Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2017 Sep;49(9):1373-1384.
doi: 10.1038/ng.3916. Epub 2017 Jul 17.

Rare Coding Variants in PLCG2, ABI3, and TREM2 Implicate Microglial-Mediated Innate Immunity in Alzheimer's Disease

Rebecca Sims  1 Sven J van der Lee  2 Adam C Naj  3 Céline Bellenguez  4   5   6 Nandini Badarinarayan  1 Johanna Jakobsdottir  7 Brian W Kunkle  8 Anne Boland  9 Rachel Raybould  1 Joshua C Bis  10 Eden R Martin  8   11 Benjamin Grenier-Boley  4   5   6 Stefanie Heilmann-Heimbach  12   13 Vincent Chouraki  14   15 Amanda B Kuzma  16 Kristel Sleegers  17   18 Maria Vronskaya  1 Agustin Ruiz  19 Robert R Graham  20 Robert Olaso  9 Per Hoffmann  12   13   21 Megan L Grove  22 Badri N Vardarajan  23   24   25 Mikko Hiltunen  26   27 Markus M Nöthen  12   13 Charles C White  28 Kara L Hamilton-Nelson  8 Jacques Epelbaum  29 Wolfgang Maier  30   31 Seung-Hoan Choi  14   32 Gary W Beecham  8   11 Cécile Dulary  9 Stefan Herms  12   13   21 Albert V Smith  7   33 Cory C Funk  34 Céline Derbois  9 Andreas J Forstner  12   13 Shahzad Ahmad  2 Hongdong Li  34 Delphine Bacq  9 Denise Harold  35 Claudia L Satizabal  14   15 Otto Valladares  16 Alessio Squassina  36 Rhodri Thomas  1 Jennifer A Brody  10 Liming Qu  16 Pascual Sánchez-Juan  37 Taniesha Morgan  1 Frank J Wolters  2 Yi Zhao  16 Florentino Sanchez Garcia  38 Nicola Denning  1 Myriam Fornage  39 John Malamon  16 Maria Candida Deniz Naranjo  38 Elisa Majounie  1 Thomas H Mosley  40 Beth Dombroski  16 David Wallon  41   42 Michelle K Lupton  43   44 Josée Dupuis  32 Patrice Whitehead  8 Laura Fratiglioni  45   46 Christopher Medway  47 Xueqiu Jian  39 Shubhabrata Mukherjee  48 Lina Keller  46 Kristelle Brown  47 Honghuang Lin  49 Laura B Cantwell  16 Francesco Panza  50 Bernadette McGuinness  51 Sonia Moreno-Grau  19 Jeremy D Burgess  52 Vincenzo Solfrizzi  53 Petra Proitsi  43 Hieab H Adams  2 Mariet Allen  52 Davide Seripa  54 Pau Pastor  55 L Adrienne Cupples  15   32 Nathan D Price  34 Didier Hannequin  42   56 Ana Frank-García  57   58   59 Daniel Levy  14   15   60 Paramita Chakrabarty  61 Paolo Caffarra  62   63 Ina Giegling  64 Alexa S Beiser  15   32 Vilmantas Giedraitis  65 Harald Hampel  66   67   68 Melissa E Garcia  69 Xue Wang  52 Lars Lannfelt  65 Patrizia Mecocci  55 Gudny Eiriksdottir  7 Paul K Crane  48 Florence Pasquier  70   71 Virginia Boccardi  55 Isabel Henández  19 Robert C Barber  72 Martin Scherer  73 Lluis Tarraga  19 Perrie M Adams  74 Markus Leber  75 Yuning Chen  32 Marilyn S Albert  76 Steffi Riedel-Heller  77 Valur Emilsson  7   78 Duane Beekly  79 Anne Braae  80 Reinhold Schmidt  81 Deborah Blacker  82   83 Carlo Masullo  84 Helena Schmidt  85 Rachelle S Doody  86 Gianfranco Spalletta  87 W T Longstreth Jr  88   89 Thomas J Fairchild  90 Paola Bossù  87 Oscar L Lopez  91   92 Matthew P Frosch  93 Eleonora Sacchinelli  87 Bernardino Ghetti  94 Qiong Yang  32 Ryan M Huebinger  95 Frank Jessen  30   31   75 Shuo Li  32 M Ilyas Kamboh  96   97 John Morris  98   99 Oscar Sotolongo-Grau  19 Mindy J Katz  100 Chris Corcoran  101 Melanie Dunstan  1 Amy Braddel  1 Charlene Thomas  1 Alun Meggy  1 Rachel Marshall  1 Amy Gerrish  1 Jade Chapman  1 Miquel Aguilar  102   103 Sarah Taylor  1 Matt Hill  1 Mònica Díez Fairén  59   102 Angela Hodges  104 Bruno Vellas  105 Hilkka Soininen  27 Iwona Kloszewska  106 Makrina Daniilidou  107 James Uphill  108 Yogen Patel  43 Joseph T Hughes  43 Jenny Lord  47 James Turton  47 Annette M Hartmann  64 Roberta Cecchetti  55 Chiara Fenoglio  109 Maria Serpente  109 Marina Arcaro  109 Carlo Caltagirone  87 Maria Donata Orfei  87 Antonio Ciaramella  87 Sabrina Pichler  110 Manuel Mayhaus  110 Wei Gu  110 Alberto Lleó  59   111 Juan Fortea  59   111 Rafael Blesa  59   111 Imelda S Barber  80 Keeley Brookes  80 Chiara Cupidi  112 Raffaele Giovanni Maletta  112 David Carrell  113 Sandro Sorbi  114   115 Susanne Moebus  116 Maria Urbano  54 Alberto Pilotto  54 Johannes Kornhuber  117 Paolo Bosco  118 Stephen Todd  51 David Craig  51 Janet Johnston  51 Michael Gill  119 Brian Lawlor  119 Aoibhinn Lynch  119 Nick C Fox  120 John Hardy  120 ARUK ConsortiumRoger L Albin  121   122   123 Liana G Apostolova  124   125   126   127 Steven E Arnold  128 Sanjay Asthana  129   130   131 Craig S Atwood  129   130   131 Clinton T Baldwin  132 Lisa L Barnes  133   134   135 Sandra Barral  23   24   25 Thomas G Beach  136 James T Becker  137 Eileen H Bigio  138   139 Thomas D Bird  88   140 Bradley F Boeve  141 James D Bowen  142 Adam Boxer  143 James R Burke  144 Jeffrey M Burns  145 Joseph D Buxbaum  146   147   148 Nigel J Cairns  149 Chuanhai Cao  150 Chris S Carlson  151 Cynthia M Carlsson  130   131 Regina M Carney  152 Minerva M Carrasquillo  52 Steven L Carroll  153 Carolina Ceballos Diaz  61 Helena C Chui  154 David G Clark  155   156 David H Cribbs  157 Elizabeth A Crocco  152 Charles DeCarli  158 Malcolm Dick  159 Ranjan Duara  160 Denis A Evans  161 Kelley M Faber  125 Kenneth B Fallon  162 David W Fardo  163 Martin R Farlow  126 Steven Ferris  164 Tatiana M Foroud  125 Douglas R Galasko  165 Marla Gearing  166   167 Daniel H Geschwind  168 John R Gilbert  8   11 Neill R Graff-Radford  52   169 Robert C Green  170 John H Growdon  171 Ronald L Hamilton  172 Lindy E Harrell  173 Lawrence S Honig  23 Matthew J Huentelman  174 Christine M Hulette  175 Bradley T Hyman  171 Gail P Jarvik  176   177 Erin Abner  178 Lee-Way Jin  179 Gyungah Jun  132   180   181 Anna Karydas  143 Jeffrey A Kaye  182   183 Ronald Kim  184 Neil W Kowall  185   186 Joel H Kramer  187 Frank M LaFerla  188 James J Lah  189 James B Leverenz  190 Allan I Levey  189 Ge Li  113   140 Andrew P Lieberman  191 Kathryn L Lunetta  180 Constantine G Lyketsos  192 Daniel C Marson  173 Frank Martiniuk  193 Deborah C Mash  194 Eliezer Masliah  165   195 Wayne C McCormick  48 Susan M McCurry  196 Andrew N McDavid  151 Ann C McKee  185   186 Marsel Mesulam  139   197 Bruce L Miller  143 Carol A Miller  198 Joshua W Miller  179 John C Morris  149   199 Jill R Murrell  94   125 Amanda J Myers  152 Sid O'Bryant  200 John M Olichney  158 Vernon S Pankratz  201 Joseph E Parisi  202 Henry L Paulson  121   123 William Perry  8 Elaine Peskind  113 Aimee Pierce  157 Wayne W Poon  159 Huntington Potter  203 Joseph F Quinn  182   183 Ashok Raj  150 Murray Raskind  113 Barry Reisberg  164   204 Christiane Reitz  24   25   205 John M Ringman  206 Erik D Roberson  173 Ekaterina Rogaeva  207 Howard J Rosen  143 Roger N Rosenberg  208 Mark A Sager  130 Andrew J Saykin  125   127 Julie A Schneider  133   135   209 Lon S Schneider  154   210 William W Seeley  143 Amanda G Smith  150 Joshua A Sonnen  211 Salvatore Spina  94 Robert A Stern  185 Russell H Swerdlow  145 Rudolph E Tanzi  171 Tricia A Thornton-Wells  212 John Q Trojanowski  213 Juan C Troncoso  214 Vivianna M Van Deerlin  213 Linda J Van Eldik  215 Harry V Vinters  206   216 Jean Paul Vonsattel  217 Sandra Weintraub  139   218 Kathleen A Welsh-Bohmer  144   219 Kirk C Wilhelmsen  220 Jennifer Williamson  23 Thomas S Wingo  189 Randall L Woltjer  221 Clinton B Wright  222 Chang-En Yu  48 Lei Yu  133   135 Fabienne Garzia  9 Feroze Golamaully  9 Gislain Septier  9 Sebastien Engelborghs  18   223 Rik Vandenberghe  223   224 Peter P De Deyn  18   223 Carmen Muñoz Fernadez  38 Yoland Aladro Benito  38 Hakan Thonberg  225   226 Charlotte Forsell  225   226 Lena Lilius  225   226 Anne Kinhult-Stählbom  225   226 Lena Kilander  65 RoseMarie Brundin  65 Letizia Concari  62   63 Seppo Helisalmi  27   227 Anne Maria Koivisto  27   227 Annakaisa Haapasalo  27   227 Vincent Dermecourt  228 Nathalie Fievet  4   5   6   229 Olivier Hanon  229 Carole Dufouil  230   231 Alexis Brice  232   233 Karen Ritchie  234 Bruno Dubois  235   236   237   238 Jayanadra J Himali  14 C Dirk Keene  211 JoAnn Tschanz  101 Annette L Fitzpatrick  89   239 Walter A Kukull  89 Maria Norton  101 Thor Aspelund  7   240 Eric B Larson  48   241 Ron Munger  101 Jerome I Rotter  242 Richard B Lipton  100 María J Bullido  58   59   243 Albert Hofman  2 Thomas J Montine  211 Eliecer Coto  244 Eric Boerwinkle  22   245 Ronald C Petersen  141 Victoria Alvarez  244 Fernando Rivadeneira  2   246   247 Eric M Reiman  174   248   249   250 Maura Gallo  112 Christopher J O'Donnell  15 Joan S Reisch  251 Amalia Cecilia Bruni  112 Donald R Royall  252 Martin Dichgans  253   254 Mary Sano  148 Daniela Galimberti  109 Peter St George-Hyslop  207   255 Elio Scarpini  109 Debby W Tsuang  113   140 Michelangelo Mancuso  256 Ubaldo Bonuccelli  256 Ashley R Winslow  257 Antonio Daniele  258 Chuang-Kuo Wu  259 GERAD/PERADES, CHARGE, ADGC, EADIOliver Peters  260 Benedetta Nacmias  114   115 Matthias Riemenschneider  110 Reinhard Heun  31 Carol Brayne  261 David C Rubinsztein  255 Jose Bras  120   262 Rita Guerreiro  120   262 Ammar Al-Chalabi  263 Christopher E Shaw  263 John Collinge  108 David Mann  264 Magda Tsolaki  265 Jordi Clarimón  59   111 Rebecca Sussams  266 Simon Lovestone  267 Michael C O'Donovan  1 Michael J Owen  1 Timothy W Behrens  20 Simon Mead  108 Alison M Goate  147 Andre G Uitterlinden  2   108   109 Clive Holmes  140 Carlos Cruchaga  98   99 Martin Ingelsson  65 David A Bennett  133   135 John Powell  43 Todd E Golde  61   268 Caroline Graff  45   226 Philip L De Jager  269 Kevin Morgan  47 Nilufer Ertekin-Taner  52   169 Onofre Combarros  37 Bruce M Psaty  10   59   89   270 Peter Passmore  51 Steven G Younkin  52   169 Claudine Berr  235   271   272 Vilmundur Gudnason  7   33 Dan Rujescu  64 Dennis W Dickson  52 Jean-François Dartigues  273 Anita L DeStefano  15   32 Sara Ortega-Cubero  59   274   275 Hakon Hakonarson  276 Dominique Campion  41   42 Merce Boada  19 John Keoni Kauwe  277 Lindsay A Farrer  14   132   180   181   185 Christine Van Broeckhoven  17   18 M Arfan Ikram  2   278 Lesley Jones  1 Jonathan L Haines  279 Christophe Tzourio  232   280 Lenore J Launer  69 Valentina Escott-Price  1 Richard Mayeux  23   24   25 Jean-François Deleuze  9 Najaf Amin  2 Peter A Holmans  1 Margaret A Pericak-Vance  8   11 Philippe Amouyel  4   5   6   70 Cornelia M van Duijn  2 Alfredo Ramirez  12   31   75 Li-San Wang  16 Jean-Charles Lambert  4   5   6 Sudha Seshadri  14   15 Julie Williams  1 Gerard D Schellenberg  16
Affiliations
Free PMC article

Rare Coding Variants in PLCG2, ABI3, and TREM2 Implicate Microglial-Mediated Innate Immunity in Alzheimer's Disease

Rebecca Sims et al. Nat Genet. .
Free PMC article

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.

Conflict of interest statement

Competing Financial Interests Statement

Robert R. Graham and Timothy W. Behrens are full-time employees of Genentech Inc. Deborah Blacker is a consultant for Biogen Inc. Ronald C. Petersen is a consultant for Roche Inc., Merck Inc., Genentech Inc., Biogen Inc., and Eli Lilly. Ashley R. Winslow is a former employee and stockholder of Pfizer, Inc., and a current employee of the Perelman School of Medicine at the University of Pennsylvania Orphan Disease Center in partnership with the Loulou. Alison M. Goate is a member of the scientific advisory board for Denali Therapeutics. Nilufer Ertekin-Taner is a consultant for Cytox. John Hardy holds a collaborative grant with Cytox cofunded by Department of Business (Biz). Frank Jessen acts as a consultant for Novartis, Eli Lilly, Nutricia, MSD, Roche and Piramal. Neither Dr. Morris nor his family owns stock or has equity interest (outside of mutual funds or other externally directed accounts) in any pharmaceutical or biotechnology company. Dr. Morris is currently participating in clinical trials of antidementia drugs from Eli Lilly and Company, Biogen, and Janssen. Dr. Morris serves as a consultant for Lilly USA. He receives research support from Eli Lilly/Avid Radiopharmaceuticals and is funded by NIH grants # P50AG005681; P01AG003991; P01AG026276 and UF01AG032438.

Figures

Figure 1
Figure 1
Association plots of PLCG2, ABI3, and TREM2. (a) Regional plot of identified association at the PLCG2 locus. Top hit rs72824905 indicated in purple. Data presented for rs72824905 includes stage 1, stage 2 and stage 3 (N=84,905). (b) Regional plot of identified association at the ABI3 locus. Top hit rs616338 indicated in purple. Data presented for rs616338 includes stage 1, stage 2 and stage 3 (N=84,493). (c) Regional plot of identified association at the TREM2 locus. Top hit rs75932628 indicated in purple. Data presented for rs75932628 and rs143332484 includes stage 1, stage 2 and stage 3 (N=80,733 and 53,042, respectively). SNVs with missing LD information are shown in grey.
Figure 1
Figure 1
Association plots of PLCG2, ABI3, and TREM2. (a) Regional plot of identified association at the PLCG2 locus. Top hit rs72824905 indicated in purple. Data presented for rs72824905 includes stage 1, stage 2 and stage 3 (N=84,905). (b) Regional plot of identified association at the ABI3 locus. Top hit rs616338 indicated in purple. Data presented for rs616338 includes stage 1, stage 2 and stage 3 (N=84,493). (c) Regional plot of identified association at the TREM2 locus. Top hit rs75932628 indicated in purple. Data presented for rs75932628 and rs143332484 includes stage 1, stage 2 and stage 3 (N=80,733 and 53,042, respectively). SNVs with missing LD information are shown in grey.
Figure 1
Figure 1
Association plots of PLCG2, ABI3, and TREM2. (a) Regional plot of identified association at the PLCG2 locus. Top hit rs72824905 indicated in purple. Data presented for rs72824905 includes stage 1, stage 2 and stage 3 (N=84,905). (b) Regional plot of identified association at the ABI3 locus. Top hit rs616338 indicated in purple. Data presented for rs616338 includes stage 1, stage 2 and stage 3 (N=84,493). (c) Regional plot of identified association at the TREM2 locus. Top hit rs75932628 indicated in purple. Data presented for rs75932628 and rs143332484 includes stage 1, stage 2 and stage 3 (N=80,733 and 53,042, respectively). SNVs with missing LD information are shown in grey.
Figure 2
Figure 2
Protein-protein interaction network (using high-confidence human interactions from the STRING database) of 56 genes enriched for both common and rare variants associated with AD risk. Colours of edges refer to the type of evidence linking the corresponding proteins: red=gene fusion, dark blue = co-occurrence, black = co-expression, magenta = experiments, cyan=databases, light green = text mining, mauve = homology. TREM2, PLCG2 and ABI3 highlighted by red circles, SYK, CSF1R and TYROBP highlighted by blue circles, and INPP5D, SPI1 and CD33 identified as common variant risk loci,-, highlighted by black circles.

Similar articles

  • Transethnic meta-analysis of rare coding variants in PLCG2, ABI3, and TREM2 supports their general contribution to Alzheimer's disease.
    Dalmasso MC, Brusco LI, Olivar N, Muchnik C, Hanses C, Milz E, Becker J, Heilmann-Heimbach S, Hoffmann P, Prestia FA, Galeano P, Avalos MSS, Martinez LE, Carulla ME, Azurmendi PJ, Liberczuk C, Fezza C, Sampaño M, Fierens M, Jemar G, Solis P, Medel N, Lisso J, Sevillano Z, Bosco P, Bossù P, Spalletta G, Galimberti D, Mancuso M, Nacmias B, Sorbi S, Mecocci P, Pilotto A, