D, Boxer, Adam, Burke, James R, Burns, Jeffrey M, Buxbaum, Joseph D, Cairns, Nigel J, Cao, Chuanhai, Carlson, Chris S, Carlsson, Cynthia M, Carney, Regina M, Carrasquillo, Minerva M, Carroll, Steven L, Diaz, Carolina Ceballos, Chui, Helena C, Clark, David G, Cribbs, David H, Crocco, Elizabeth A, DeCarli, Charles, Dick, Malcolm, Duara, Ranjan, Evans, Denis A, Faber, Kelley M, Fallon, Kenneth B, Fardo, David W, Farlow, Martin R, Ferris, Steven, Foroud, Tatiana M, Galasko, Douglas R, Gearing, Marla, Geschwind, Daniel H, Gilbert, John R, Graff-Radford, Neill R, Green, Robert C, Growdon, John H, Hamilton, Ronald L, Harrell, Lindy E, Honig, Lawrence S, Huentelman, Matthew J, Hulette, Christine M, Hyman, Bradley T, Jarvik, Gail P, Abner, Erin, Jin, Lee-Way, Jun, Gyungah, Karydas, Anna, Kaye, Jeffrey A, Kim, Ronald, Kowall, Neil W, Kramer, Joel H, LaFerla, Frank M, Lah, James J, Leverenz, James B, Levey, Allan I, Li, Ge, Lieberman, Andrew P, Lunetta, Kathryn L, Lyketsos, Constantine G, Marson, Daniel C, Martiniuk, Frank, Mash, Deborah C, Masliah, Eliezer, McCormick, Wayne C, McCurry, Susan M, McDavid, Andrew N, McKee, Ann C, Mesulam, Marsel, Miller, Bruce L, Miller, Carol A, Miller, Joshua W, Morris, John C, Murrell, Jill R, Myers, Amanda J, O'Bryant, Sid, Olichney, John M, Pankratz, Vernon S, Parisi, Joseph E, Paulson, Henry L, Perry, William, Peskind, Elaine, Pierce, Aimee, Poon, Wayne W, Potter, Huntington, Quinn, Joseph F, Raj, Ashok, Raskind, Murray, Reisberg, Barry, Reitz, Christiane, Ringman, John M, Roberson, Erik D, Rogaeva, Ekaterina, Rosen, Howard J, Rosenberg, Roger N, Sager, Mark A, Saykin, Andrew J, Schneider, Julie A, Schneider, Lon S, Seeley, William W, Smith, Amanda G, Sonnen, Joshua A, Spina, Salvatore, Stern, Robert A, Swerdlow, Russell H, Tanzi, Rudolph E, Thornton-Wells, Tricia A, Trojanowski, John Q, Troncoso, Juan C, Van Deerlin, Vivianna M, Van Eldik, Linda J, Vinters, Harry V, Vonsattel, Jean Paul, Weintraub, Sandra, Welsh-Bohmer, Kathleen A, Wilhelmsen, Kirk C, Williamson, Jennifer, Wingo, Thomas S, Woltjer, Randall L, Wright, Clinton B, Yu, Chang-En, Yu, Lei, Garzia, Fabienne, Golamaully, Feroze, Septier, Gislain, Engelborghs, Sebastien, Vandenberghe, Rik, De Deyn, Peter P, Fernadez, Carmen Muñoz, Benito, Yoland Aladro, Thonberg, Hakan, Forsell, Charlotte, Lilius, Lena, Kinhult-Stählbom, Anne, Kilander, Lena, Brundin, RoseMarie, Concari, Letizia, Helisalmi, Seppo, Koivisto, Anne Maria, Haapasalo, Annakaisa, Dermecourt, Vincent, Fievet, Nathalie, Hanon, Olivier, Dufouil, Carole, Brice, Alexis, Ritchie, Karen, Dubois, Bruno, Himali, Jayanadra J, Keene, C Dirk, Tschanz, JoAnn, Fitzpatrick, Annette L, Kukull, Walter A, Norton, Maria, Aspelund, Thor, Larson, Eric B, Munger, Ron, Rotter, Jerome I, Lipton, Richard B, Bullido, María J, Hofman, Albert, Montine, Thomas J, Coto, Eliecer, Boerwinkle, Eric, Petersen, Ronald C, Alvarez, Victoria, Rivadeneira, Fernando, Reiman, Eric M, Gallo, Maura, O'Donnell, Christopher J, Reisch, Joan S, Bruni, Amalia Cecilia, Royall, Donald R, Dichgans, Martin, Sano, Mary, Galimberti, Daniela, St George-Hyslop, Peter, Scarpini, Elio, Tsuang, Debby W, Mancuso, Michelangelo, Bonuccelli, Ubaldo, Winslow, Ashley R, Daniele, Antonio, Wu, Chuang-Kuo, GERAD/PERADES, CHARGE, Peters, Oliver, Nacmias, Benedetta, Riemenschneider, Matthias, Heun, Reinhard, Brayne, Carol, Rubinsztein, David C, Bras, Jose, Guerreiro, Rita, Al-Chalabi, Ammar, Shaw, Christopher E, Collinge, John, Mann, David, Tsolaki, Magda, Clarimón, Jordi, Sussams, Rebecca, Lovestone, Simon, O'Donovan, Michael C, Owen, Michael J, Behrens, Timothy W, Mead, Simon, Goate, Alison M, Uitterlinden, Andre G, Holmes, Clive, Cruchaga, Carlos, Ingelsson, Martin, Bennett, David A, Powell, John, Golde, Todd E, Graff, Caroline, De Jager, Philip L, Morgan, Kevin, Ertekin-Taner, Nilufer, Combarros, Onofre, Psaty, Bruce M, Passmore, Peter, Younkin, Steven G, Berr, Claudine, Gudnason, Vilmundur, Rujescu, Dan, Dickson, Dennis W, Dartigues, Jean-François, DeStefano, Anita L, Ortega-Cubero, Sara, Hakonarson, Hakon, Campion, Dominique, Boada, Merce, Kauwe, John Keoni, Farrer, Lindsay A, Van Broeckhoven, Christine, Ikram, M Arfan, Jones, Lesley, Haines, Jonathan L, Tzourio, Christophe, Launer, Lenore J, Escott-Price, Valentina, Mayeux, Richard, Deleuze, Jean-François, Amin, Najaf, Holmans, Peter A, Pericak-Vance, Margaret A, Amouyel, Philippe, Van Duijn, Cornelia M, Ramirez, Alfredo, Wang, Li-San, Lambert, Jean-Charles, Seshadri, Sudha, Williams, Julie, and Schellenberg, Gerard D

Subjects
Membrane Glycoproteins, Genotype, Sequence Homology, Amino Acid, Phospholipase C gamma, Gene Expression Profiling, Polymorphism, Single Nucleotide, Immunity, Innate, Linkage Disequilibrium, 3. Good health, Gene Frequency, Alzheimer Disease, Case-Control Studies, Odds Ratio, Humans, Exome, Genetic Predisposition to Disease, Amino Acid Sequence, Microglia, Protein Interaction Maps, Receptors, Immunologic, Adaptor Proteins, Signal Transducing
Abstract

We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10-10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10-14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

4. Mitochondrial haplogroups and cognitive progression in Parkinson's disease

Author

Liu, Ganqiang, Ni, Chunming, Zhan, Jiamin, Li, Weimin, Luo, Junfeng, Liao, Zhixiang, Locascio, Joseph J, Xian, Wenbiao, Chen, Ling, Pei, Zhong, Corvol, Jean-Christophe, Maple-Grødem, Jodi, Campbell, Meghan C, Elbaz, Alexis, Lesage, Suzanne, Brice, Alexis, Hung, Albert Y, Schwarzschild, Michael A, Hayes, Michael T, Wills, Anne-Marie, Ravina, Bernard, Shoulson, Ira, Taba, Pille, Kõks, Sulev, Beach, Thomas G, Cormier-Dequaire, Florence, Alves, Guido, Tysnes, Ole-Bjørn, Perlmutter, Joel S, Heutink, Peter, Van Hilten, Jacobus J, Barker, Roger A, Williams-Gray, Caroline H, Scherzer, Clemens R, International Genetics Of Parkinson Disease Progression (IGPP) Consortium, Liu, Ganqiang [0000-0002-1921-9542], Pei, Zhong [0000-0002-8425-2867], Elbaz, Alexis [0000-0001-9724-5490], Apollo - University of Cambridge Repository, Liu, Ganqiang, Valentino, Rebecca R, Peng, Jiajie, Liao, Zhixiang, Locascio, Joseph J, Corvol, Jean-Christophe, Dong, Xianjun, Maple-Grødem, Jodi, Campbell, Meghan C, Elbaz, Alexis, Lesage, Suzanne, Brice, Alexis, Mangone, Graziella, Growdon, John H, Hung, Albert Y, Schwarzchild, Michael A, Hayes, Michael T, Wills, Anne-Marie, Herrington, Todd M, Ravian, Bernard, Shoulson, Ira, Taba, Pille, Kõks, Sulev, Beach, Thomas G, Cormier-Dequaire, Florence, Alves, Guido, Tysnes, Ole-Bjørn, Perlmutter, Joel S, Heutink, Peter, van Hilten, Jacobus J, Kasten, Meike, Mollenhauer, Brit, Trenkwalder, Claudia, Klein, Christine, Barker, Roger A, Williams-Gray, Caroline H, Marinus, Johan, and Scherzer, Clemens R

Subjects
mitochondrial haplogroups, Parkinson's disease, cognitive progression, Parkinson Disease, genetics [DNA, Mitochondrial], DNA, Mitochondrial, Mitochondria, Cognition, Haplotypes, genetics [Parkinson Disease], Report, Parkinson’s disease, Disease Progression, Humans, Neurology (clinical), ddc:610, epidemiology [Parkinson Disease], genetics [Mitochondria]
Abstract

Liu et al. report that specific mitochondrial haplogroups are associated with the progression of cognitive decline in patients with Parkinson's disease, but not with the progression of motor impairment. Mitochondrial haplotypes may thus be useful for stratifying patients according to their risk of cognitive decline.Mitochondria are a culprit in the onset of Parkinson's disease, but their role during disease progression is unclear. Here we used Cox proportional hazards models to exam the effect of variation in the mitochondrial genome on longitudinal cognitive and motor progression over time in 4064 patients with Parkinson's disease. Mitochondrial macro-haplogroup was associated with reduced risk of cognitive disease progression in the discovery and replication population. In the combined analysis, patients with the super macro-haplogroup J, T, U-# had a 41% lower risk of cognitive progression with P = 2.42 x 10(-6) compared to those with macro-haplogroup H. Exploratory analysis indicated that the common mitochondrial DNA variant, m.2706A>G, was associated with slower cognitive decline with a hazard ratio of 0.68 (95% confidence interval 0.56-0.81) and P = 2.46 x 10(-5). Mitochondrial haplogroups were not appreciably linked to motor progression. This initial genetic survival study of the mitochondrial genome suggests that mitochondrial haplogroups may be associated with the pace of cognitive progression in Parkinson's disease over time.

Published
2023
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