Citations 3
Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes
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Proceedings of the National Academy of Sciences | August 29, 2023 | Volume: 120 | Issue: 36 | Pages: No page available
Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1 *04 subtypes best accounted for the association, strongest with HLA-DRB1 *04:04 and HLA-DRB1 *04:07, and intermediary with HLA-DRB1 *04:01 and HLA-DRB1 *04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1 *04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1 *04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.
Genetically Elevated LDL Associates with Lower Risk of Intracerebral Hemorrhage
Falcone, Guido J. , Kirsch, Elayna , Noche, Rommell B. , Leasure, Audrey C. , Marini, Sandro , Chung, Jaeyoon , Meschia, James F. , Brown, Devin L. , Worrall, Bradford B. , Tirschwell, David , Jagiełła, Jeremiasz , Schmidt, Helena , Jiménez-Conde, Jordi , Lindgren, Arne, Słowik, Agnieszka , Gill, Dipender , Petersen, Nils , Matouk, Charles N., Bennett, Derrick , Sun, Luan L., Clarke, Robert , Biffi, Alessandro , Kathiresan, Sekar , Langefeld, Carl D. , Woo, Daniel , Anderson, Christopher D. , James, Michael L. , Leasure, Audrey , Meschia, James F , Biffi, Alessandro , Acosta, Julián , Selim, Magdy H. , Fernández‐Cadenas, Israel , Lindgren, Arne, Holmes, Michael Vaclav , Phuah, Chia‐Ling , Matouk, Charles , Günel, Murat , Sansing, Lauren H , Chen, Zhengming , Walters, Robin G. , Gill, Thomas M. , Rosand, Jonathan M. , Sheth, Kevin N.
Annals of Neurology | April 11, 2020 | Volume: 88 | Issue: 1 | Pages: 56-66
ObjectiveObservational studies point to an inverse correlation between low‐density lipoprotein (LDL) cholesterol levels and risk of intracerebral hemorrhage (ICH), but it remains unclear whether this association is causal. We tested the hypothesis that genetically elevated LDL is associated with reduced risk of ICH.MethodsWe constructed one polygenic risk score (PRS) per lipid trait (total cholesterol, LDL, high‐density lipoprotein [HDL], and triglycerides) using independent genomewide significant single nucleotide polymorphisms (SNPs) for each trait. We used data from 316,428 individuals enrolled in the UK Biobank to estimate the effect of each PRS on its corresponding trait, and data from 1,286 ICH cases and 1,261 matched controls to estimate the effect of each PRS on ICH risk. We used these estimates to conduct Mendelian Randomization (MR) analyses.ResultsWe identified 410, 339, 393, and 317 lipid‐related SNPs for total cholesterol, LDL, HDL, and triglycerides, respectively. All four PRSs were strongly associated with their corresponding trait (all p < 1.00 × 10‐100). While one SD increase in the PRSs for total cholesterol (odds ratio [OR] = 0.92; 95% confidence interval [CI] = 0.85–0.99; p = 0.03) and LDL cholesterol (OR = 0.88; 95% CI = 0.81–0.95; p = 0.002) were inversely associated with ICH risk, no significant associations were found for HDL and triglycerides (both p > 0.05). MR analyses indicated that 1mmol/L (38.67mg/dL) increase of genetically instrumented total and LDL cholesterol were associated with 23% (OR = 0.77; 95% CI = 0.65–0.98; p = 0.03) and 41% lower risks of ICH (OR = 0.59; 95% CI = 0.42–0.82; p = 0.002), respectively.InterpretationGenetically elevated LDL levels were associated with lower risk of ICH, providing support for a potential causal role of LDL cholesterol in ICH. ANN NEUROL 2020 ANN NEUROL 2020;88:56–66
Convergent genetic and expression data implicate immunity in Alzheimer's disease
Jones, Lesley , Lambert, Jean‐Charles , Choi, Seung‐Hoan, Harold, Denise , Vedernikov, Alexey , Escott‐Price, Valentina , Stone, Timothy, Richards, Alexander , Bellenguez, Céline , Sims, Rebecca , DeStefano, Anita L. , Bis, Joshua C. , Beecham, Gary W. , Grenier‐Boley, Benjamin , Russo, Giancarlo , Thornton‐Wells, Tricia A., Jones, Nicola, Smith, Albert V. , Thomas, Charlene , Zélénika, Diana, Kamatani, Yoichiro, Lin, Chiao‐Feng , Schmidt, Helena , Kunkle, Brian W. , Dunstan, Melanie , Ruiz, Agustı́n , Bihoreau, Marie‐Thérèse, Reitz, Christiane, Hollingworth, Paul, Hanon, Olivier , Fitzpatrick, Annette L., Buxbaum, Joseph D. , Campion, Dominique , Crane, Paul K. , Guðnason, Vilmundur , Cruchaga, Carlos , Craig, David