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151. Identification of genes associated with dissociation of cognitive performance and neuropathological burden: Multistep analysis of genetic, epigenetic, and transcriptional data

Author

White, Charles C., Yang, Hyun-Sik, Yu, Lei, Chibnik, Lori B., Dawe, Robert J., Yang, Jingyun, Klein, Hans-Ulrich, Felsky, Daniel, Ramos-Miguel, Alfredo, Arfanakis, Konstantinos, Honer, William G., Sperling, Reisa A., Schneider, Julie A., Bennett, David A., and De Jager, Philip Lawrence

Subjects
Cognition, Neurology, Genes, Nervous system--Diseases, Cognitive neuroscience, 3. Good health
Abstract

Introduction: The molecular underpinnings of the dissociation of cognitive performance and neuropathological burden are poorly understood, and there are currently no known genetic or epigenetic determinants of the dissociation. Methods and findings: “Residual cognition” was quantified by regressing out the effects of cerebral pathologies and demographic characteristics on global cognitive performance proximate to death. To identify genes influencing residual cognition, we leveraged neuropathological, genetic, epigenetic, and transcriptional data available for deceased participants of the Religious Orders Study (n = 492) and the Rush Memory and Aging Project (n = 487). Given that our sample size was underpowered to detect genome-wide significance, we applied a multistep approach to identify genes influencing residual cognition, based on our prior observation that independent genetic and epigenetic risk factors can converge on the same locus. In the first step (n = 979), we performed a genome-wide association study with a predefined suggestive p < 10−5, and nine independent loci met this threshold in eight distinct chromosomal regions. Three of the six genes within 100 kb of the lead SNP are expressed in the dorsolateral prefrontal cortex (DLPFC): UNC5C, ENC1, and TMEM106B. In the second step, in the subset of participants with DLPFC DNA methylation data (n = 648), we found that residual cognition was related to differential DNA methylation of UNC5C and ENC1 (false discovery rate < 0.05). In the third step, in the subset of participants with DLPFC RNA sequencing data (n = 469), brain transcription levels of UNC5C and ENC1 were evaluated for their association with residual cognition: RNA levels of both UNC5C (estimated effect = −0.40, 95% CI −0.69 to −0.10, p = 0.0089) and ENC1 (estimated effect = 0.0064, 95% CI 0.0033 to 0.0096, p = 5.7 × 10−5) were associated with residual cognition. In secondary analyses, we explored the mechanism of these associations and found that ENC1 may be related to the previously documented effect of depression on cognitive decline, while UNC5C may alter the composition of presynaptic terminals. Of note, the TMEM106B allele identified in the first step as being associated with better residual cognition is in strong linkage disequilibrium with rs1990622A (r2 = 0.66), a previously identified protective allele for TDP-43 proteinopathy. Limitations include the small sample size for the genetic analysis, which was underpowered to detect genome-wide significance, the evaluation being limited to a single cortical region for epigenetic and transcriptomic data, and the use of categorical measures for certain non-amyloid-plaque, non-neurofibrillary-tangle neuropathologies. Conclusions: Through a multistep analysis of cognitive, neuropathological, genomic, epigenomic, and transcriptomic data, we identified ENC1 and UNC5C as genes with convergent genetic, epigenetic, and transcriptomic evidence supporting a potential role in the dissociation of cognition and neuropathology in an aging population, and we expanded our understanding of the TMEM106B haplotype that is protective against TDP-43 proteinopathy.

152. The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study

Author

Westra, Harm-Jan, Mägi, Reedik, Karjalainen, Juha, Ehret, Georg B., Jansen, Rick, Justice, Anne E., Absher, Devin, Teslovich, Tanya M., Lagou, Vasiliki, Graff, Mariaelisa, Rüeger, Sina, Fall, Tove, Ahluwalia, Tarunveer S., Simino, Jeannette, Neinast, Michael D., Pers, Tune H., Mahajan, Anubha, Ferreira, Teresa, Barata, Llilda, Winkler, Thomas W., Prokopenko, Inga, Kilpeläinen, Tuomas O., Heard-Costa, Nancy L., Ahmad, Shafqat, Mihailov, Evelin, Chu, Su, Teumer, Alexander, White, Charles C., Lu, Yingchang, Czajkowski, Jacek, Esko, Tõnu, and Feitosa, Mary F.

Subjects
3. Good health
Abstract

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR

153. Genome-wide association for abdominal subcutaneous and visceral adipose reveals a novel locus for visceral fat in women

Author

Fox, Caroline S, Liu, Yongmei, White, Charles C, Feitosa, Mary, Smith, Albert V, Heard-Costa, Nancy, Lohman, Kurt, GIANT Consortium, MAGIC Consortium, GLGC Consortium, Johnson, Andrew D, Foster, Meredith C, Greenawalt, Danielle M, Griffin, Paula, Ding, Jinghong, Newman, Anne B, Tylavsky, Fran, Miljkovic, Iva, Kritchevsky, Stephen B, Launer, Lenore, Garcia, Melissa, Eiriksdottir, Gudny, Carr, J Jeffrey, Gudnason, Vilmunder, Harris, Tamara B, Cupples, L Adrienne, and Borecki, Ingrid B

Subjects
2. Zero hunger, Adult, Male, Sex Characteristics, nutritional and metabolic diseases, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Proteins, HapMap Project, Intra-Abdominal Fat, Middle Aged, Polymorphism, Single Nucleotide, Subcutaneous Fat, Abdominal, White People, Body Mass Index, Phenotype, Cytokines, Humans, Female, Lysophospholipase, Aged, Genome-Wide Association Study
Abstract

Body fat distribution, particularly centralized obesity, is associated with metabolic risk above and beyond total adiposity. We performed genome-wide association of abdominal adipose depots quantified using computed tomography (CT) to uncover novel loci for body fat distribution among participants of European ancestry. Subcutaneous and visceral fat were quantified in 5,560 women and 4,997 men from 4 population-based studies. Genome-wide genotyping was performed using standard arrays and imputed to ~2.5 million Hapmap SNPs. Each study performed a genome-wide association analysis of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), VAT adjusted for body mass index, and VAT/SAT ratio (a metric of the propensity to store fat viscerally as compared to subcutaneously) in the overall sample and in women and men separately. A weighted z-score meta-analysis was conducted. For the VAT/SAT ratio, our most significant p-value was rs11118316 at LYPLAL1 gene (p = 3.1 × 10E-09), previously identified in association with waist-hip ratio. For SAT, the most significant SNP was in the FTO gene (p = 5.9 × 10E-08). Given the known gender differences in body fat distribution, we performed sex-specific analyses. Our most significant finding was for VAT in women, rs1659258 near THNSL2 (p = 1.6 × 10-08), but not men (p = 0.75). Validation of this SNP in the GIANT consortium data demonstrated a similar sex-specific pattern, with observed significance in women (p = 0.006) but not men (p = 0.24) for BMI and waist circumference (p = 0.04 [women], p = 0.49 [men]). Finally, we interrogated our data for the 14 recently published loci for body fat distribution (measured by waist-hip ratio adjusted for BMI); associations were observed at 7 of these loci. In contrast, we observed associations at only 7/32 loci previously identified in association with BMI; the majority of overlap was observed with SAT. Genome-wide association for visceral and subcutaneous fat revealed a SNP for VAT in women. More refined phenotypes for body composition and fat distribution can detect new loci not previously uncovered in large-scale GWAS of anthropometric traits.

154. Correction: The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study

Author

Winkler, Thomas W, Justice, Anne E, Graff, Mariaelisa, Barata, Llilda, Feitosa, Mary F, Chu, Su, Czajkowski, Jacek, Esko, Tõnu, Fall, Tove, Kilpeläinen, Tuomas O, Lu, Yingchang, Mägi, Reedik, Mihailov, Evelin, Pers, Tune H, Rüeger, Sina, Teumer, Alexander, Ehret, Georg B, Ferreira, Teresa, Heard-Costa, Nancy L, Karjalainen, Juha, Lagou, Vasiliki, Mahajan, Anubha, Neinast, Michael D, Prokopenko, Inga, Simino, Jeannette, Teslovich, Tanya M, Jansen, Rick, Westra, Harm-Jan, White, Charles C, Absher, Devin, Ahluwalia, Tarunveer S, Ahmad, Shafqat, Albrecht, Eva, Alves, Alexessander Couto, Bragg-Gresham, Jennifer L, De Craen, Anton JM, Bis, Joshua C, Bonnefond, Amélie, Boucher, Gabrielle, Cadby, Gemma, Cheng, Yu-Ching, Chiang, Charleston WK, Delgado, Graciela, Demirkan, Ayse, Dueker, Nicole, Eklund, Niina, Eiriksdottir, Gudny, Eriksson, Joel, Feenstra, Bjarke, Fischer, Krista, Frau, Francesca, Galesloot, Tessel E, Geller, Frank, Goel, Anuj, Gorski, Mathias, Grammer, Tanja B, Gustafsson, Stefan, Haitjema, Saskia, Hottenga, Jouke-Jan, Huffman, Jennifer E, Jackson, Anne U, Jacobs, Kevin B, Johansson, Åsa, Kaakinen, Marika, Kleber, Marcus E, Lahti, Jari, Mateo Leach, Irene, Lehne, Benjamin, Liu, Youfang, Lo, Ken Sin, Lorentzon, Mattias, Luan, Jian'an, Madden, Pamela AF, Mangino, Massimo, McKnight, Barbara, Medina-Gomez, Carolina, Monda, Keri L, Montasser, May E, Müller, Gabriele, Müller-Nurasyid, Martina, Nolte, Ilja M, Panoutsopoulou, Kalliope, Pascoe, Laura, Paternoster, Lavinia, Rayner, Nigel W, Renström, Frida, Rizzi, Federica, Rose, Lynda M, Ryan, Kathy A, Salo, Perttu, Sanna, Serena, Scharnagl, Hubert, Shi, Jianxin, Smith, Albert Vernon, Southam, Lorraine, Stančáková, Alena, Steinthorsdottir, Valgerdur, Strawbridge, Rona J, Sung, Yun Ju, Tachmazidou, Ioanna, Tanaka, Toshiko, Thorleifsson, Gudmar, Trompet, Stella, Pervjakova, Natalia, Tyrer, Jonathan P, Vandenput, Liesbeth, Van Der Laan, Sander W, Van Der Velde, Nathalie, Van Setten, Jessica, Van Vliet-Ostaptchouk, Jana V, Verweij, Niek, Vlachopoulou, Efthymia, Waite, Lindsay L, Wang, Sophie R, Wang, Zhaoming, Wild, Sarah H, Willenborg, Christina, Wilson, James F, Wong, Andrew, Yang, Jian, Yengo, Loïc, Yerges-Armstrong, Laura M, Yu, Lei, Zhang, Weihua, Zhao, Jing Hua, Andersson, Ehm A, Bakker, Stephan JL, Baldassarre, Damiano, Banasik, Karina, Barcella, Matteo, Barlassina, Cristina, Bellis, Claire, Benaglio, Paola, Blangero, John, Blüher, Matthias, Bonnet, Fabrice, Bonnycastle, Lori L, Boyd, Heather A, Bruinenberg, Marcel, Buchman, Aron S, Campbell, Harry, Chen, Yii-Der Ida, Chines, Peter S, Claudi-Boehm, Simone, Cole, John, Collins, Francis S, De Geus, Eco JC, De Groot, Lisette CPGM, Dimitriou, Maria, Duan, Jubao, Enroth, Stefan, Eury, Elodie, Farmaki, Aliki-Eleni, Forouhi, Nita G, Friedrich, Nele, Gejman, Pablo V, Gigante, Bruna, Glorioso, Nicola, Go, Alan S, Gottesman, Omri, Gräßler, Jürgen, Grallert, Harald, Grarup, Niels, Gu, Yu-Mei, Broer, Linda, Ham, Annelies C, Hansen, Torben, Harris, Tamara B, Hartman, Catharina A, Hassinen, Maija, Hastie, Nicholas, Hattersley, Andrew T, Heath, Andrew C, Henders, Anjali K, Hernandez, Dena, Hillege, Hans, Holmen, Oddgeir, Hovingh, Kees G, Hui, Jennie, Husemoen, Lise L, Hutri-Kähönen, Nina, Hysi, Pirro G, Illig, Thomas, De Jager, Philip L, Jalilzadeh, Shapour, Jørgensen, Torben, Jukema, J Wouter, Juonala, Markus, Kanoni, Stavroula, Karaleftheri, Maria, Khaw, Kay Tee, Kinnunen, Leena, Kittner, Steven J, Koenig, Wolfgang, Kolcic, Ivana, Kovacs, Peter, Krarup, Nikolaj T, Kratzer, Wolfgang, Krüger, Janine, Kuh, Diana, Kumari, Meena, Kyriakou, Theodosios, Langenberg, Claudia, Lannfelt, Lars, Lanzani, Chiara, Lotay, Vaneet, Launer, Lenore J, Leander, Karin, Lindström, Jaana, Linneberg, Allan, Liu, Yan-Ping, Lobbens, Stéphane, Luben, Robert, Lyssenko, Valeriya, Männistö, Satu, Magnusson, Patrik K, McArdle, Wendy L, Menni, Cristina, Merger, Sigrun, Milani, Lili, Montgomery, Grant W, Morris, Andrew P, Narisu, Narisu, Nelis, Mari, Ong, Ken K, Palotie, Aarno, Pérusse, Louis, Pichler, Irene, Pilia, Maria G, Pouta, Anneli, Rheinberger, Myriam, Ribel-Madsen, Rasmus, Richards, Marcus, Rice, Kenneth M, Rice, Treva K, Rivolta, Carlo, Salomaa, Veikko, Sanders, Alan R, Sarzynski, Mark A, Scholtens, Salome, Scott, Robert A, Scott, William R, Sebert, Sylvain, Sengupta, Sebanti, Sennblad, Bengt, Seufferlein, Thomas, Silveira, Angela, Slagboom, P Eline, Smit, Jan H, Sparsø, Thomas H, Stirrups, Kathleen, Stolk, Ronald P, Stringham, Heather M, Swertz, Morris A, Swift, Amy J, Syvänen, Ann-Christine, Tan, Sian-Tsung, Thorand, Barbara, Tönjes, Anke, Tremblay, Angelo, Tsafantakis, Emmanouil, Van Der Most, Peter J, Völker, Uwe, Vohl, Marie-Claude, Vonk, Judith M, Waldenberger, Melanie, Walker, Ryan W, Wennauer, Roman, Widén, Elisabeth, Willemsen, Gonneke, Wilsgaard, Tom, Wright, Alan F, Zillikens, M Carola, Van Dijk, Suzanne C, Van Schoor, Natasja M, Asselbergs, Folkert W, De Bakker, Paul IW, Beckmann, Jacques S, Beilby, John, Bennett, David A, Bergman, Richard N, Bergmann, Sven, Böger, Carsten A, Boehm, Bernhard O, Boerwinkle, Eric, Boomsma, Dorret I, Bornstein, Stefan R, Bottinger, Erwin P, Bouchard, Claude, Chambers, John C, Chanock, Stephen J, Chasman, Daniel I, Cucca, Francesco, Cusi, Daniele, Dedoussis, George, Erdmann, Jeanette, Eriksson, Johan G, Evans, Denis A, De Faire, Ulf, Farrall, Martin, Ferrucci, Luigi, Ford, Ian, Franke, Lude, Franks, Paul W, Froguel, Philippe, Gansevoort, Ron T, Gieger, Christian, Grönberg, Henrik, Gudnason, Vilmundur, Gyllensten, Ulf, Hall, Per, Hamsten, Anders, Van Der Harst, Pim, Hayward, Caroline, Heliövaara, Markku, Hengstenberg, Christian, Hicks, Andrew A, Hingorani, Aroon, Hofman, Albert, Hu, Frank, Huikuri, Heikki V, Hveem, Kristian, James, Alan L, Jordan, Joanne M, Jula, Antti, Kähönen, Mika, Kajantie, Eero, Kathiresan, Sekar, Kiemeney, Lambertus ALM, Kivimaki, Mika, Knekt, Paul B, Koistinen, Heikki A, Kooner, Jaspal S, Koskinen, Seppo, Kuusisto, Johanna, Maerz, Winfried, Martin, Nicholas G, Laakso, Markku, Lakka, Timo A, Lehtimäki, Terho, Lettre, Guillaume, Levinson, Douglas F, Lind, Lars, Lokki, Marja-Liisa, Mäntyselkä, Pekka, Melbye, Mads, Metspalu, Andres, Mitchell, Braxton D, Moll, Frans L, Murray, Jeffrey C, Musk, Arthur W, Nieminen, Markku S, Njølstad, Inger, Ohlsson, Claes, Oldehinkel, Albertine J, Oostra, Ben A, Palmer, Lyle J, Pankow, James S, Pasterkamp, Gerard, Pedersen, Nancy L, Pedersen, Oluf, Penninx, Brenda W, Perola, Markus, Peters, Annette, Polašek, Ozren, Pramstaller, Peter P, Psaty, Bruce M, Qi, Lu, Quertermous, Thomas, Raitakari, Olli T, Rankinen, Tuomo, Rauramaa, Rainer, Ridker, Paul M, Rioux, John D, Rivadeneira, Fernando, Rotter, Jerome I, Rudan, Igor, Den Ruijter, Hester M, Saltevo, Juha, Sattar, Naveed, Schunkert, Heribert, Schwarz, Peter EH, Shuldiner, Alan R, Sinisalo, Juha, Snieder, Harold, Sørensen, Thorkild IA, Spector, Tim D, Staessen, Jan A, Stefania, Bandinelli, Thorsteinsdottir, Unnur, Stumvoll, Michael, Tardif, Jean-Claude, Tremoli, Elena, Tuomilehto, Jaakko, Uitterlinden, André G, Uusitupa, Matti, Verbeek, André LM, Vermeulen, Sita H, Viikari, Jorma S, Vitart, Veronique, Völzke, Henry, Vollenweider, Peter, Waeber, Gérard, Walker, Mark, Wallaschofski, Henri, Wareham, Nicholas J, Watkins, Hugh, Zeggini, Eleftheria, ArcOGEN Consortium, CHARGE Consortium, DIAGRAM Consortium, GLGC Consortium, Global-BPGen Consortium, ICBP Consortium, MAGIC Consortium, Chakravarti, Aravinda, Clegg, Deborah J, Cupples, L Adrienne, Gordon-Larsen, Penny, Jaquish, Cashell E, Rao, DC, Abecasis, Goncalo R, Assimes, Themistocles L, Barroso, Inês, Berndt, Sonja I, Boehnke, Michael, Deloukas, Panos, Fox, Caroline S, Groop, Leif C, Hunter, David J, Ingelsson, Erik, Kaplan, Robert C, McCarthy, Mark I, Mohlke, Karen L, O'Connell, Jeffrey R, Schlessinger, David, Strachan, David P, Stefansson, Kari, Van Duijn, Cornelia M, Hirschhorn, Joel N, Lindgren, Cecilia M, Heid, Iris M, North, Kari E, Borecki, Ingrid B, Kutalik, Zoltán, and Loos, Ruth JF

Subjects
GLGC Consortium, Global-BPGen Consortium, MAGIC Consortium, CHARGE Consortium, ICBP Consortium, DIAGRAM Consortium, 3. Good health, arcOGEN Consortium
Abstract

[This corrects the article DOI: 10.1371/journal.pgen.1005378.].

155. A transcriptomic atlas of aged human microglia

Author

Olah, Marta, Patrick, Ellis, Villani, Alexandra-Chloe, Xu, Jishu, White, Charles C., Ryan, Katie J., Piehowski, Paul, Kapasi, Alifiya, Nejad, Parham, Cimpean, Maria, Connor, Sarah, Yung, Christina J., Frangieh, Michael, McHenry, Allison, Elyaman, Wassim, Petyuk, Vlad, Schneider, Julie A., Bennett, David A., De Jager, Philip Lawrence, and Bradshaw, Elizabeth

Subjects
Nervous system--Degeneration, Neuroimmunology, Microglia, Brain--Aging, 3. Good health
Abstract

With a rapidly aging global human population, finding a cure for late onset neurodegenerative diseases has become an urgent enterprise. However, these efforts are hindered by the lack of understanding of what constitutes the phenotype of aged human microglia—the cell type that has been strongly implicated by genetic studies in the pathogenesis of age-related neurodegenerative disease. Here, we establish the set of genes that is preferentially expressed by microglia in the aged human brain. This HuMi_Aged gene set captures a unique phenotype, which we confirm at the protein level. Furthermore, we find this gene set to be enriched in susceptibility genes for Alzheimer’s disease and multiple sclerosis, to be increased with advancing age, and to be reduced by the protective APOEε2 haplotype. APOEε4 has no effect. These findings confirm the existence of an aging-related microglial phenotype in the aged human brain and its involvement in the pathological processes associated with brain aging.

156. 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.

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

Author

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

Subjects
3. Good health
Abstract

We identified rare coding variants associated with Alzheimer’s disease (AD) in a 3-stage case-control study of 85,133 subjects. In stage 1, 34,174 samples were genotyped using a whole-exome microarray. In stage 2, we tested associated variants (P

158. The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study

Author

Winkler, Thomas W., Justice, Anne E., Graff, Mariaelisa, Barata, Llilda, Feitosa, Mary F., Chu, Su, Czajkowski, Jacek, Esko, Tõnu, Fall, Tove, Kilpeläinen, Tuomas O., Lu, Yingchang, Mägi, Reedik, Mihailov, Evelin, Pers, Tune H., Rüeger, Sina, Teumer, Alexander, Ehret, Georg B., Ferreira, Teresa, Heard-Costa, Nancy L., Karjalainen, Juha, Lagou, Vasiliki, Mahajan, Anubha, Neinast, Michael D., Prokopenko, Inga, Simino, Jeannette, Teslovich, Tanya M., Jansen, Rick, Westra, Harm-Jan, White, Charles C., Absher, Devin, Ahluwalia, Tarunveer S., Ahmad, Shafqat, Albrecht, Eva, Alves, Alexessander Couto, Bragg-Gresham, Jennifer L., de Craen, Anton J. M., Bis, Joshua C., Bonnefond, Amélie, Boucher, Gabrielle, Cadby, Gemma, Cheng, Yu-Ching, Chiang, Charleston W. K., Delgado, Graciela, Demirkan, Ayse, Dueker, Nicole, Eklund, Niina, Eiriksdottir, Gudny, Eriksson, Joel, Feenstra, Bjarke, Fischer, Krista, Frau, Francesca, Galesloot, Tessel E., Geller, Frank, Goel, Anuj, Gorski, Mathias, Grammer, Tanja B., Gustafsson, Stefan, Haitjema, Saskia, Hottenga, Jouke-Jan, Huffman, Jennifer E., Jackson, Anne U., Jacobs, Kevin B., Johansson, Åsa, Kaakinen, Marika, Kleber, Marcus E., Lahti, Jari, Mateo Leach, Irene, Lehne, Benjamin, Liu, Youfang, Lo, Ken Sin, Lorentzon, Mattias, Luan, Jian'an, Madden, Pamela A. F., Mangino, Massimo, McKnight, Barbara, Medina-Gomez, Carolina, Monda, Keri L., Montasser, May E., Müller, Gabriele, Müller-Nurasyid, Martina, Nolte, Ilja M., Panoutsopoulou, Kalliope, Pascoe, Laura, Paternoster, Lavinia, Rayner, Nigel W., Renström, Frida, Rizzi, Federica, Rose, Lynda M., Ryan, Kathy A., Salo, Perttu, Sanna, Serena, Scharnagl, Hubert, Shi, Jianxin, Smith, Albert Vernon, Southam, Lorraine, Stančáková, Alena, Steinthorsdottir, Valgerdur, Strawbridge, Rona J., Sung, Yun Ju, Tachmazidou, Ioanna, Tanaka, Toshiko, Thorleifsson, Gudmar, Trompet, Stella, Pervjakova, Natalia, Tyrer, Jonathan P., Vandenput, Liesbeth, van der Laan, Sander W., van der Velde, Nathalie, van Setten, Jessica, van Vliet-Ostaptchouk, Jana V., Verweij, Niek, Vlachopoulou, Efthymia, Waite, Lindsay L., Wang, Sophie R., Wang, Zhaoming, Wild, Sarah H., Willenborg, Christina, Wilson, James F., Wong, Andrew, Yang, Jian, Yengo, Loïc, Yerges-Armstrong, Laura M., Yu, Lei, Zhang, Weihua, Zhao, Jing Hua, Andersson, Ehm A., Bakker, Stephan J. L., Baldassarre, Damiano, Banasik, Karina, Barcella, Matteo, Barlassina, Cristina, Bellis, Claire, Benaglio, Paola, Blangero, John, Blüher, Matthias, Bonnet, Fabrice, Bonnycastle, Lori L., Boyd, Heather A., Bruinenberg, Marcel, Buchman, Aron S., Campbell, Harry, Chen, Yii-Der Ida, Chines, Peter S., Claudi-Boehm, Simone, Cole, John, Collins, Francis S., de Geus, Eco J. C., de Groot, Lisette C. P. G. M., Dimitriou, Maria, Duan, Jubao, Enroth, Stefan, Eury, Elodie, Farmaki, Aliki-Eleni, Forouhi, Nita G., Friedrich, Nele, Gejman, Pablo V., Gigante, Bruna, Glorioso, Nicola, Go, Alan S., Gottesman, Omri, Gräßler, Jürgen, Grallert, Harald, Grarup, Niels, Gu, Yu-Mei, Broer, Linda, Ham, Annelies C., Hansen, Torben, Harris, Tamara B., Hartman, Catharina A., Hassinen, Maija, Hastie, Nicholas, Hattersley, Andrew T., Heath, Andrew C., Henders, Anjali K., Hernandez, Dena, Hillege, Hans, Holmen, Oddgeir, Hovingh, Kees G., Hui, Jennie, Husemoen, Lise L., Hutri-Kähönen, Nina, Hysi, Pirro G., Illig, Thomas, De Jager, Philip L., Jalilzadeh, Shapour, Jørgensen, Torben, Jukema, J. Wouter, Juonala, Markus, Kanoni, Stavroula, Karaleftheri, Maria, Khaw, Kay Tee, Kinnunen, Leena, Kittner, Steven J., Koenig, Wolfgang, Kolcic, Ivana, Kovacs, Peter, Krarup, Nikolaj T., Kratzer, Wolfgang, Krüger, Janine, Kuh, Diana, Kumari, Meena, Kyriakou, Theodosios, Langenberg, Claudia, Lannfelt, Lars, Lanzani, Chiara, Lotay, Vaneet, Launer, Lenore J., Leander, Karin, Lindström, Jaana, Linneberg, Allan, Liu, Yan-Ping, Lobbens, Stéphane, Luben, Robert, Lyssenko, Valeriya, Männistö, Satu, Magnusson, Patrik K., McArdle, Wendy L., Menni, Cristina, Merger, Sigrun, Milani, Lili, Montgomery, Grant W., Morris, Andrew P., Narisu, Narisu, Nelis, Mari, Ong, Ken K., Palotie, Aarno, Pérusse, Louis, Pichler, Irene, Pilia, Maria G., Pouta, Anneli, Rheinberger, Myriam, Ribel-Madsen, Rasmus, Richards, Marcus, Rice, Kenneth M., Rice, Treva K., Rivolta, Carlo, Salomaa, Veikko, Sanders, Alan R., Sarzynski, Mark A., Scholtens, Salome, Scott, Robert A., Scott, William R., Sebert, Sylvain, Sengupta, Sebanti, Sennblad, Bengt, Seufferlein, Thomas, Silveira, Angela, Slagboom, P. Eline, Smit, Jan H., Sparsø, Thomas H., Stirrups, Kathleen, Stolk, Ronald P., Stringham, Heather M., Swertz, Morris A., Swift, Amy J., Syvänen, Ann-Christine, Tan, Sian-Tsung, Thorand, Barbara, Tönjes, Anke, Tremblay, Angelo, Tsafantakis, Emmanouil, van der Most, Peter J., Völker, Uwe, Vohl, Marie-Claude, Vonk, Judith M., Waldenberger, Melanie, Walker, Ryan W., Wennauer, Roman, Widén, Elisabeth, Willemsen, Gonneke, Wilsgaard, Tom, Wright, Alan F., Zillikens, M. Carola, van Dijk, Suzanne C., van Schoor, Natasja M., Asselbergs, Folkert W., de Bakker, Paul I. W., Beckmann, Jacques S., Beilby, John, Bennett, David A., Bergman, Richard N., Bergmann, Sven, Böger, Carsten A., Boehm, Bernhard O., Boerwinkle, Eric, Boomsma, Dorret I., Bornstein, Stefan R., Bottinger, Erwin P., Bouchard, Claude, Chambers, John C., Chanock, Stephen J., Chasman, Daniel I., Cucca, Francesco, Cusi, Daniele, Dedoussis, George, Erdmann, Jeanette, Eriksson, Johan G., Evans, Denis A., de Faire, Ulf, Farrall, Martin, Ferrucci, Luigi, Ford, Ian, Franke, Lude, Franks, Paul W., Froguel, Philippe, Gansevoort, Ron T., Gieger, Christian, Grönberg, Henrik, Gudnason, Vilmundur, Gyllensten, Ulf, Hall, Per, Hamsten, Anders, van der Harst, Pim, Hayward, Caroline, Heliövaara, Markku, Hengstenberg, Christian, Hicks, Andrew A., Hingorani, Aroon, Hofman, Albert, Hu, Frank, Huikuri, Heikki V., Hveem, Kristian, James, Alan L., Jordan, Joanne M., Jula, Antti, Kähönen, Mika, Kajantie, Eero, Kathiresan, Sekar, Kiemeney, Lambertus A. L. M., Kivimaki, Mika, Knekt, Paul B., Koistinen, Heikki A., Kooner, Jaspal S., Koskinen, Seppo, Kuusisto, Johanna, Maerz, Winfried, Martin, Nicholas G., Laakso, Markku, Lakka, Timo A., Lehtimäki, Terho, Lettre, Guillaume, Levinson, Douglas F., Lind, Lars, Lokki, Marja-Liisa, Mäntyselkä, Pekka, Melbye, Mads, Metspalu, Andres, Mitchell, Braxton D., Moll, Frans L., Murray, Jeffrey C., Musk, Arthur W., Nieminen, Markku S., Njølstad, Inger, Ohlsson, Claes, Oldehinkel, Albertine J., Oostra, Ben A., Palmer, Lyle J., Pankow, James S., Pasterkamp, Gerard, Pedersen, Nancy L., Pedersen, Oluf, Penninx, Brenda W., Perola, Markus, Peters, Annette, Polašek, Ozren, Pramstaller, Peter P., Psaty, Bruce M., Qi, Lu, Quertermous, Thomas, Raitakari, Olli T., Rankinen, Tuomo, Rauramaa, Rainer, Ridker, Paul M., Rioux, John D., Rivadeneira, Fernando, Rotter, Jerome I., Rudan, Igor, den Ruijter, Hester M., Saltevo, Juha, Sattar, Naveed, Schunkert, Heribert, Schwarz, Peter E. H., Shuldiner, Alan R., Sinisalo, Juha, Snieder, Harold, Sørensen, Thorkild I. A., Spector, Tim D., Staessen, Jan A., Stefania, Bandinelli, Thorsteinsdottir, Unnur, Stumvoll, Michael, Tardif, Jean-Claude, Tremoli, Elena, Tuomilehto, Jaakko, Uitterlinden, André G., Uusitupa, Matti, Verbeek, André L. M., Vermeulen, Sita H., Viikari, Jorma S., Vitart, Veronique, Völzke, Henry, Vollenweider, Peter, Waeber, Gérard, Walker, Mark, Wallaschofski, Henri, Wareham, Nicholas J., Watkins, Hugh, Zeggini, Eleftheria, Charge Consortium, Diagram Consortium, Glgc Consortium, Global-BPGen Consortium, Icbp Consortium, Magic Consortium, Chakravarti, Aravinda, Clegg, Deborah J., Cupples, L. Adrienne, Gordon-Larsen, Penny, Jaquish, Cashell E., Rao, D. C., Abecasis, Goncalo R., Assimes, Themistocles L., Barroso, Inês, Berndt, Sonja I., Boehnke, Michael, Deloukas, Panos, Fox, Caroline S., Groop, Leif C., Hunter, David J., Ingelsson, Erik, Kaplan, Robert C., McCarthy, Mark I., Mohlke, Karen L., O'Connell, Jeffrey R., Schlessinger, David, Strachan, David P., Stefansson, Kari, van Duijn, Cornelia M., Hirschhorn, Joel N., Lindgren, Cecilia M., Heid, Iris M., North, Kari E., Borecki, Ingrid B., Kutalik, Zoltán, and Loos, Ruth J. F.

Subjects
3. Good health

159. Identification of additional risk loci for stroke and small vessel disease: a meta-analysis of genome-wide association studies

Author

Chauhan, Ganesh, Arnold, Corey R., Chu, Audrey Y., Fornage, Myriam, Reyahi, Azadeh, Bis, Joshua C., Havulinna, Aki S., Sargurupremraj, Muralidharan, Smith, Albert Vernon, Adams, Hieab H. H., Choi, Seung Hoan, Pulit, Sara L., Trompet, Stella, Garcia, Melissa E., Manichaikul, Ani, Teumer, Alexander, Gustafsson, Stefan, Bartz, Traci M., Bellenguez, Céline, Vidal, Jean Sebastien, Jian, Xueqiu, Kjartansson, Olafur, Wiggins, Kerri L., Satizabal, Claudia L., Xue, Flora, Ripatti, Samuli, Liu, Yongmei, Deelen, Joris, den Hoed, Marcel, Bevan, Steve, Hopewell, Jemma C., Malik, Rainer, Heckbert, Susan R., Rice, Kenneth, Smith, Nicholas L., Levi, Christopher, Sharma, Pankaj, Sudlow, Cathie LM, Nik, Ali Moussavi, Cole, John W., Schmidt, Reinhold, Meschia, James, Thijs, Vincent, Lindgren, Arne, Melander, Olle, Grewal, Raji P., Sacco, Ralph L., Rundek, Tatjana, Rothwell, Peter M., Arnett, Donna K., Jern, Christina, Johnson, Julie A., Benavente, Oscar R., Wassertheil-Smoller, Sylvia, Lee, Jin-Moo, Wong, Quenna, Aparicio, Hugo J., Engelter, Stefan T., Kloss, Manja, Leys, Didier, Pezzini, Alessandro, Buring, Julie E., Ridker, Paul M., Berr, Claudine, Dartigues, Jean-François, Hamsten, Anders, Magnusson, Patrik K., Traylor, Matthew, Pedersen, Nancy L., Lannfelt, Lars, Lindgren, Lars, Lindgren, Cecilia M., Morris, Andrew P., Jimenez-Conde, Jordi, Montaner, Joan, Radmanesh, Farid, Slowik, Agnieszka, Woo, Daniel, Hofman, Albert, Koudstaal, Peter J., Portegies, Marileen L. P., Uitterlinden, André G., de Craen, Anton J. M., Ford, Ian, Jukema, J. Wouter, Stott, David J., Allen, Norrina B., Sale, Michele M., Johnson, Andrew D., Bennett, David A., De Jager, Philip L., White, Charles C., Grabe, Hans Jörgen, Markus, Marcello Ricardo Paulista, Schminke, Ulf, Boncoraglio, Giorgio B., Clarke, Robert, Kamatani, Yoichiro, Dallongeville, Jean, Lopez, Oscar L., Rotter, Jerome I., Nalls, Michael A., Gottesman, Rebecca F., Griswold, Michael E., Knopman, David S., Windham, B. Gwen, Beiser, Alexa, Markus, Hugh S., Vartiainen, Erkki, French, Curtis R., Dichgans, Martin, Pastinen, Tomi, Lathrop, Mark, Gudnason, Vilmundur, Kurth, Tobias, Psaty, Bruce M., Harris, Tamara B., Rich, Stephen S., deStefano, Anita L., Schmidt, Carsten Oliver, Worrall, Bradford B., Rosand, Jonathan, Salomaa, Veikko, Mosley, Thomas H., Ingelsson, Erik, van Duijn, Cornelia M., Tzourio, Christophe, Rexrode, Kathryn M., Lehmann, Ordan J., Launer, Lenore J., Ikram, M. Arfan, Carlsson, Peter, Chasman, Daniel I., Childs, Sarah J., Longstreth, William T., Seshadri, Sudha, Debette, Stéphanie, Chauhan, Ganesh, Arnold, Corey R., Chu, Audrey Y., Fornage, Myriam, Reyahi, Azadeh, Bis, Joshua C., Havulinna, Aki S., Sargurupremraj, Muralidharan, Smith, Albert Vernon, Adams, Hieab H. H., Choi, Seung Hoan, Pulit, Sara L., Trompet, Stella, Garcia, Melissa E., Manichaikul, Ani, Teumer, Alexander, Gustafsson, Stefan, Bartz, Traci M., Bellenguez, Céline, Vidal, Jean Sebastien, Jian, Xueqiu, Kjartansson, Olafur, Wiggins, Kerri L., Satizabal, Claudia L., Xue, Flora, Ripatti, Samuli, Liu, Yongmei, Deelen, Joris, den Hoed, Marcel, Bevan, Steve, Hopewell, Jemma C., Malik, Rainer, Heckbert, Susan R., Rice, Kenneth, Smith, Nicholas L., Levi, Christopher, Sharma, Pankaj, Sudlow, Cathie LM, Nik, Ali Moussavi, Cole, John W., Schmidt, Reinhold, Meschia, James, Thijs, Vincent, Lindgren, Arne, Melander, Olle, Grewal, Raji P., Sacco, Ralph L., Rundek, Tatjana, Rothwell, Peter M., Arnett, Donna K., Jern, Christina, Johnson, Julie A., Benavente, Oscar R., Wassertheil-Smoller, Sylvia, Lee, Jin-Moo, Wong, Quenna, Aparicio, Hugo J., Engelter, Stefan T., Kloss, Manja, Leys, Didier, Pezzini, Alessandro, Buring, Julie E., Ridker, Paul M., Berr, Claudine, Dartigues, Jean-François, Hamsten, Anders, Magnusson, Patrik K., Traylor, Matthew, Pedersen, Nancy L., Lannfelt, Lars, Lindgren, Lars, Lindgren, Cecilia M., Morris, Andrew P., Jimenez-Conde, Jordi, Montaner, Joan, Radmanesh, Farid, Slowik, Agnieszka, Woo, Daniel, Hofman, Albert, Koudstaal, Peter J., Portegies, Marileen L. P., Uitterlinden, André G., de Craen, Anton J. M., Ford, Ian, Jukema, J. Wouter, Stott, David J., Allen, Norrina B., Sale, Michele M., Johnson, Andrew D., Bennett, David A., De Jager, Philip L., White, Charles C., Grabe, Hans Jörgen, Markus, Marcello Ricardo Paulista, Schminke, Ulf, Boncoraglio, Giorgio B., Clarke, Robert, Kamatani, Yoichiro, Dallongeville, Jean, Lopez, Oscar L., Rotter, Jerome I., Nalls, Michael A., Gottesman, Rebecca F., Griswold, Michael E., Knopman, David S., Windham, B. Gwen, Beiser, Alexa, Markus, Hugh S., Vartiainen, Erkki, French, Curtis R., Dichgans, Martin, Pastinen, Tomi, Lathrop, Mark, Gudnason, Vilmundur, Kurth, Tobias, Psaty, Bruce M., Harris, Tamara B., Rich, Stephen S., deStefano, Anita L., Schmidt, Carsten Oliver, Worrall, Bradford B., Rosand, Jonathan, Salomaa, Veikko, Mosley, Thomas H., Ingelsson, Erik, van Duijn, Cornelia M., Tzourio, Christophe, Rexrode, Kathryn M., Lehmann, Ordan J., Launer, Lenore J., Ikram, M. Arfan, Carlsson, Peter, Chasman, Daniel I., Childs, Sarah J., Longstreth, William T., Seshadri, Sudha, and Debette, Stéphanie

Abstract

BACKGROUND: Genetic determinants of stroke, the leading neurological cause of death and disability, are poorly understood and have seldom been explored in the general population. Our aim was to identify additional loci for stroke by doing a meta-analysis of genome-wide association studies. METHODS: For the discovery sample, we did a genome-wide analysis of common genetic variants associated with incident stroke risk in 18 population-based cohorts comprising 84 961 participants, of whom 4348 had stroke. Stroke diagnosis was ascertained and validated by the study investigators. Mean age at stroke ranged from 45·8 years to 76·4 years, and data collection in the studies took place between 1948 and 2013. We did validation analyses for variants yielding a significant association (at p<5 × 10(-6)) with all-stroke, ischaemic stroke, cardioembolic ischaemic stroke, or non-cardioembolic ischaemic stroke in the largest available cross-sectional studies (70 804 participants, of whom 19 816 had stroke). Summary-level results of discovery and follow-up stages were combined using inverse-variance weighted fixed-effects meta-analysis, and in-silico lookups were done in stroke subtypes. For genome-wide significant findings (at p<5 × 10(-8)), we explored associations with additional cerebrovascular phenotypes and did functional experiments using conditional (inducible) deletion of the probable causal gene in mice. We also studied the expression of orthologs of this probable causal gene and its effects on cerebral vasculature in zebrafish mutants. FINDINGS: We replicated seven of eight known loci associated with risk for ischaemic stroke, and identified a novel locus at chromosome 6p25 (rs12204590, near FOXF2) associated with risk of all-stroke (odds ratio [OR] 1·08, 95% CI 1·05-1·12, p=1·48 × 10(-8); minor allele frequency 21%). The rs12204590 stroke risk allele was also associated with increased MRI-defined burden of white matter hyperintensity-a marker of cerebral small vessel dise

160. Evaluation of TDP-43 proteinopathy and hippocampal sclerosis in relation to APOE ε4 haplotype status: a community-based cohort study.

Author

Yang, Hyun-Sik, Yu, Lei, White, Charles C, Chibnik, Lori B, Chhatwal, Jasmeer P, Sperling, Reisa A, Bennett, David A, Schneider, Julie A, and De Jager, Philip L

Subjects
*DNA-binding proteins, *ALZHEIMER'S disease, *COGNITIVE testing, *COGNITIVE ability, *MONTE Carlo method, *REACTIVE oxygen species, *APOLIPOPROTEINS, *COMPARATIVE studies, *HIPPOCAMPUS (Brain), *LONGITUDINAL method, *RESEARCH methodology, *MEDICAL cooperation, *NEURONS, *RESEARCH, *RESEARCH funding, *TRANSFERASES, *LOGISTIC regression analysis, *RESIDENTIAL patterns, *EVALUATION research, *HAPLOTYPES, *TDP-43 proteinopathies, *DISEASE complications
Abstract

Background: Transactive response DNA-binding protein of 43 kDa (TDP-43) proteinopathy in older adults frequently coexists with Alzheimer's disease pathology and hippocampal sclerosis. It is unclear whether there is a link between APOE ε4 and TDP-43 proteinopathy, and the role of APOE ε4 in the association of TDP-43 proteinopathy with hippocampal sclerosis remains to be examined. We investigated the relationships of TDP-43 proteinopathy and hippocampal sclerosis with APOE ε4.Methods: We used data from two community-based cohort studies of ageing and dementia: the Religious Orders Study (ROS) and the Rush Memory and Aging Project (MAP). A battery of cognitive tests examining multiple cognitive domains is given to ROS-MAP participants each year, and a measure of annual global cognitive function for each participant is derived by averaging Z scores of these tests. The final clinical diagnosis is assigned after death by a neurologist using all available clinical data without access to post-mortem pathology. Amyloid-β, paired helical filament tau, Lewy bodies, TDP-43, and hippocampal sclerosis were microscopically evaluated in the midbrain, medial temporal, and neocortical regions that capture the progression of each neuropathology. TDP-43 proteinopathy topographic stage was recorded as an ordinal variable, and TDP-43 burden was defined by averaging a semi-quantitative six-point scale across six brain regions. The relationships among APOE ε4, TDP-43 proteinopathy, and hippocampal sclerosis were tested with regression models controlled for sex and age at death, and they were further explored with a mediation analysis using the quasi-Bayesian Monte Carlo method.Findings: ROS began data collection in 1994, and MAP began data collection in 1997. The data included in this study were analysed from Jan 16, 2017, to July 12, 2017. When analysis began in January, 2017, a total of 1059 ROS-MAP participants who were deceased had APOE genotype and complete pathological measures for amyloid-β, paired helical filament tau, and TDP-43 proteinopathy stage. After excluding 15 participants with other pathological diagnoses, 1044 participants, 1042 of whom also had measures of Lewy body pathology, were included in this study (470 from ROS and 574 from MAP). APOE ε4 count was associated with higher TDP-43 proteinopathy stage (odds ratio [OR] 2·0, 95% CI 1·6-2·6; p=1·9 × 10-9) and TDP-43 burden (0·40, 0·28-0·52; p=1·2 × 10-10). Amyloid-β, paired helical filament tau, or Lewy body pathology did not fully explain this association. APOE ε4 increased the odds of hippocampal sclerosis (OR 2·1, 95% CI 1·4-3·0; p=1·7 × 10-4); this effect was largely mediated by TDP-43 burden (mediated effect p<1·0 × 10-4) but not directly by APOE ε4 (direct effect p=0·40). APOE ε4 was associated with worse global cognition proximate to death even after adjusting for amyloid-β and paired helical filament tau (estimated effect -0·18, 95% CI -0·31 to -0·04; p=0·010), but this association was attenuated by additionally adjusting for TDP-43 burden (-0·09, -0·22 to 0·04; p=0·18).Interpretation: APOE ε4 seems to increase TDP-43 burden, and this effect in turn was associated with higher odds of hippocampal sclerosis, a pathology potentially downstream of TDP-43 proteinopathy. TDP-43 proteinopathy contributes to the detrimental effect of APOE ε4 on late-life cognition through mechanisms independent of Alzheimer's disease pathology, and future research should consider that TDP-43 proteinopathy might be an integral component of APOE-related neurodegeneration.Funding: US National Institute on Aging and Alzheimer's Association. [ABSTRACT FROM AUTHOR]

Published
2018
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161. Evaluating and extending a Bayesian approach to using historical control data in an actively controlled non-inferiority clinical trial

Author

White, Charles C.

Subjects
Biostatistics, Active control, Clinical trial, Historical control, Historical data, Non-inferiority
Abstract

Obstacles sometimes limit enrollment in randomized clinical trials of an exper- imental product versus an active control, making it desirable to augment the ran- domized control group with historical control groups. However, bias between control groups with respect to the mean outcome could lead to spurious conclusions. Meth- ods are necessary that allow for the combination of control groups while controlling for bias. Pocock (1976) developed a Bayesian test to address this need, but it requires sub- jective specification of the variance of the bias between the randomized and historical control groups and is designed to include only a single historical control group. In the context of an actively controlled non-inferiority trial, we extend his method on three fronts. First, we replace subjective specification of the variance of the bias with empirically driven estimates. Second, we develop an adaptive design that re-powers a trial based on an interim estimate of the variance of the bias using observed data. Third, we modify the test to include multiple historical control groups. When including a single historical control group, simulations show that the true bias, if known, can be used in place of the variance of the bias, and that this estimate ivmaintains Type I Error with no loss in power as compared to using the true variance of the bias. Further, we show that using an empirical estimate of the bias to estimate the variance of bias may result in moderately inflated Type I Error, but that using a conservative estimate of the bias (the upper bound of a 90% confidence interval) maintains Type I Error. Simulations also demonstrate that using an estimate of the bias at the interim and conclusion provides designed power but may result in moder- ately inflated Type I Error. Therefore, a conservative estimate of the bias should be used at trial end when using this approach. Lastly, it is shown that if an adequate number of multiple historical control groups are available, the modified test maintains Type I Error when using bias estimates. These methods provide objective guidance on parameter estimation, but further research is necessary in order to improve power.

Published
2013

162. Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution.

Author

Heid, Iris M, Jackson, Anne U, Randall, Joshua C, Winkler, Thomas W, Qi, Lu, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Zillikens, M Carola, Speliotes, Elizabeth K, Mägi, Reedik, Workalemahu, Tsegaselassie, White, Charles C, Bouatia-Naji, Nabila, Harris, Tamara B, Berndt, Sonja I, Ingelsson, Erik, Willer, Cristen J, Weedon, Michael N, Luan, Jian'an, and Vedantam, Sailaja

Subjects
GENE frequency, GENETIC polymorphisms, SEXUAL dimorphism, META-analysis
Abstract

Corrections to the article "Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution" that was published in the October 10, 2011 issue are presented, such as the effect allele frequencies for eight single nucleotide polymorphisms (SNPs) that include rs984222, rs9491696, and rs4846567.

Published
2011
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163. A Bayesian Framework for Generalized Linear Mixed Modeling Identifies New Candidate Loci for Late-Onset Alzheimer's Disease.

Author

Xulong Wang, Philip, Vivek M., Ananda, Guruprasad, White, Charles C., Malhotra, Ankit, Michalski, Paul J., Murthy Karuturi, Krishna R., Chintalapudi, Sumana R., Acklin, Casey, Sasner, Michael, Bennett, David A., De Jager, Philip L., Howell, Gareth R., and Carter, Gregory W.

Subjects
*ALZHEIMER'S disease, *NUCLEOTIDE sequencing, *NEUROLOGICAL disorders, *SINGLE nucleotide polymorphisms, *ALLELES
Abstract

Recent technical and methodological advances have greatly enhanced genome-wide association studies (GWAS). The advent of low-cost, whole-genome sequencing facilitates high-resolution variant identification, and the development of linear mixed models (LMM) allows improved identification of putatively causal variants. While essential for correcting false positive associations due to sample relatedness and population stratification, LMMs have commonly been restricted to quantitative variables. However, phenotypic traits in association studies are often categorical, coded as binary case-control or ordered variables describing disease stages. To address these issues, we have devised a method for genomic association studies that implements a generalized LMM (GLMM) in a Bayesian framework, called Bayes- GLMM. Bayes-GLMM has four major features: (1) support of categorical, binary, and quantitative variables; (2) cohesive integration of previous GWAS results for related traits; (3) correction for sample relatedness by mixed modeling; and (4) model estimation by both Markov chain Monte Carlo sampling and maximal likelihood estimation. We applied Bayes-GLMM to the whole-genome sequencing cohort of the Alzheimer's Disease Sequencing Project. This study contains 570 individuals from 111 families, each with Alzheimer's disease diagnosed at one of four confidence levels. Using Bayes-GLMM we identified four variants in three loci significantly associated with Alzheimer's disease. Two variants, rs140233081 and rs149372995, lie between PRKAR1B and PDGFA. The coded proteins are localized to the glial-vascular unit, and PDGFA transcript levels are associated with Alzheimer's disease-related neuropathology. In summary, this work provides implementation of a flexible, generalized mixed-model approach in a Bayesian framework for association studies. [ABSTRACT FROM AUTHOR]

Published
2018
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164. Cellular communities reveal trajectories of brain ageing and Alzheimer's disease.

Author

Green GS, Fujita M, Yang HS, Taga M, Cain A, McCabe C, Comandante-Lou N, White CC, Schmidtner AK, Zeng L, Sigalov A, Wang Y, Regev A, Klein HU, Menon V, Bennett DA, Habib N, and De Jager PL

Subjects
Aged, Aged, 80 and over, Animals, Female, Humans, Male, Amyloid beta-Peptides metabolism, Astrocytes pathology, Astrocytes metabolism, Cognitive Dysfunction genetics, Cognitive Dysfunction metabolism, Cognitive Dysfunction pathology, Microglia pathology, Microglia metabolism, Neurons pathology, Neurons metabolism, Single-Cell Gene Expression Analysis, tau Proteins metabolism, Tauopathies genetics, Tauopathies metabolism, Tauopathies pathology, Atlases as Topic, Aging genetics, Aging metabolism, Aging pathology, Alzheimer Disease genetics, Alzheimer Disease metabolism, Alzheimer Disease pathology, Cell Biology, Prefrontal Cortex pathology, Prefrontal Cortex cytology, Prefrontal Cortex metabolism
Abstract

Alzheimer's disease (AD) has recently been associated with diverse cell states 1-11 , yet when and how these states affect the onset of AD remains unclear. Here we used a data-driven approach to reconstruct the dynamics of the brain's cellular environment and identified a trajectory leading to AD that is distinct from other ageing-related effects. First, we built a comprehensive cell atlas of the aged prefrontal cortex from 1.65 million single-nucleus RNA-sequencing profiles sampled from 437 older individuals, and identified specific glial and neuronal subpopulations associated with AD-related traits. Causal modelling then prioritized two distinct lipid-associated microglial subpopulations-one drives amyloid-β proteinopathy while the other mediates the effect of amyloid-β on tau proteinopathy-as well as an astrocyte subpopulation that mediates the effect of tau on cognitive decline. To model the dynamics of cellular environments, we devised the BEYOND methodology, which identified two distinct trajectories of brain ageing, each defined by coordinated progressive changes in certain cellular communities that lead to (1) AD dementia or (2) alternative brain ageing. Thus, we provide a cellular foundation for a new perspective on AD pathophysiology that informs personalized therapeutic development, targeting different cellular communities for individuals on the path to AD or to alternative brain ageing., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Published
2024
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166. Cell subtype-specific effects of genetic variation in the Alzheimer's disease brain.

Author

Fujita M, Gao Z, Zeng L, McCabe C, White CC, Ng B, Green GS, Rozenblatt-Rosen O, Phillips D, Amir-Zilberstein L, Lee H, Pearse RV 2nd, Khan A, Vardarajan BN, Kiryluk K, Ye CJ, Klein HU, Wang G, Regev A, Habib N, Schneider JA, Wang Y, Young-Pearse T, Mostafavi S, Bennett DA, Menon V, and De Jager PL

Subjects
Humans, Genome-Wide Association Study methods, Brain metabolism, Quantitative Trait Loci genetics, Genetic Variation genetics, Membrane Proteins genetics, Nerve Tissue Proteins genetics, Alzheimer Disease metabolism
Abstract

The relationship between genetic variation and gene expression in brain cell types and subtypes remains understudied. Here, we generated single-nucleus RNA sequencing data from the neocortex of 424 individuals of advanced age; we assessed the effect of genetic variants on RNA expression in cis (cis-expression quantitative trait loci) for seven cell types and 64 cell subtypes using 1.5 million transcriptomes. This effort identified 10,004 eGenes at the cell type level and 8,099 eGenes at the cell subtype level. Many eGenes are only detected within cell subtypes. A new variant influences APOE expression only in microglia and is associated with greater cerebral amyloid angiopathy but not Alzheimer's disease pathology, after adjusting for APOEε4, providing mechanistic insights into both pathologies. Furthermore, only a TMEM106B variant affects the proportion of cell subtypes. Integration of these results with genome-wide association studies highlighted the targeted cell type and probable causal gene within Alzheimer's disease, schizophrenia, educational attainment and Parkinson's disease loci., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Published
2024
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167. Multicellular communities are perturbed in the aging human brain and Alzheimer's disease.

Author

Cain A, Taga M, McCabe C, Green GS, Hekselman I, White CC, Lee DI, Gaur P, Rozenblatt-Rosen O, Zhang F, Yeger-Lotem E, Bennett DA, Yang HS, Regev A, Menon V, Habib N, and De Jager PL

Subjects
Humans, Endothelial Cells metabolism, Brain metabolism, Aging pathology, Alzheimer Disease metabolism, Cognitive Dysfunction pathology, Neocortex pathology
Abstract

The role of different cell types and their interactions in Alzheimer's disease (AD) is a complex and open question. Here, we pursued this question by assembling a high-resolution cellular map of the aging frontal cortex using single-nucleus RNA sequencing of 24 individuals with a range of clinicopathologic characteristics. We used this map to infer the neocortical cellular architecture of 638 individuals profiled by bulk RNA sequencing, providing the sample size necessary for identifying statistically robust associations. We uncovered diverse cell populations associated with AD, including a somatostatin inhibitory neuronal subtype and oligodendroglial states. We further identified a network of multicellular communities, each composed of coordinated subpopulations of neuronal, glial and endothelial cells, and we found that two of these communities are altered in AD. Finally, we used mediation analyses to prioritize cellular changes that might contribute to cognitive decline. Thus, our deconstruction of the aging neocortex provides a roadmap for evaluating the cellular microenvironments underlying AD and dementia., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Published
2023
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168. Genetic insights into the association between inflammatory bowel disease and Alzheimer's disease.

Author

Zeng L, White CC, Bennett DA, Klein HU, and De Jager PL

Abstract

Background: Myeloid cells, including monocytes, macrophages, microglia, dendritic cells and neutrophils are a part of innate immunity, playing a major role in orchestrating innate and adaptive immune responses. Microglia are the resident myeloid cells of the central nervous system, and many Alzheimer's disease (AD) risk loci are found in or near genes that are highly or sometimes uniquely expressed in myeloid cells. Similarly, inflammatory bowel disease (IBD) loci are also enriched for genes expressed by myeloid cells. However, the extent to which there is overlap between the effects of AD and IBD susceptibility loci in myeloid cells remains poorly described, and the substantial IBD genetic maps may help to accelerate AD research., Methods: Here, we leveraged summary statistics from large-scale genome-wide association studies (GWAS) to investigate the causal effect of IBD (including ulcerative colitis and Crohn's disease) variants on AD and AD endophenotypes. Microglia and monocyte expression Quantitative Trait Locus (eQTLs) were used to examine the functional consequences of IBD and AD risk variants enrichment in two different myeloid cell subtypes., Results: Our results showed that, while PTK2B is implicated in both diseases and both sets of risk loci are enriched for myeloid genes, AD and IBD susceptibility loci largely implicate distinct sets of genes and pathways. AD loci are significantly more enriched for microglial eQTLs than IBD. We also found that genetically determined IBD is associated with a lower risk of AD, which may driven by a negative effect on the accumulation of neurofibrillary tangles (beta=-1.04, p=0.013). In addition, IBD displayed a significant positive genetic correlation with psychiatric disorders and multiple sclerosis, while AD showed a significant positive genetic correlation with amyotrophic lateral sclerosis., Conclusion: To our knowledge, this is the first study to systematically contrast the genetic association between IBD and AD, our findings highlight a possible genetically protective effect of IBD on AD even if the majority of effects on myeloid cell gene expression by the two sets of disease variants are distinct. Thus, IBD myeloid studies may not help to accelerate AD functional studies, but our observation reinforces the role of myeloid cells in the accumulation of tau proteinopathy and provides a new avenue for discovering a protective factor.

Published
2023
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169. A single-nucleus transcriptome-wide association study implicates novel genes in depression pathogenesis.

Author

Zeng L, Fujita M, Gao Z, White CC, Green GS, Habib N, Menon V, Bennett DA, Boyle PA, Klein HU, and De Jager PL

Abstract

Background: Depression is a common psychiatric illness and global public health problem. However, our limited understanding of the biological basis of depression has hindered the development of novel treatments and interventions., Methods: To identify new candidate genes for therapeutic development, we examined single-nucleus RNA sequencing (snucRNAseq) data from the dorsolateral prefrontal cortex (N=424) in relation to ante-mortem depressive symptoms. To complement these direct analyses, we also used genome-wide association study (GWAS) results for depression (N=500,199) along with genetic tools for inferring the expression of 22,159 genes in 7 cell types and 55 cell subtypes to perform transcriptome-wide association studies (TWAS) of depression followed by Mendelian randomization (MR)., Results: Our single-nucleus TWAS analysis identified 71 causal genes in depression that have a role in specific neocortical cell subtypes; 59 of 71 genes were novel compared to previous studies. Depression TWAS genes showed a cell type specific pattern, with the greatest enrichment being in both excitatory and inhibitory neurons as well as astrocytes. Gene expression in different neuron subtypes have different directions of effect on depression risk. Compared to lower genetically correlated traits (e.g. body mass index) with depression, higher correlated traits (e.g., neuroticism) have more common TWAS genes with depression. In parallel, we performed differential gene expression analysis in relation to depression in 55 cortical cell subtypes, and we found that genes such as ANKRD36, MADD, TAOK3 , SCAI and CHUK are associated with depression in specific cell subtypes., Conclusions: These two sets of analyses illustrate the utility of large snucRNAseq data to uncover both genes whose expression is altered in specific cell subtypes in the context of depression and to enhance the interpretation of well-powered GWAS so that we can prioritize specific susceptibility genes for further analysis and therapeutic development.

Published
2023
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170. Cellular dynamics across aged human brains uncover a multicellular cascade leading to Alzheimer's disease.

Author

Green GS, Fujita M, Yang HS, Taga M, McCabe C, Cain A, White CC, Schmidtner AK, Zeng L, Wang Y, Regev A, Menon V, Bennett DA, Habib N, and De Jager PL

Abstract

Alzheimer's Disease (AD) is a progressive neurodegenerative disease seen with advancing age. Recent studies have revealed diverse AD-associated cell states, yet when and how they impact the causal chain leading to AD remains unknown. To reconstruct the dynamics of the brain's cellular environment along the disease cascade and to distinguish between AD and aging effects, we built a comprehensive cell atlas of the aged prefrontal cortex from 1.64 million single-nucleus RNA-seq profiles. We associated glial, vascular and neuronal subpopulations with AD-related traits for 424 aging individuals, and aligned them along the disease cascade using causal modeling. We identified two distinct lipid-associated microglial subpopulations, one contributed to amyloid-β proteinopathy while the other mediated the effect of amyloid-β in accelerating tau proteinopathy, as well as an astrocyte subpopulation that mediated the effect of tau on cognitive decline. To model the coordinated dynamics of the entire cellular environment we devised the BEYOND methodology which uncovered two distinct trajectories of brain aging that are defined by distinct sequences of changes in cellular communities. Older individuals are engaged in one of two possible trajectories, each associated with progressive changes in specific cellular communities that end with: (1) AD dementia or (2) alternative brain aging. Thus, we provide a cellular foundation for a new perspective of AD pathophysiology that could inform the development of new therapeutic interventions targeting cellular communities, while designing a different clinical management for those individuals on the path to AD or to alternative brain aging.

Published
2023
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171. Postoperative Infection and Revision Surgery Rates in Foot and Ankle Surgery Without Routine Prescription of Prophylactic Antibiotics.

Author

Huang N, Miles DT, Read CR, White CC, Murray RD, Wilson AW, and Doty JF

Subjects
Humans, Reoperation, Anti-Bacterial Agents therapeutic use, Antibiotic Prophylaxis adverse effects, Prescriptions, Ankle surgery, Communicable Diseases drug therapy, Communicable Diseases etiology, Communicable Diseases surgery
Abstract

Introduction: Surgical site infections (SSIs) are associated with patient morbidity and increased healthcare costs. Limited literature in foot and ankle surgery provides guidance about routine administration of postoperative antibiotic prophylaxis. The purpose of this study was to examine the incidence and revision surgery rates of SSI in outpatient foot and ankle surgeries in patients not receiving oral postoperative antibiotic prophylaxis., Methods: A retrospective review of all outpatient surgeries (n = 1517) conducted by a single surgeon in a tertiary referral academic center was conducted through electronic medical records. Incidence of SSI, revision surgery rate, and associated risk factors were determined. The median follow-up was 6 months., Results: Postoperative infection occurred in 2.9% (n = 44) of the surgeries conducted, with 0.9% of patients (n = 14) requiring return to the operating room. Thirty patients (2.0%) were diagnosed with simple superficial infections, which resolved with local wound care and oral antibiotics. Diabetes (adjusted odds ratio, 2.09; 95% confidence interval, 1.00 to 4.38; P = 0.049) and increasing age (adjusted odds ratio, 1.02; 95% confidence interval, 1.00 to 1.04; P = 0.016) were significantly associated with postoperative infection., Discussion: This study demonstrated low postoperative infection and revision surgery rates without the routine prescription of prophylactic postoperative antibiotics. Increasing age and diabetes are signficant risk factors for developing a postoperative infection., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Orthopaedic Surgeons.)

Published
2023
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172. Atlas of RNA editing events affecting protein expression in aged and Alzheimer's disease human brain tissue.

Author

Ma Y, Dammer EB, Felsky D, Duong DM, Klein HU, White CC, Zhou M, Logsdon BA, McCabe C, Xu J, Wang M, Wingo TS, Lah JJ, Zhang B, Schneider J, Allen M, Wang X, Ertekin-Taner N, Seyfried NT, Levey AI, Bennett DA, and De Jager PL

Subjects
Alzheimer Disease metabolism, Alzheimer Disease pathology, Atlases as Topic, Brain metabolism, Brain pathology, Brain Chemistry, Gene Expression Profiling, Humans, Hydroxysteroid Dehydrogenases genetics, Hydroxysteroid Dehydrogenases metabolism, Membrane Proteins genetics, Membrane Proteins metabolism, Mitochondrial Proteins genetics, Mitochondrial Proteins metabolism, ORAI2 Protein metabolism, Phosphofructokinase-1, Type C genetics, Phosphofructokinase-1, Type C metabolism, RNA metabolism, Receptors, G-Protein-Coupled genetics, Receptors, G-Protein-Coupled metabolism, Superoxide Dismutase genetics, Superoxide Dismutase metabolism, Synaptotagmins metabolism, Alzheimer Disease genetics, ORAI2 Protein genetics, RNA genetics, RNA Editing, Synaptotagmins genetics, Transcriptome
Abstract

RNA editing is a feature of RNA maturation resulting in the formation of transcripts whose sequence differs from the genome template. Brain RNA editing may be altered in Alzheimer's disease (AD). Here, we analyzed data from 1,865 brain samples covering 9 brain regions from 1,074 unrelated subjects on a transcriptome-wide scale to identify inter-regional differences in RNA editing. We expand the list of known brain editing events by identifying 58,761 previously unreported events. We note that only a small proportion of these editing events are found at the protein level in our proteome-wide validation effort. We also identified the occurrence of editing events associated with AD dementia, neuropathological measures and longitudinal cognitive decline in: SYT11, MCUR1, SOD2, ORAI2, HSDL2, PFKP, and GPRC5B. Thus, we present an extended reference set of brain RNA editing events, identify a subset that are found to be expressed at the protein level, and extend the narrative of transcriptomic perturbation in AD to RNA editing., (© 2021. The Author(s).)

Published
2021
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173. Sex-Specific Association of the X Chromosome With Cognitive Change and Tau Pathology in Aging and Alzheimer Disease.

Author

Davis EJ, Solsberg CW, White CC, Miñones-Moyano E, Sirota M, Chibnik L, Bennett DA, De Jager PL, Yokoyama JS, and Dubal DB

Subjects
Aged, Aged, 80 and over, Cognition, Cognitive Dysfunction, Cohort Studies, Female, Humans, Male, Middle Aged, Neurofibrillary Tangles pathology, Transcriptome, Aging physiology, Alzheimer Disease genetics, Alzheimer Disease pathology, Chromosomes, Human, X, Dorsolateral Prefrontal Cortex, Sex Characteristics
Abstract

Importance: The X chromosome represents 5% of the human genome in women and men, and its influence on cognitive aging and Alzheimer disease (AD) is largely unknown., Objective: To determine whether the X chromosome is associated with sex-specific cognitive change and tau pathology in aging and AD., Design, Setting, Participants: This study examined differential gene expression profiling of the X chromosome from an RNA sequencing data set of the dorsolateral prefrontal cortex obtained from autopsied, elderly individuals enrolled in the Religious Orders Study and Rush Memory and Aging Project joint cohorts. Samples were collected from the cohort study with enrollment from 1994 to 2017. Data were last analyzed in May 2021., Main Outcomes and Measures: The main analysis examined whether X chromosome gene expression measured by RNA sequencing of the dorsolateral prefrontal cortex was associated with cognitive change during aging and AD, independent of AD pathology and at the transcriptome-wide level in women and men. Whether X chromosome gene expression was associated with neurofibrillary tangle burden, a measure of tau pathology that influences cognition, in women and men was also explored., Results: Samples for RNA sequencing of the dorsolateral prefrontal cortex were obtained from 508 individuals (mean [SD] age at death, 88.4 [6.6] years; 315 [62.0%] were female; 197 [38.8%] had clinical diagnosis of AD at death; 293 [58.2%] had pathological diagnosis of AD at death) enrolled in the Religious Orders Study and Rush Memory and Aging Project joint cohorts and were followed up annually for a mean (SD) of 6.3 (3.9) years. X chromosome gene expression (29 genes), adjusted for age at death, education, and AD pathology, was significantly associated with cognitive change at the genome-wide level in women but not men. In the majority of identified X genes (19 genes), increased expression was associated with slower cognitive decline in women. In contrast with cognition, X chromosome gene expression (3 genes), adjusted for age at death and education, was associated with neuropathological tau burden at the genome-wide level in men but not women., Conclusions and Relevance: In this study, the X chromosome was associated with cognitive trajectories and neuropathological tau burden in aging and AD in a sex-specific manner. This is important because specific X chromosome factors could contribute risk or resilience to biological pathways of aging and AD in women, men, or both.

Published
2021
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174. Effects of the Obesity Epidemic on Total Hip and Knee Arthroplasty Demographics.

Author

Johnson CA, White CC, Kunkle BF, Eichinger JK, and Friedman RJ

Subjects
Demography, Humans, Obesity epidemiology, Retrospective Studies, Arthroplasty, Replacement, Hip, Arthroplasty, Replacement, Knee, Epidemics, Osteoarthritis, Hip epidemiology, Osteoarthritis, Hip surgery, Osteoarthritis, Knee epidemiology, Osteoarthritis, Knee etiology, Osteoarthritis, Knee surgery
Abstract

Background: Higher body mass index (BMI) is a well-known risk factor for the development of hip and knee osteoarthritis and predicts total hip arthroplasty (THA) and total knee arthroplasty (TKA) at an earlier age. The purpose of this study is to document the nationwide trends in age and obesity in primary THA and TKA throughout the obesity epidemic., Methods: A retrospective analysis of the National Inpatient Sample database was conducted on patients undergoing primary THA and TKA for primary OA between 2002 and 2017. Analysis of variance and chi-square tests were performed to examine changes in age and obesity percentage over time, respectively. Pearson correlations were used to assess the relationship between patient age, BMI, and year of surgery., Results: A total of 688,371 THA and 1,556,651 TKA were identified over the sixteen-year period. Between 2002 and 2017, the proportion of obese patients increased for both THA (7.0% to 22.7%, P < .001) and TKA (10.7% to 30.4%, P < .001). Mean age significantly decreased for both THA (66.7 to 65.9 years, P < .001) and TKA (67.6 to 66.8 years; P < .001). Over time, BMI significantly increased (THA: r = 0.221 vs. TKA: r = 0.272) and patient age decreased (THA: r = -0.031 vs. TKA: r = -0.137) for both procedures (P < .001 for all)., Conclusion: THA and TKA patients have become younger and increasingly more obese throughout the obesity epidemic, as obesity rates have tripled over this time period. The current investigation is the first to demonstrate significant trends in both age and obesity in the THA and TKA populations on a national level., Level of Evidence: III., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Published
2021
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175. Neuroticism alters the transcriptome of the frontal cortex to contribute to the cognitive decline and onset of Alzheimer's disease.

Author

De Jager CH, White CC, Bennett DA, and Ma Y

Subjects
Amyloid beta-Peptides metabolism, Brain metabolism, Frontal Lobe metabolism, Humans, Neuroticism, Transcriptome, tau Proteins metabolism, Alzheimer Disease genetics, Cognitive Dysfunction genetics
Abstract

Accumulating evidence has suggested that the molecular transcriptional mechanism contributes to Alzheimer's disease (AD) and its endophenotypes of cognitive decline and neuropathological traits, β-amyloid (Aβ) and phosphorylated tangles (TAU). However, it is unknown what is the impact of the AD risk factors, personality characteristics assessed by the NEO Five-Factor Inventory, on the human brain's transcriptome. Using postmortem human brain samples from 466 subjects, we found that neuroticism has a significant overall impact on the brain transcriptome (omnibus P = 0.005) but not the other four personality characteristics. Focused on those cognitive decline related gene co-expressed modules, neuroticism has nominally significant associations (P < 0.05) with four neuronal modules, which are more related to PHFtau than Aβ across all eight brain regions. Furthermore, the effect of neuroticism on cognitive decline and AD might be mediated through the expression of module 7 and TAU pathology (P = 0.008). To conclude, neuroticism has a broad impact on the transcriptome of human brains, and its effect on cognitive decline and AD may be mediated through gene transcription programs related to TAU pathology.

Published
2021
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176. A cortical immune network map identifies distinct microglial transcriptional programs associated with β-amyloid and Tau pathologies.

Author

Patrick E, Olah M, Taga M, Klein HU, Xu J, White CC, Felsky D, Agrawal S, Gaiteri C, Chibnik LB, Mostafavi S, Schneider JA, Bennett DA, Bradshaw EM, and De Jager PL

Subjects
Amyloid beta-Peptides metabolism, Brain metabolism, Humans, Microglia metabolism, tau Proteins genetics, tau Proteins metabolism, Alzheimer Disease genetics, Cognitive Dysfunction
Abstract

Microglial dysfunction has been proposed as one of the many cellular mechanisms that can contribute to the development of Alzheimer's disease (AD). Here, using a transcriptional network map of the human frontal cortex, we identify five modules of co-expressed genes related to microglia and assess their role in the neuropathologic features of AD in 540 subjects from two cohort studies of brain aging. Two of these transcriptional programs-modules 113 and 114-relate to the accumulation of β-amyloid, while module 5 relates to tau pathology. We replicate these associations in brain epigenomic data and in two independent datasets. In terms of tau, we propose that module 5, a marker of activated microglia, may lead to tau accumulation and subsequent cognitive decline. We validate our model further by showing that three representative module 5 genes (ACADVL, TRABD, and VASP) encode proteins that are upregulated in activated microglia in AD.

Published
2021
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177. Genetic architecture of subcortical brain structures in 38,851 individuals.

Author

Satizabal CL, Adams HHH, Hibar DP, White CC, Knol MJ, Stein JL, Scholz M, Sargurupremraj M, Jahanshad N, Roshchupkin GV, Smith AV, Bis JC, Jian X, Luciano M, Hofer E, Teumer A, van der Lee SJ, Yang J, Yanek LR, Lee TV, Li S, Hu Y, Koh JY, Eicher JD, Desrivières S, Arias-Vasquez A, Chauhan G, Athanasiu L, Rentería ME, Kim S, Hoehn D, Armstrong NJ, Chen Q, Holmes AJ, den Braber A, Kloszewska I, Andersson M, Espeseth T, Grimm O, Abramovic L, Alhusaini S, Milaneschi Y, Papmeyer M, Axelsson T, Ehrlich S, Roiz-Santiañez R, Kraemer B, Håberg AK, Jones HJ, Pike GB, Stein DJ, Stevens A, Bralten J, Vernooij MW, Harris TB, Filippi I, Witte AV, Guadalupe T, Wittfeld K, Mosley TH, Becker JT, Doan NT, Hagenaars SP, Saba Y, Cuellar-Partida G, Amin N, Hilal S, Nho K, Mirza-Schreiber N, Arfanakis K, Becker DM, Ames D, Goldman AL, Lee PH, Boomsma DI, Lovestone S, Giddaluru S, Le Hellard S, Mattheisen M, Bohlken MM, Kasperaviciute D, Schmaal L, Lawrie SM, Agartz I, Walton E, Tordesillas-Gutierrez D, Davies GE, Shin J, Ipser JC, Vinke LN, Hoogman M, Jia T, Burkhardt R, Klein M, Crivello F, Janowitz D, Carmichael O, Haukvik UK, Aribisala BS, Schmidt H, Strike LT, Cheng CY, Risacher SL, Pütz B, Fleischman DA, Assareh AA, Mattay VS, Buckner RL, Mecocci P, Dale AM, Cichon S, Boks MP, Matarin M, Penninx BWJH, Calhoun VD, Chakravarty MM, Marquand AF, Macare C, Kharabian Masouleh S, Oosterlaan J, Amouyel P, Hegenscheid K, Rotter JI, Schork AJ, Liewald DCM, de Zubicaray GI, Wong TY, Shen L, Sämann PG, Brodaty H, Roffman JL, de Geus EJC, Tsolaki M, Erk S, van Eijk KR, Cavalleri GL, van der Wee NJA, McIntosh AM, Gollub RL, Bulayeva KB, Bernard M, Richards JS, Himali JJ, Loeffler M, Rommelse N, Hoffmann W, Westlye LT, Valdés Hernández MC, Hansell NK, van Erp TGM, Wolf C, Kwok JBJ, Vellas B, Heinz A, Olde Loohuis LM, Delanty N, Ho BC, Ching CRK, Shumskaya E, Singh B, Hofman A, van der Meer D, Homuth G, Psaty BM, Bastin ME, Montgomery GW, Foroud TM, Reppermund S, Hottenga JJ, Simmons A, Meyer-Lindenberg A, Cahn W, Whelan CD, van Donkelaar MMJ, Yang Q, Hosten N, Green RC, Thalamuthu A, Mohnke S, Hulshoff Pol HE, Lin H, Jack CR Jr, Schofield PR, Mühleisen TW, Maillard P, Potkin SG, Wen W, Fletcher E, Toga AW, Gruber O, Huentelman M, Davey Smith G, Launer LJ, Nyberg L, Jönsson EG, Crespo-Facorro B, Koen N, Greve DN, Uitterlinden AG, Weinberger DR, Steen VM, Fedko IO, Groenewold NA, Niessen WJ, Toro R, Tzourio C, Longstreth WT Jr, Ikram MK, Smoller JW, van Tol MJ, Sussmann JE, Paus T, Lemaître H, Schroeter ML, Mazoyer B, Andreassen OA, Holsboer F, Depondt C, Veltman DJ, Turner JA, Pausova Z, Schumann G, van Rooij D, Djurovic S, Deary IJ, McMahon KL, Müller-Myhsok B, Brouwer RM, Soininen H, Pandolfo M, Wassink TH, Cheung JW, Wolfers T, Martinot JL, Zwiers MP, Nauck M, Melle I, Martin NG, Kanai R, Westman E, Kahn RS, Sisodiya SM, White T, Saremi A, van Bokhoven H, Brunner HG, Völzke H, Wright MJ, van 't Ent D, Nöthen MM, Ophoff RA, Buitelaar JK, Fernández G, Sachdev PS, Rietschel M, van Haren NEM, Fisher SE, Beiser AS, Francks C, Saykin AJ, Mather KA, Romanczuk-Seiferth N, Hartman CA, DeStefano AL, Heslenfeld DJ, Weiner MW, Walter H, Hoekstra PJ, Nyquist PA, Franke B, Bennett DA, Grabe HJ, Johnson AD, Chen C, van Duijn CM, Lopez OL, Fornage M, Wardlaw JM, Schmidt R, DeCarli C, De Jager PL, Villringer A, Debette S, Gudnason V, Medland SE, Shulman JM, Thompson PM, Seshadri S, and Ikram MA

Subjects
Adult, Aged, Animals, Cohort Studies, Drosophila melanogaster genetics, Drosophila melanogaster growth & development, Humans, Magnetic Resonance Imaging, Middle Aged, Organ Size, Brain anatomy & histology, Brain metabolism, Drosophila melanogaster metabolism, Genetic Variation, Genome-Wide Association Study, Neurodevelopmental Disorders genetics, Neurodevelopmental Disorders pathology
Abstract

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

Published
2019
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178. Author Correction: Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing.

Author

Kunkle BW, Grenier-Boley B, Sims R, Bis JC, Damotte V, Naj AC, Boland A, Vronskaya M, van der Lee SJ, Amlie-Wolf A, Bellenguez C, Frizatti A, Chouraki V, Martin ER, Sleegers K, Badarinarayan N, Jakobsdottir J, Hamilton-Nelson KL, Moreno-Grau S, Olaso R, Raybould R, Chen Y, Kuzma AB, Hiltunen M, Morgan T, Ahmad S, Vardarajan BN, Epelbaum J, Hoffmann P, Boada M, Beecham GW, Garnier JG, Harold D, Fitzpatrick AL, Valladares O, Moutet ML, Gerrish A, Smith AV, Qu L, Bacq D, Denning N, Jian X, Zhao Y, Del Zompo M, Fox NC, Choi SH, Mateo I, Hughes JT, Adams HH, Malamon J, Sanchez-Garcia F, Patel Y, Brody JA, Dombroski BA, Naranjo MCD, Daniilidou M, Eiriksdottir G, Mukherjee S, Wallon D, Uphill J, Aspelund T, Cantwell LB, Garzia F, Galimberti D, Hofer E, Butkiewicz M, Fin B, Scarpini E, Sarnowski C, Bush WS, Meslage S, Kornhuber J, White CC, Song Y, Barber RC, Engelborghs S, Sordon S, Voijnovic D, Adams PM, Vandenberghe R, Mayhaus M, Cupples LA, Albert MS, De Deyn PP, Gu W, Himali JJ, Beekly D, Squassina A, Hartmann AM, Orellana A, Blacker D, Rodriguez-Rodriguez E, Lovestone S, Garcia ME, Doody RS, Munoz-Fernadez C, Sussams R, Lin H, Fairchild TJ, Benito YA, Holmes C, Karamujić-Čomić H, Frosch MP, Thonberg H, Maier W, Roshchupkin G, Ghetti B, Giedraitis V, Kawalia A, Li S, Huebinger RM, Kilander L, Moebus S, Hernández I, Kamboh MI, Brundin R, Turton J, Yang Q, Katz MJ, Concari L, Lord J, Beiser AS, Keene CD, Helisalmi S, Kloszewska I, Kukull WA, Koivisto AM, Lynch A, Tarraga L, Larson EB, Haapasalo A, Lawlor B, Mosley TH, Lipton RB, Solfrizzi V, Gill M, Longstreth WT Jr, Montine TJ, Frisardi V, Diez-Fairen M, Rivadeneira F, Petersen RC, Deramecourt V, Alvarez I, Salani F, Ciaramella A, Boerwinkle E, Reiman EM, Fievet N, Rotter JI, Reisch JS, Hanon O, Cupidi C, Uitterlinden AGA, Royall DR, Dufouil C, Maletta RG, de Rojas I, Sano M, Brice A, Cecchetti R, George-Hyslop PS, Ritchie K, Tsolaki M, Tsuang DW, Dubois B, Craig D, Wu CK, Soininen H, Avramidou D, Albin RL, Fratiglioni L, Germanou A, Apostolova LG, Keller L, Koutroumani M, Arnold SE, Panza F, Gkatzima O, Asthana S, Hannequin D, Whitehead P, Atwood CS, Caffarra P, Hampel H, Quintela I, Carracedo Á, Lannfelt L, Rubinsztein DC, Barnes LL, Pasquier F, Frölich L, Barral S, McGuinness B, Beach TG, Johnston JA, Becker JT, Passmore P, Bigio EH, Schott JM, Bird TD, Warren JD, Boeve BF, Lupton MK, Bowen JD, Proitsi P, Boxer A, Powell JF, Burke JR, Kauwe JSK, Burns JM, Mancuso M, Buxbaum JD, Bonuccelli U, Cairns NJ, McQuillin A, Cao C, Livingston G, Carlson CS, Bass NJ, Carlsson CM, Hardy J, Carney RM, Bras J, Carrasquillo MM, Guerreiro R, Allen M, Chui HC, Fisher E, Masullo C, Crocco EA, DeCarli C, Bisceglio G, Dick M, Ma L, Duara R, Graff-Radford NR, Evans DA, Hodges A, Faber KM, Scherer M, Fallon KB, Riemenschneider M, Fardo DW, Heun R, Farlow MR, Kölsch H, Ferris S, Leber M, Foroud TM, Heuser I, Galasko DR, Giegling I, Gearing M, Hüll M, Geschwind DH, Gilbert JR, Morris J, Green RC, Mayo K, Growdon JH, Feulner T, Hamilton RL, Harrell LE, Drichel D, Honig LS, Cushion TD, Huentelman MJ, Hollingworth P, Hulette CM, Hyman BT, Marshall R, Jarvik GP, Meggy A, Abner E, Menzies GE, Jin LW, Leonenko G, Real LM, Jun GR, Baldwin CT, Grozeva D, Karydas A, Russo G, Kaye JA, Kim R, Jessen F, Kowall NW, Vellas B, Kramer JH, Vardy E, LaFerla FM, Jöckel KH, Lah JJ, Dichgans M, Leverenz JB, Mann D, Levey AI, Pickering-Brown S, Lieberman AP, Klopp N, Lunetta KL, Wichmann HE, Lyketsos CG, Morgan K, Marson DC, Brown K, Martiniuk F, Medway C, Mash DC, Nöthen MM, Masliah E, Hooper NM, McCormick WC, Daniele A, McCurry SM, Bayer A, McDavid AN, Gallacher J, McKee AC, van den Bussche H, Mesulam M, Brayne C, Miller BL, Riedel-Heller S, Miller CA, Miller JW, Al-Chalabi A, Morris JC, Shaw CE, Myers AJ, Wiltfang J, O'Bryant S, Olichney JM, Alvarez V, Parisi JE, Singleton AB, Paulson HL, Collinge J, Perry WR, Mead S, Peskind E, Cribbs DH, Rossor M, Pierce A, Ryan NS, Poon WW, Nacmias B, Potter H, Sorbi S, Quinn JF, Sacchinelli E, Raj A, Spalletta G, Raskind M, Caltagirone C, Bossù P, Orfei MD, Reisberg B, Clarke R, Reitz C, Smith AD, Ringman JM, Warden D, Roberson ED, Wilcock G, Rogaeva E, Bruni AC, Rosen HJ, Gallo M, Rosenberg RN, Ben-Shlomo Y, Sager MA, Mecocci P, Saykin AJ, Pastor P, Cuccaro ML, Vance JM, Schneider JA, Schneider LS, Slifer S, Seeley WW, Smith AG, Sonnen JA, Spina S, Stern RA, Swerdlow RH, Tang M, Tanzi RE, Trojanowski JQ, Troncoso JC, Van Deerlin VM, Van Eldik LJ, Vinters HV, Vonsattel JP, Weintraub S, Welsh-Bohmer KA, Wilhelmsen KC, Williamson J, Wingo TS, Woltjer RL, Wright CB, Yu CE, Yu L, Saba Y, Pilotto A, Bullido MJ, Peters O, Crane PK, Bennett D, Bosco P, Coto E, Boccardi V, De Jager PL, Lleo A, Warner N, Lopez OL, Ingelsson M, Deloukas P, Cruchaga C, Graff C, Gwilliam R, Fornage M, Goate AM, Sanchez-Juan P, Kehoe PG, Amin N, Ertekin-Taner N, Berr C, Debette S, Love S, Launer LJ, Younkin SG, Dartigues JF, Corcoran C, Ikram MA, Dickson DW, Nicolas G, Campion D, Tschanz J, Schmidt H, Hakonarson H, Clarimon J, Munger R, Schmidt R, Farrer LA, Van Broeckhoven C, O'Donovan MC, DeStefano AL, Jones L, Haines JL, Deleuze JF, Owen MJ, Gudnason V, Mayeux R, Escott-Price V, Psaty BM, Ramirez A, Wang LS, Ruiz A, van Duijn CM, Holmans PA, Seshadri S, Williams J, Amouyel P, Schellenberg GD, Lambert JC, and Pericak-Vance MA

Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2019
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179. Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing.

Author

Kunkle BW, Grenier-Boley B, Sims R, Bis JC, Damotte V, Naj AC, Boland A, Vronskaya M, van der Lee SJ, Amlie-Wolf A, Bellenguez C, Frizatti A, Chouraki V, Martin ER, Sleegers K, Badarinarayan N, Jakobsdottir J, Hamilton-Nelson KL, Moreno-Grau S, Olaso R, Raybould R, Chen Y, Kuzma AB, Hiltunen M, Morgan T, Ahmad S, Vardarajan BN, Epelbaum J, Hoffmann P, Boada M, Beecham GW, Garnier JG, Harold D, Fitzpatrick AL, Valladares O, Moutet ML, Gerrish A, Smith AV, Qu L, Bacq D, Denning N, Jian X, Zhao Y, Del Zompo M, Fox NC, Choi SH, Mateo I, Hughes JT, Adams HH, Malamon J, Sanchez-Garcia F, Patel Y, Brody JA, Dombroski BA, Naranjo MCD, Daniilidou M, Eiriksdottir G, Mukherjee S, Wallon D, Uphill J, Aspelund T, Cantwell LB, Garzia F, Galimberti D, Hofer E, Butkiewicz M, Fin B, Scarpini E, Sarnowski C, Bush WS, Meslage S, Kornhuber J, White CC, Song Y, Barber RC, Engelborghs S, Sordon S, Voijnovic D, Adams PM, Vandenberghe R, Mayhaus M, Cupples LA, Albert MS, De Deyn PP, Gu W, Himali JJ, Beekly D, Squassina A, Hartmann AM, Orellana A, Blacker D, Rodriguez-Rodriguez E, Lovestone S, Garcia ME, Doody RS, Munoz-Fernadez C, Sussams R, Lin H, Fairchild TJ, Benito YA, Holmes C, Karamujić-Čomić H, Frosch MP, Thonberg H, Maier W, Roshchupkin G, Ghetti B, Giedraitis V, Kawalia A, Li S, Huebinger RM, Kilander L, Moebus S, Hernández I, Kamboh MI, Brundin R, Turton J, Yang Q, Katz MJ, Concari L, Lord J, Beiser AS, Keene CD, Helisalmi S, Kloszewska I, Kukull WA, Koivisto AM, Lynch A, Tarraga L, Larson EB, Haapasalo A, Lawlor B, Mosley TH, Lipton RB, Solfrizzi V, Gill M, Longstreth WT Jr, Montine TJ, Frisardi V, Diez-Fairen M, Rivadeneira F, Petersen RC, Deramecourt V, Alvarez I, Salani F, Ciaramella A, Boerwinkle E, Reiman EM, Fievet N, Rotter JI, Reisch JS, Hanon O, Cupidi C, Andre Uitterlinden AG, Royall DR, Dufouil C, Maletta RG, de Rojas I, Sano M, Brice A, Cecchetti R, George-Hyslop PS, Ritchie K, Tsolaki M, Tsuang DW, Dubois B, Craig D, Wu CK, Soininen H, Avramidou D, Albin RL, Fratiglioni L, Germanou A, Apostolova LG, Keller L, Koutroumani M, Arnold SE, Panza F, Gkatzima O, Asthana S, Hannequin D, Whitehead P, Atwood CS, Caffarra P, Hampel H, Quintela I, Carracedo Á, Lannfelt L, Rubinsztein DC, Barnes LL, Pasquier F, Frölich L, Barral S, McGuinness B, Beach TG, Johnston JA, Becker JT, Passmore P, Bigio EH, Schott JM, Bird TD, Warren JD, Boeve BF, Lupton MK, Bowen JD, Proitsi P, Boxer A, Powell JF, Burke JR, Kauwe JSK, Burns JM, Mancuso M, Buxbaum JD, Bonuccelli U, Cairns NJ, McQuillin A, Cao C, Livingston G, Carlson CS, Bass NJ, Carlsson CM, Hardy J, Carney RM, Bras J, Carrasquillo MM, Guerreiro R, Allen M, Chui HC, Fisher E, Masullo C, Crocco EA, DeCarli C, Bisceglio G, Dick M, Ma L, Duara R, Graff-Radford NR, Evans DA, Hodges A, Faber KM, Scherer M, Fallon KB, Riemenschneider M, Fardo DW, Heun R, Farlow MR, Kölsch H, Ferris S, Leber M, Foroud TM, Heuser I, Galasko DR, Giegling I, Gearing M, Hüll M, Geschwind DH, Gilbert JR, Morris J, Green RC, Mayo K, Growdon JH, Feulner T, Hamilton RL, Harrell LE, Drichel D, Honig LS, Cushion TD, Huentelman MJ, Hollingworth P, Hulette CM, Hyman BT, Marshall R, Jarvik GP, Meggy A, Abner E, Menzies GE, Jin LW, Leonenko G, Real LM, Jun GR, Baldwin CT, Grozeva D, Karydas A, Russo G, Kaye JA, Kim R, Jessen F, Kowall NW, Vellas B, Kramer JH, Vardy E, LaFerla FM, Jöckel KH, Lah JJ, Dichgans M, Leverenz JB, Mann D, Levey AI, Pickering-Brown S, Lieberman AP, Klopp N, Lunetta KL, Wichmann HE, Lyketsos CG, Morgan K, Marson DC, Brown K, Martiniuk F, Medway C, Mash DC, Nöthen MM, Masliah E, Hooper NM, McCormick WC, Daniele A, McCurry SM, Bayer A, McDavid AN, Gallacher J, McKee AC, van den Bussche H, Mesulam M, Brayne C, Miller BL, Riedel-Heller S, Miller CA, Miller JW, Al-Chalabi A, Morris JC, Shaw CE, Myers AJ, Wiltfang J, O'Bryant S, Olichney JM, Alvarez V, Parisi JE, Singleton AB, Paulson HL, Collinge J, Perry WR, Mead S, Peskind E, Cribbs DH, Rossor M, Pierce A, Ryan NS, Poon WW, Nacmias B, Potter H, Sorbi S, Quinn JF, Sacchinelli E, Raj A, Spalletta G, Raskind M, Caltagirone C, Bossù P, Orfei MD, Reisberg B, Clarke R, Reitz C, Smith AD, Ringman JM, Warden D, Roberson ED, Wilcock G, Rogaeva E, Bruni AC, Rosen HJ, Gallo M, Rosenberg RN, Ben-Shlomo Y, Sager MA, Mecocci P, Saykin AJ, Pastor P, Cuccaro ML, Vance JM, Schneider JA, Schneider LS, Slifer S, Seeley WW, Smith AG, Sonnen JA, Spina S, Stern RA, Swerdlow RH, Tang M, Tanzi RE, Trojanowski JQ, Troncoso JC, Van Deerlin VM, Van Eldik LJ, Vinters HV, Vonsattel JP, Weintraub S, Welsh-Bohmer KA, Wilhelmsen KC, Williamson J, Wingo TS, Woltjer RL, Wright CB, Yu CE, Yu L, Saba Y, Pilotto A, Bullido MJ, Peters O, Crane PK, Bennett D, Bosco P, Coto E, Boccardi V, De Jager PL, Lleo A, Warner N, Lopez OL, Ingelsson M, Deloukas P, Cruchaga C, Graff C, Gwilliam R, Fornage M, Goate AM, Sanchez-Juan P, Kehoe PG, Amin N, Ertekin-Taner N, Berr C, Debette S, Love S, Launer LJ, Younkin SG, Dartigues JF, Corcoran C, Ikram MA, Dickson DW, Nicolas G, Campion D, Tschanz J, Schmidt H, Hakonarson H, Clarimon J, Munger R, Schmidt R, Farrer LA, Van Broeckhoven C, C O'Donovan M, DeStefano AL, Jones L, Haines JL, Deleuze JF, Owen MJ, Gudnason V, Mayeux R, Escott-Price V, Psaty BM, Ramirez A, Wang LS, Ruiz A, van Duijn CM, Holmans PA, Seshadri S, Williams J, Amouyel P, Schellenberg GD, Lambert JC, and Pericak-Vance MA

Subjects
Aged, Case-Control Studies, Female, Genetic Testing methods, Genome-Wide Association Study methods, Haplotypes genetics, Humans, Lipid Metabolism genetics, Male, Alzheimer Disease genetics, Amyloid beta-Peptides genetics, Genetic Loci genetics, Genetic Predisposition to Disease genetics, Immunity genetics, Lipids genetics, tau Proteins genetics
Abstract

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10 -7 ), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.

Published
2019
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180. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease.

Author

Sims R, van der Lee SJ, Naj AC, Bellenguez C, Badarinarayan N, Jakobsdottir J, Kunkle BW, Boland A, Raybould R, Bis JC, Martin ER, Grenier-Boley B, Heilmann-Heimbach S, Chouraki V, Kuzma AB, Sleegers K, Vronskaya M, Ruiz A, Graham RR, Olaso R, Hoffmann P, Grove ML, Vardarajan BN, Hiltunen M, Nöthen MM, White CC, Hamilton-Nelson KL, Epelbaum J, Maier W, Choi SH, Beecham GW, Dulary C, Herms S, Smith AV, Funk CC, Derbois C, Forstner AJ, Ahmad S, Li H, Bacq D, Harold D, Satizabal CL, Valladares O, Squassina A, Thomas R, Brody JA, Qu L, Sánchez-Juan P, Morgan T, Wolters FJ, Zhao Y, Garcia FS, Denning N, Fornage M, Malamon J, Naranjo MCD, Majounie E, Mosley TH, Dombroski B, Wallon D, Lupton MK, Dupuis J, Whitehead P, Fratiglioni L, Medway C, Jian X, Mukherjee S, Keller L, Brown K, Lin H, Cantwell LB, Panza F, McGuinness B, Moreno-Grau S, Burgess JD, Solfrizzi V, Proitsi P, Adams HH, Allen M, Seripa D, Pastor P, Cupples LA, Price ND, Hannequin D, Frank-García A, Levy D, Chakrabarty P, Caffarra P, Giegling I, Beiser AS, Giedraitis V, Hampel H, Garcia ME, Wang X, Lannfelt L, Mecocci P, Eiriksdottir G, Crane PK, Pasquier F, Boccardi V, Henández I, Barber RC, Scherer M, Tarraga L, Adams PM, Leber M, Chen Y, Albert MS, Riedel-Heller S, Emilsson V, Beekly D, Braae A, Schmidt R, Blacker D, Masullo C, Schmidt H, Doody RS, Spalletta G, Longstreth WT Jr, Fairchild TJ, Bossù P, Lopez OL, Frosch MP, Sacchinelli E, Ghetti B, Yang Q, Huebinger RM, Jessen F, Li S, Kamboh MI, Morris J, Sotolongo-Grau O, Katz MJ, Corcoran C, Dunstan M, Braddel A, Thomas C, Meggy A, Marshall R, Gerrish A, Chapman J, Aguilar M, Taylor S, Hill M, Fairén MD, Hodges A, Vellas B, Soininen H, Kloszewska I, Daniilidou M, Uphill J, Patel Y, Hughes JT, Lord J, Turton J, Hartmann AM, Cecchetti R, Fenoglio C, Serpente M, Arcaro M, Caltagirone C, Orfei MD, Ciaramella A, Pichler S, Mayhaus M, Gu W, Lleó A, Fortea J, Blesa R, Barber IS, Brookes K, Cupidi C, Maletta RG, Carrell D, Sorbi S, Moebus S, Urbano M, Pilotto A, Kornhuber J, Bosco P, Todd S, Craig D, Johnston J, Gill M, Lawlor B, Lynch A, Fox NC, Hardy J, Albin RL, Apostolova LG, Arnold SE, Asthana S, Atwood CS, Baldwin CT, Barnes LL, Barral S, Beach TG, Becker JT, Bigio EH, Bird TD, Boeve BF, Bowen JD, Boxer A, Burke JR, Burns JM, Buxbaum JD, Cairns NJ, Cao C, Carlson CS, Carlsson CM, Carney RM, Carrasquillo MM, Carroll SL, Diaz CC, Chui HC, Clark DG, Cribbs DH, Crocco EA, DeCarli C, Dick M, Duara R, Evans DA, Faber KM, Fallon KB, Fardo DW, Farlow MR, Ferris S, Foroud TM, Galasko DR, Gearing M, Geschwind DH, Gilbert JR, Graff-Radford NR, Green RC, Growdon JH, Hamilton RL, Harrell LE, Honig LS, Huentelman MJ, Hulette CM, Hyman BT, Jarvik GP, Abner E, Jin LW, Jun G, Karydas A, Kaye JA, Kim R, Kowall NW, Kramer JH, LaFerla FM, Lah JJ, Leverenz JB, Levey AI, Li G, Lieberman AP, Lunetta KL, Lyketsos CG, Marson DC, Martiniuk F, Mash DC, Masliah E, McCormick WC, McCurry SM, McDavid AN, McKee AC, Mesulam M, Miller BL, Miller CA, Miller JW, Morris JC, Murrell JR, Myers AJ, O'Bryant S, Olichney JM, Pankratz VS, Parisi JE, Paulson HL, Perry W, Peskind E, Pierce A, Poon WW, Potter H, Quinn JF, Raj A, Raskind M, Reisberg B, Reitz C, Ringman JM, Roberson ED, Rogaeva E, Rosen HJ, Rosenberg RN, Sager MA, Saykin AJ, Schneider JA, Schneider LS, Seeley WW, Smith AG, Sonnen JA, Spina S, Stern RA, Swerdlow RH, Tanzi RE, Thornton-Wells TA, Trojanowski JQ, Troncoso JC, Van Deerlin VM, Van Eldik LJ, Vinters HV, Vonsattel JP, Weintraub S, Welsh-Bohmer KA, Wilhelmsen KC, Williamson J, Wingo TS, Woltjer RL, Wright CB, Yu CE, Yu L, Garzia F, Golamaully F, Septier G, Engelborghs S, Vandenberghe R, De Deyn PP, Fernadez CM, Benito YA, Thonberg H, Forsell C, Lilius L, Kinhult-Stählbom A, Kilander L, Brundin R, Concari L, Helisalmi S, Koivisto AM, Haapasalo A, Dermecourt V, Fievet N, Hanon O, Dufouil C, Brice A, Ritchie K, Dubois B, Himali JJ, Keene CD, Tschanz J, Fitzpatrick AL, Kukull WA, Norton M, Aspelund T, Larson EB, Munger R, Rotter JI, Lipton RB, Bullido MJ, Hofman A, Montine TJ, Coto E, Boerwinkle E, Petersen RC, Alvarez V, Rivadeneira F, Reiman EM, Gallo M, O'Donnell CJ, Reisch JS, Bruni AC, Royall DR, Dichgans M, Sano M, Galimberti D, St George-Hyslop P, Scarpini E, Tsuang DW, Mancuso M, Bonuccelli U, Winslow AR, Daniele A, Wu CK, Peters O, Nacmias B, Riemenschneider M, Heun R, Brayne C, Rubinsztein DC, Bras J, Guerreiro R, Al-Chalabi A, Shaw CE, Collinge J, Mann D, Tsolaki M, Clarimón J, Sussams R, Lovestone S, O'Donovan MC, Owen MJ, Behrens TW, Mead S, Goate AM, Uitterlinden AG, Holmes C, Cruchaga C, Ingelsson M, Bennett DA, Powell J, Golde TE, Graff C, De Jager PL, Morgan K, Ertekin-Taner N, Combarros O, Psaty BM, Passmore P, Younkin SG, Berr C, Gudnason V, Rujescu D, Dickson DW, Dartigues JF, DeStefano AL, Ortega-Cubero S, Hakonarson H, Campion D, Boada M, Kauwe JK, Farrer LA, Van Broeckhoven C, Ikram MA, Jones L, Haines JL, Tzourio C, Launer LJ, Escott-Price V, Mayeux R, Deleuze JF, Amin N, Holmans PA, Pericak-Vance MA, Amouyel P, van Duijn CM, Ramirez A, Wang LS, Lambert JC, Seshadri S, Williams J, and Schellenberg GD

Subjects
Amino Acid Sequence, Case-Control Studies, Exome genetics, Gene Expression Profiling, Gene Frequency, Genetic Predisposition to Disease genetics, Genotype, Humans, Linkage Disequilibrium, Odds Ratio, Protein Interaction Maps genetics, Sequence Homology, Amino Acid, Adaptor Proteins, Signal Transducing genetics, Alzheimer Disease genetics, Immunity, Innate genetics, Membrane Glycoproteins genetics, Microglia metabolism, Phospholipase C gamma genetics, Polymorphism, Single Nucleotide, Receptors, Immunologic genetics
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, MAF controls = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10 -10 , OR = 1.43, MAF cases = 0.011, MAF controls = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10 -14 , OR = 1.67, MAF cases = 0.0143, MAF controls = 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.

Published
2017
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181. Meta-analysis of 49 549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels.

Author

van Leeuwen EM, Sabo A, Bis JC, Huffman JE, Manichaikul A, Smith AV, Feitosa MF, Demissie S, Joshi PK, Duan Q, Marten J, van Klinken JB, Surakka I, Nolte IM, Zhang W, Mbarek H, Li-Gao R, Trompet S, Verweij N, Evangelou E, Lyytikäinen LP, Tayo BO, Deelen J, van der Most PJ, van der Laan SW, Arking DE, Morrison A, Dehghan A, Franco OH, Hofman A, Rivadeneira F, Sijbrands EJ, Uitterlinden AG, Mychaleckyj JC, Campbell A, Hocking LJ, Padmanabhan S, Brody JA, Rice KM, White CC, Harris T, Isaacs A, Campbell H, Lange LA, Rudan I, Kolcic I, Navarro P, Zemunik T, Salomaa V, Kooner AS, Kooner JS, Lehne B, Scott WR, Tan ST, de Geus EJ, Milaneschi Y, Penninx BW, Willemsen G, de Mutsert R, Ford I, Gansevoort RT, Segura-Lepe MP, Raitakari OT, Viikari JS, Nikus K, Forrester T, McKenzie CA, de Craen AJ, de Ruijter HM, Pasterkamp G, Snieder H, Oldehinkel AJ, Slagboom PE, Cooper RS, Kähönen M, Lehtimäki T, Elliott P, van der Harst P, Jukema JW, Mook-Kanamori DO, Boomsma DI, Chambers JC, Swertz M, Ripatti S, Willems van Dijk K, Vitart V, Polasek O, Hayward C, Wilson JG, Wilson JF, Gudnason V, Rich SS, Psaty BM, Borecki IB, Boerwinkle E, Rotter JI, Cupples LA, and van Duijn CM

Subjects
Angiopoietin-Like Protein 4, Fasting physiology, Female, Genome-Wide Association Study methods, Genotype, Humans, Male, Middle Aged, Angiopoietins genetics, Exons genetics, Genome, Human genetics, Polymorphism, Single Nucleotide genetics
Abstract

Background: So far, more than 170 loci have been associated with circulating lipid levels through genome-wide association studies (GWAS). These associations are largely driven by common variants, their function is often not known, and many are likely to be markers for the causal variants. In this study we aimed to identify more new rare and low-frequency functional variants associated with circulating lipid levels., Methods: We used the 1000 Genomes Project as a reference panel for the imputations of GWAS data from ∼60 000 individuals in the discovery stage and ∼90 000 samples in the replication stage., Results: Our study resulted in the identification of five new associations with circulating lipid levels at four loci. All four loci are within genes that can be linked biologically to lipid metabolism. One of the variants, rs116843064, is a damaging missense variant within the ANGPTL4 gene., Conclusions: This study illustrates that GWAS with high-scale imputation may still help us unravel the biological mechanism behind circulating lipid levels., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Published
2016
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182. Correction: The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study.

Author

Winkler TW, Justice AE, Graff M, Barata L, Feitosa MF, Chu S, Czajkowski J, Esko T, Fall T, Kilpeläinen TO, Lu Y, Mägi R, Mihailov E, Pers TH, Rüeger S, Teumer A, Ehret GB, Ferreira T, Heard-Costa NL, Karjalainen J, Lagou V, Mahajan A, Neinast MD, Prokopenko I, Simino J, Teslovich TM, Jansen R, Westra HJ, White CC, Absher D, Ahluwalia TS, Ahmad S, Albrecht E, Alves AC, Bragg-Gresham JL, de Craen AJ, Bis JC, Bonnefond A, Boucher G, Cadby G, Cheng YC, Chiang CW, Delgado G, Demirkan A, Dueker N, Eklund N, Eiriksdottir G, Eriksson J, Feenstra B, Fischer K, Frau F, Galesloot TE, Geller F, Goel A, Gorski M, Grammer TB, Gustafsson S, Haitjema S, Hottenga JJ, Huffman JE, Jackson AU, Jacobs KB, Johansson Å, Kaakinen M, Kleber ME, Lahti J, Mateo Leach I, Lehne B, Liu Y, Lo KS, Lorentzon M, Luan J, Madden PA, Mangino M, McKnight B, Medina-Gomez C, Monda KL, Montasser ME, Müller G, Müller-Nurasyid M, Nolte IM, Panoutsopoulou K, Pascoe L, Paternoster L, Rayner NW, Renström F, Rizzi F, Rose LM, Ryan KA, Salo P, Sanna S, Scharnagl H, Shi J, Smith AV, Southam L, Stančáková A, Steinthorsdottir V, Strawbridge RJ, Sung YJ, Tachmazidou I, Tanaka T, Thorleifsson G, Trompet S, Pervjakova N, Tyrer JP, Vandenput L, van der Laan SW, van der Velde N, van Setten J, van Vliet-Ostaptchouk JV, Verweij N, Vlachopoulou E, Waite LL, Wang SR, Wang Z, Wild SH, Willenborg C, Wilson JF, Wong A, Yang J, Yengo L, Yerges-Armstrong LM, Yu L, Zhang W, Zhao JH, Andersson EA, Bakker SJ, Baldassarre D, Banasik K, Barcella M, Barlassina C, Bellis C, Benaglio P, Blangero J, Blüher M, Bonnet F, Bonnycastle LL, Boyd HA, Bruinenberg M, Buchman AS, Campbell H, Chen YI, Chines PS, Claudi-Boehm S, Cole J, Collins FS, de Geus EJ, de Groot LC, Dimitriou M, Duan J, Enroth S, Eury E, Farmaki AE, Forouhi NG, Friedrich N, Gejman PV, Gigante B, Glorioso N, Go AS, Gottesman O, Gräßler J, Grallert H, Grarup N, Gu YM, Broer L, Ham AC, Hansen T, Harris TB, Hartman CA, Hassinen M, Hastie N, Hattersley AT, Heath AC, Henders AK, Hernandez D, Hillege H, Holmen O, Hovingh KG, Hui J, Husemoen LL, Hutri-Kähönen N, Hysi PG, Illig T, De Jager PL, Jalilzadeh S, Jørgensen T, Jukema JW, Juonala M, Kanoni S, Karaleftheri M, Khaw KT, Kinnunen L, Kittner SJ, Koenig W, Kolcic I, Kovacs P, Krarup NT, Kratzer W, Krüger J, Kuh D, Kumari M, Kyriakou T, Langenberg C, Lannfelt L, Lanzani C, Lotay V, Launer LJ, Leander K, Lindström J, Linneberg A, Liu YP, Lobbens S, Luben R, Lyssenko V, Männistö S, Magnusson PK, McArdle WL, Menni C, Merger S, Milani L, Montgomery GW, Morris AP, Narisu N, Nelis M, Ong KK, Palotie A, Pérusse L, Pichler I, Pilia MG, Pouta A, Rheinberger M, Ribel-Madsen R, Richards M, Rice KM, Rice TK, Rivolta C, Salomaa V, Sanders AR, Sarzynski MA, Scholtens S, Scott RA, Scott WR, Sebert S, Sengupta S, Sennblad B, Seufferlein T, Silveira A, Slagboom PE, Smit JH, Sparsø TH, Stirrups K, Stolk RP, Stringham HM, Swertz MA, Swift AJ, Syvänen AC, Tan ST, Thorand B, Tönjes A, Tremblay A, Tsafantakis E, van der Most PJ, Völker U, Vohl MC, Vonk JM, Waldenberger M, Walker RW, Wennauer R, Widén E, Willemsen G, Wilsgaard T, Wright AF, Zillikens MC, van Dijk SC, van Schoor NM, Asselbergs FW, de Bakker PI, Beckmann JS, Beilby J, Bennett DA, Bergman RN, Bergmann S, Böger CA, Boehm BO, Boerwinkle E, Boomsma DI, Bornstein SR, Bottinger EP, Bouchard C, Chambers JC, Chanock SJ, Chasman DI, Cucca F, Cusi D, Dedoussis G, Erdmann J, Eriksson JG, Evans DA, de Faire U, Farrall M, Ferrucci L, Ford I, Franke L, Franks PW, Froguel P, Gansevoort RT, Gieger C, Grönberg H, Gudnason V, Gyllensten U, Hall P, Hamsten A, van der Harst P, Hayward C, Heliövaara M, Hengstenberg C, Hicks AA, Hingorani A, Hofman A, Hu F, Huikuri HV, Hveem K, James AL, Jordan JM, Jula A, Kähönen M, Kajantie E, Kathiresan S, Kiemeney LA, Kivimaki M, Knekt PB, Koistinen HA, Kooner JS, Koskinen S, Kuusisto J, Maerz W, Martin NG, Laakso M, Lakka TA, Lehtimäki T, Lettre G, Levinson DF, Lind L, Lokki ML, Mäntyselkä P, Melbye M, Metspalu A, Mitchell BD, Moll FL, Murray JC, Musk AW, Nieminen MS, Njølstad I, Ohlsson C, Oldehinkel AJ, Oostra BA, Palmer LJ, Pankow JS, Pasterkamp G, Pedersen NL, Pedersen O, Penninx BW, Perola M, Peters A, Polašek O, Pramstaller PP, Psaty BM, Qi L, Quertermous T, Raitakari OT, Rankinen T, Rauramaa R, Ridker PM, Rioux JD, Rivadeneira F, Rotter JI, Rudan I, den Ruijter HM, Saltevo J, Sattar N, Schunkert H, Schwarz PE, Shuldiner AR, Sinisalo J, Snieder H, Sørensen TI, Spector TD, Staessen JA, Stefania B, Thorsteinsdottir U, Stumvoll M, Tardif JC, Tremoli E, Tuomilehto J, Uitterlinden AG, Uusitupa M, Verbeek AL, Vermeulen SH, Viikari JS, Vitart V, Völzke H, Vollenweider P, Waeber G, Walker M, Wallaschofski H, Wareham NJ, Watkins H, Zeggini E, Chakravarti A, Clegg DJ, Cupples LA, Gordon-Larsen P, Jaquish CE, Rao DC, Abecasis GR, Assimes TL, Barroso I, Berndt SI, Boehnke M, Deloukas P, Fox CS, Groop LC, Hunter DJ, Ingelsson E, Kaplan RC, McCarthy MI, Mohlke KL, O'Connell JR, Schlessinger D, Strachan DP, Stefansson K, van Duijn CM, Hirschhorn JN, Lindgren CM, Heid IM, North KE, Borecki IB, Kutalik Z, and Loos RJ

Abstract

[This corrects the article DOI: 10.1371/journal.pgen.1005378.].

Published
2016
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183. Fine mapping the CETP region reveals a common intronic insertion associated to HDL-C.

Author

van Leeuwen EM, Huffman JE, Bis JC, Isaacs A, Mulder M, Sabo A, Smith AV, Demissie S, Manichaikul A, Brody JA, Feitosa MF, Duan Q, Schraut KE, Navarro P, van Vliet-Ostaptchouk JV, Zhu G, Mbarek H, Trompet S, Verweij N, Lyytikäinen LP, Deelen J, Nolte IM, van der Laan SW, Davies G, Vermeij-Verdoold AJ, van Oosterhout AA, Vergeer-Drop JM, Arking DE, Trochet H, Medina-Gomez C, Rivadeneira F, Uitterlinden AG, Dehghan A, Franco OH, Sijbrands EJ, Hofman A, White CC, Mychaleckyj JC, Peloso GM, Swertz MA, Willemsen G, de Geus EJ, Milaneschi Y, Penninx BW, Ford I, Buckley BM, de Craen AJ, Starr JM, Deary IJ, Pasterkamp G, Oldehinkel AJ, Snieder H, Slagboom PE, Nikus K, Kähönen M, Lehtimäki T, Viikari JS, Raitakari OT, van der Harst P, Jukema JW, Hottenga JJ, Boomsma DI, Whitfield JB, Montgomery G, Martin NG, Polasek O, Vitart V, Hayward C, Kolcic I, Wright AF, Rudan I, Joshi PK, Wilson JF, Lange LA, Wilson JG, Gudnason V, Harris TB, Morrison AC, Borecki IB, Rich SS, Padmanabhan S, Psaty BM, Rotter JI, Smith BH, Boerwinkle E, Cupples LA, and van Duijn C

Abstract

Background: Individuals with exceptional longevity and their offspring have significantly larger high-density lipoprotein concentrations (HDL-C) particle sizes due to the increased homozygosity for the I405V variant in the cholesteryl ester transfer protein ( CETP) gene. In this study, we investigate the association of CETP and HDL-C further to identify novel, independent CETP variants associated with HDL-C in humans., Methods: We performed a meta-analysis of HDL-C within the CETP region using 59,432 individuals imputed with 1000 Genomes data. We performed replication in an independent sample of 47,866 individuals and validation was done by Sanger sequencing., Results: The meta-analysis of HDL-C within the CETP region identified five independent variants, including an exonic variant and a common intronic insertion. We replicated these 5 variants significantly in an independent sample of 47,866 individuals. Sanger sequencing of the insertion within a single family confirmed segregation of this variant. The strongest reported association between HDL-C and CETP variants, was rs3764261; however, after conditioning on the five novel variants we identified the support for rs3764261 was highly reduced ( β unadjusted =3.179 mg/dl ( P value=5.25×10 -509 ), β adjusted =0.859 mg/dl ( P with HDL-C. Indeed, three of the five novel variants (rs34065661, rs5817082, rs7499892) are independent of rs3764261.-25 )), and this finding suggests that these five novel variants may partly explain the association of CETP with HDL-C. Indeed, three of the five novel variants (rs34065661, rs5817082, rs7499892) are independent of rs3764261., Conclusions: The causal variants in CETP that account for the association with HDL-C remain unknown. We used studies imputed to the 1000 Genomes reference panel for fine mapping of the CETP region. We identified and validated five variants within this region that may partly account for the association of the known variant (rs3764261), as well as other sources of genetic contribution to HDL-C., Competing Interests: PSM serves on the DSMB of a clinical trial of a device funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. SWvL is a former employee of Cavadis B.V. GP is a founder and stockholder of Cavadis B.V.

Published
2015
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184. Genome-wide association study for coronary artery calcification with follow-up in myocardial infarction.

Author

O'Donnell CJ, Kavousi M, Smith AV, Kardia SL, Feitosa MF, Hwang SJ, Sun YV, Province MA, Aspelund T, Dehghan A, Hoffmann U, Bielak LF, Zhang Q, Eiriksdottir G, van Duijn CM, Fox CS, de Andrade M, Kraja AT, Sigurdsson S, Elias-Smale SE, Murabito JM, Launer LJ, van der Lugt A, Kathiresan S, Krestin GP, Herrington DM, Howard TD, Liu Y, Post W, Mitchell BD, O'Connell JR, Shen H, Shuldiner AR, Altshuler D, Elosua R, Salomaa V, Schwartz SM, Siscovick DS, Voight BF, Bis JC, Glazer NL, Psaty BM, Boerwinkle E, Heiss G, Blankenberg S, Zeller T, Wild PS, Schnabel RB, Schillert A, Ziegler A, Münzel TF, White CC, Rotter JI, Nalls M, Oudkerk M, Johnson AD, Newman AB, Uitterlinden AG, Massaro JM, Cunningham J, Harris TB, Hofman A, Peyser PA, Borecki IB, Cupples LA, Gudnason V, and Witteman JC

Subjects
Adult, Aged, Aged, 80 and over, Calcinosis diagnostic imaging, Calcinosis epidemiology, Coronary Artery Disease diagnostic imaging, Coronary Artery Disease epidemiology, Female, Follow-Up Studies, Humans, Male, Middle Aged, Myocardial Infarction diagnostic imaging, Myocardial Infarction epidemiology, Polymorphism, Single Nucleotide genetics, Radiography, Risk Factors, Calcinosis genetics, Coronary Artery Disease genetics, Genome-Wide Association Study, Myocardial Infarction genetics
Abstract

Background: Coronary artery calcification (CAC) detected by computed tomography is a noninvasive measure of coronary atherosclerosis, which underlies most cases of myocardial infarction (MI). We sought to identify common genetic variants associated with CAC and further investigate their associations with MI., Methods and Results: Computed tomography was used to assess quantity of CAC. A meta-analysis of genome-wide association studies for CAC was performed in 9961 men and women from 5 independent community-based cohorts, with replication in 3 additional independent cohorts (n=6032). We examined the top single-nucleotide polymorphisms (SNPs) associated with CAC quantity for association with MI in multiple large genome-wide association studies of MI. Genome-wide significant associations with CAC for SNPs on chromosome 9p21 near CDKN2A and CDKN2B (top SNP: rs1333049; P=7.58×10(-19)) and 6p24 (top SNP: rs9349379, within the PHACTR1 gene; P=2.65×10(-11)) replicated for CAC and for MI. Additionally, there is evidence for concordance of SNP associations with both CAC and MI at a number of other loci, including 3q22 (MRAS gene), 13q34 (COL4A1/COL4A2 genes), and 1p13 (SORT1 gene)., Conclusions: SNPs in the 9p21 and PHACTR1 gene loci were strongly associated with CAC and MI, and there are suggestive associations with both CAC and MI of SNPs in additional loci. Multiple genetic loci are associated with development of both underlying coronary atherosclerosis and clinical events.

Published
2011
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185. Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque.

Author

Bis JC, Kavousi M, Franceschini N, Isaacs A, Abecasis GR, Schminke U, Post WS, Smith AV, Cupples LA, Markus HS, Schmidt R, Huffman JE, Lehtimäki T, Baumert J, Münzel T, Heckbert SR, Dehghan A, North K, Oostra B, Bevan S, Stoegerer EM, Hayward C, Raitakari O, Meisinger C, Schillert A, Sanna S, Völzke H, Cheng YC, Thorsson B, Fox CS, Rice K, Rivadeneira F, Nambi V, Halperin E, Petrovic KE, Peltonen L, Wichmann HE, Schnabel RB, Dörr M, Parsa A, Aspelund T, Demissie S, Kathiresan S, Reilly MP, Taylor K, Uitterlinden A, Couper DJ, Sitzer M, Kähönen M, Illig T, Wild PS, Orru M, Lüdemann J, Shuldiner AR, Eiriksdottir G, White CC, Rotter JI, Hofman A, Seissler J, Zeller T, Usala G, Ernst F, Launer LJ, D'Agostino RB Sr, O'Leary DH, Ballantyne C, Thiery J, Ziegler A, Lakatta EG, Chilukoti RK, Harris TB, Wolf PA, Psaty BM, Polak JF, Li X, Rathmann W, Uda M, Boerwinkle E, Klopp N, Schmidt H, Wilson JF, Viikari J, Koenig W, Blankenberg S, Newman AB, Witteman J, Heiss G, Duijn Cv, Scuteri A, Homuth G, Mitchell BD, Gudnason V, and O'Donnell CJ

Subjects
Adult, Aged, Aging genetics, Atherosclerosis physiopathology, Cohort Studies, Genetic Loci, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Genotype, Heart physiopathology, Humans, Middle Aged, Phenotype, Plaque, Atherosclerotic pathology, Polymorphism, Single Nucleotide, Risk Factors, White People genetics, Atherosclerosis genetics, Carotid Intima-Media Thickness, Coronary Artery Disease genetics, Plaque, Atherosclerotic genetics
Abstract

Carotid intima media thickness (cIMT) and plaque determined by ultrasonography are established measures of subclinical atherosclerosis that each predicts future cardiovascular disease events. We conducted a meta-analysis of genome-wide association data in 31,211 participants of European ancestry from nine large studies in the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. We then sought additional evidence to support our findings among 11,273 individuals using data from seven additional studies. In the combined meta-analysis, we identified three genomic regions associated with common carotid intima media thickness and two different regions associated with the presence of carotid plaque (P < 5 × 10(-8)). The associated SNPs mapped in or near genes related to cellular signaling, lipid metabolism and blood pressure homeostasis, and two of the regions were associated with coronary artery disease (P < 0.006) in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) consortium. Our findings may provide new insight into pathways leading to subclinical atherosclerosis and subsequent cardiovascular events.

Published
2011
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