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 x 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 x 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 x 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 x 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 x 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.

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease / S. Rebecca, V.D.L. Sven J, N. Adam C, B. Céline, B. Nandini, J. Johanna, K. Brian W., B. Anne, R. Rachel, B. Joshua C., M. Eden R., G. Benjamin, H. Stefanie, C. Vincent, K. Amanda B., S. Kristel, V. Maria, R. Agustin, G. Robert R, O. Robert, H. Per, G. Megan L., V. Badri N., H. Mikko, N. Markus M., W. Charles C., H. Kara L., E. Jacques, M. Wolfgang, C. Seung-Hoan, B. Gary W., D. Cécile, H. Stefan, S. Albert V., F. Cory C., D. Céline, F. Andreas J., A. Shahzad, L. Hongdong, B. Delphine, H. Denise, S. Claudia L., V. Otto, S. Alessio, T. Rhodri, B. Jennifer A, Q. Liming, S. Pascual, M. Taniesha, W. Frank J, Z. Yi, G. Florentino Sanchez, D. Nicola, F. Myriam, M. John, N. Maria Candida Deniz, M. Elisa, M. Thomas H., D. Beth, W. David, L. Michelle K., D. Josée, W. Patrice, F. Laura, M. Christopher, J. Xueqiu, M. Shubhabrata, K. Lina, B. Kristelle, L. Honghuang, C. Laura B., P. Francesco, M. Bernadette, M. Sonia, B. Jeremy D., S. Vincenzo, P. Petra, A. Hieab H, A. Mariet, S. Davide, P. Pau, C. L. Adrienne, P. Nathan D., H. Didier, F. Ana, L. Daniel, C. Paramita, C. Paolo, G. Ina, B. Alexa S., G. Vilmantas, H. Harald, G. Melissa E., W. Xue, L. Lars, M. Patrizia, E. Gudny, C. Paul K., P. Florence, B. Virginia, H. Isabel, B. Robert C., S. Martin, T. Lluis, A. Perrie M., L. Markus, C. Yuning, A. Marilyn S., R. Steffi, E. Valur, B. Duane, B. Anne, S. Reinhold, B. Deborah, M. Carlo, S. Helena, D. Rachelle S., S. Gianfranco, J. W. T. Longstreth, F. Thomas J., B. Paola, L. Oscar L., F. Matthew P., S. Eleonora, G. Bernardino, Y. Qiong, H. Ryan M., J. Frank, L. Shuo, K. M. Ilyas, M. John, S. Oscar, K. Mindy J., C. Chris, D. Melanie, B. Amy, T. Charlene, M. Alun, M. Rachel, G. Amy, C. Jade, A. Miquel, T. Sarah, H. Matt, F. Mònica Díez, H. Angela, V. Bruno, S. Hilkka, K. Iwona, D. Makrina, U. James, P. Yogen, H. Joseph T., L. Jenny, T. James, H. Annette M., C. Roberta, C. Fenoglio, M. Serpente, M. Arcaro, C. Carlo, O. Maria Donata, C. Antonio, P. Sabrina, M. Manuel, G. Wei, L. Alberto, F. Juan, B. Rafael, B. Imelda S., B. Keeley, C. Chiara, M. Raffaele Giovanni, C. David, S. Sandro, M. Susanne, U. Maria, P. Alberto, K. Johannes, B. Paolo, T. Stephen, C. David, J. Janet, G. Michael, L. Brian, L. Aoibhinn, F. Nick C., H. John, A. Roger L., A. Liana G., A. Steven E., A. Sanjay, A. Craig S., B. Clinton T., B. Lisa L., B. Sandra, B. Thomas G., B. James T., B. Eileen H., B. Thomas D., B. Bradley F., B. James D., B. Adam, B. James R., B. Jeffrey M., B. Joseph D., C. Nigel J., C. Chuanhai, C. Chris S., C. Cynthia M., C. Regina M., C. Minerva M., C. Steven L., D. Carolina Ceballos, C. Helena C., C. David G., C. David H., C. Elizabeth A., D. Charles, D. Malcolm, D. Ranjan, E. Denis A., F. Kelley M., F. Kenneth B., F. David W., F. Martin R., F. Steven, F. Tatiana M., G. Douglas R., G. Marla, G. Daniel H., G. John R., G. Neill R., G. Robert C., G. John H., H. Ronald L., H. Lindy E., H. Lawrence S., H. Matthew J., H. Christine M., H. Bradley T., J. Gail P., A. Erin, J. Lee-Way, J. Gyungah, K. Anna, K. Jeffrey A., K. Ronald, K. Neil W., K. Joel H., L. Frank M., L. James J., L. James B., L. Allan I., L. Ge, L. Andrew P., L. Kathryn L., L. Constantine G., M. Daniel C., M. Frank, M. Deborah C., M. Eliezer, M. Wayne C., M. Susan M., M. Andrew N., M. Ann C., M. Marsel, M. Bruce L., M. Carol A., M. Joshua W., M. John C., M. Jill R., M. Amanda J., O. Sid, O. John M., P. Vernon S., P. Joseph E., P. Henry L., P. William, P. Elaine, P. Aimee, P. Wayne W., P. Huntington, Q. Joseph F., R. Ashok, R. Murray, R. Barry, R. Christiane, R. John M., R. Erik D., R. Ekaterina, R. Howard J., R. Roger N., S. Mark A., S. Andrew J., S. Julie A., S. Lon S., S. William W., S. Amanda G., S. Joshua A., S. Salvatore, S. Robert A., S. Russell H., T. Rudolph E., T. Tricia A., T. John Q., T. Juan C., V.D. Vivianna M., V.E. Linda J., V. Harry V., V. Jean Paul, W. Sandra, W. Kathleen A., W. Kirk C., W. Jennifer, W. Thomas S., W. Randall L., W. Clinton B., Y. Chang-En, Y. Lei, G. Fabienne, G. Feroze, S. Gislain, E. Sebastien, V. Rik, D.D. Peter P., F. Carmen Muñoz, B. Yoland Aladro, T. Hakan, F. Charlotte, L. Lena, K. Anne, K. Lena, B. Rosemarie, C. Letizia, H. Seppo, K. Anne Maria, H. Annakaisa, D. Vincent, F. Nathalie, H. Olivier, D. Carole, B. Alexis, R. Karen, D. Bruno, H. Jayanadra J., K. C. Dirk, T. Joann, F. Annette L., K. Walter A., N. Maria, A. Thor, L. Eric B., M. Ron, R. Jerome I., L. Richard B., B. María J., H. Albert, M. Thomas J., C. Eliecer, B. Eric, P. Ronald C., A. Victoria, R. Fernando, R. Eric M., G. Maura, O. Christopher J., R. Joan S., B. Amalia Cecilia, R. Donald R., D. Martin, S. Mary, D. Galimberti, S.G. Peter, E.A. Scarpini, T. Debby W., M. Michelangelo, B. Ubaldo, W. Ashley R., D. Antonio, W. Chuang-Kuo, P. Oliver, N. Benedetta, R. Matthias, H. Reinhard, B. Carol, R. David C, B. Jose, G. Rita, A. Ammar, S. Christopher E., C. John, M. David, T. Magda, C. Jordi, S. Rebecca, L. Simon, O. Michael C., O. Michael J., B. Timothy W., M. Simon, G. Alison M., U. Andre G., H. Clive, C. Carlos, I. Martin, B. David A., P. John, G. Todd E., G. Caroline, D.J. Philip L, M. Kevin, E. Nilufer, C. Onofre, P. Bruce M., P. Peter, Y. Steven G., B. Claudine, G. Vilmundur, R. Dan, D. Dennis W, D. Jean-François, D. Anita L., O. Sara, H. Hakon, C. Dominique, B. Merce, K. John Keoni, F. Lindsay A., V.B. Christine, I. M. Arfan, J. Lesley, H. Jonathan L., T. Christophe, L. Lenore J., E. Valentina, M. Richard, D. Jean-François, A. Najaf, H. Peter A., P. Margaret A., A. Philippe, V.D. Cornelia M., R. Alfredo, W. Li-San, L. Jean-Charles, S. Sudha, W. Julie, S. Gerard D.. - In: NATURE GENETICS. - ISSN 1061-4036. - 49:9(2017 Sep), pp. 1373-1384. [10.1038/ng.3916]

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

C. Fenoglio;M. Serpente;M. Arcaro;D. Galimberti;E.A. Scarpini;
2017

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 x 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 x 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 x 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 x 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 x 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.
adaptor proteins, signal transducing; Alzheimer disease; amino acid sequence; case-control studies; exome; gene expression profiling; gene frequency; genetic predisposition to disease; genotype; humans; immunity, innate; linkage disequilibrium; membrane glycoproteins; microglia; odds ratio; phospholipase C gamma; protein interaction maps; receptors, immunologic; sequence homology, amino acid; polymorphism, single nucleotide; genetics
Settore MED/26 - Neurologia
Settore BIO/13 - Biologia Applicata
Article (author)
File in questo prodotto:
File Dimensione Formato  
ng.3916.pdf

accesso riservato

Tipologia: Publisher's version/PDF
Dimensione 3.11 MB
Formato Adobe PDF
3.11 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/532793
Citazioni
  • ???jsp.display-item.citation.pmc??? 316
  • Scopus 511
  • ???jsp.display-item.citation.isi??? 489
social impact