W. , Amin, Najaf , Jager, Philip L. De , Deramecourt, Vincent , Johnston, Janet, Evans, Denis A., Lovestone, Simon , Letteneur, Luc, Kornhuber, Johanes, Tárraga, Lluís , Eiriksdottir, Gudny, Goate, Alison , Fiévet, Nathalie, Huentelman, Matthew J. , Gill, Michael , Emilsson, Valur , Brown, Kristelle, Kamboh, M. Ilyas , Keller, Lina, Barberger‐Gateau, Pascale, McGuinness, Bernadette , Larson, Eric B., Dufouil, Carole , Todd, Stephen , Wallon, David , Kehoe, Patrick G. , George‐Hyslop, Peter St , Lleὀ, Alberti, Bayer, Anthony, Tsuang, Debby W. , Yu, Lei, Tsolaki, Magda , Bossù, Paola , Spalletta, Gianfranco , Proitsi, Petra, Collinge, John, Sorbi, Sandro , Hardy, John , Naranjo, María Cándida Déniz, Razquín, Cristina , Bosco, Paola , Clarke, Robert , Brayne, Carol , Galimberti, Daniela , CFAS, MRC, Moebus, Susanne , Mecocci, Patrizia , Zompo, Maria Del, Maier, Wolfgang, Hampel, Harald , Pilotto, Alberto, Bullido, María J. , Panza, Francesco , Caffarra, Paolo , Nacmias, Benedetta , Gilbert, John R., Mayhaus, Manuel, Jessen, Frank , Dichgans, Martin , Lannfelt, Lars , Håkonarson, Håkon , Pichler, Sabrina, Carrasquillo, Minerva M., Beekly, Duane, Alavarez, Victoria, Zou, Fanggeng, Younkin, Steven G., Hamilton‐Nelson, Kara L., Mateo, Ignacio, Faber, Kelley M., Jónsson, Pálmi V. , Combarros, Onofre, O‘Donovan, Michael , Cantwell, Laura B., Blacker, Deborah , Mead, Simon , Harris, Tamara B., Fratiglioni, Laura , Bruijn, Renée F.A.G. de, Passmore, Peter , Montine, Thomas J. , Bettens, Karolien, Rotter, Jerome I. , Brice, Alexis , Morgan, Kevin , Foroud, Tatiana, Kukull, Walter A. , Hannequin, Didier , Powell, John , Nalls, Michael A., Ritchie, Karen , Lunetta, Kathryn L. , Kauwe, John S.K., Boerwinkle, Eric , Riemenschneider, Matthias, Boada, Merçé , Hiltunen, Mikko , Martin, Eden R. , Pástor, Pau , Schmidt, Reinhold, Dartigues, Jean‐François, Mayeux, Richard , Tzourio, Christophe , Hofman, Albert , Nöthen, Markus M. , Graff, Caroline , Haines, Jonathan L. , Lathrop, Mark, Pericak‐Vance, Margaret A. , Launer, Lenore J. , Farrer, Lindsay A. , Duijn, Cornelia M. van , Broeckhoven, Christine Van , Ramı́rez, Alfredo , Schellenberg, Gerard D., Seshadri, Sudha , Amouyel, Philippe , Williams, Julie , Holmans, Peter , Bennett, David A. , Proitsi, Petroula , Ballantyne, Christie M. , Denning, Nicola , Wang, Weixin , Ibrahim‐Verbaas, Carla A. , Naj, Adam Christian , Gerrish, Amy , Jun, Gyungah , Chouraki, Vincent Antoine , Ikram, M. Arfan , Vardarajan, Badri Narayan , Kamatani, Yoichiro, Pasquier, Florence , Becker, Tim , Cruchaga, Carlos , Berr, Claudine , López, Oscar L. , Rubinsztein, David Chaim , Sleegers, Kristel , Myers, Amanda , Love, Seth , Rogaeva, Ekaterina A. , Gallacher, John , Clarimón, Jordi , Bayer, Anthony, Proitsi, Petra, Sánchez-García, Florentino , Fox, Nick C. , Mancuso, Michelangelo , CFAS, MRC, Carrasquillo, Minerva M. , Ingelsson, Martin , Valladares, Otto , Coto, Eliécer , Hamilton‐Nelson, Kara L. , Owen, Michael J. , Soininen, Hilkka S. , Mosley, Thomas H. , Bennett, David , Holmes, Clive , Riemenschneider, Matthias, Rujescu, Dan , Psaty, Bruce M. , Bennett, David A. , Dichgans, Martin , Ramirez, Alfredo , Hakonarson, Hakon , Nöthen, Markus M , Seshadri, Sudha , Hardy, John , Amouyel, Philippe , Tzourio, Christophe , van Duijn, Cornelia M , Smith, Albert V , Ballantyne, Christie M , Rotter, Jerome I , Moebus, Susanne , Ruiz, Agustín , Pastor, Pau , Boada, Merce , Tsolaki, Magda , Brice, Alexis , Goate, Alison M , Galimberti, Daniela , Escott-Price, Valentina , Mecocci, Patrizia , Nacmias, Benedetta , Graff, Caroline , Riemenschneider, Markus J.
Alzheimer's & Dementia | December 20, 2014 | Volume: 11 | Issue: 6 | Pages: 658-671
AbstractBackgroundLate‐onset Alzheimer's disease (AD) is heritable with 20 genes showing genome‐wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis.MethodsThe ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain.ResultsALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 × 10−12 after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 × 10−11), cholesterol transport (P = 2.96 × 10−9), and proteasome‐ubiquitin activity (P = 1.34 × 10−6). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002–.05).ConclusionsThe immune response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics.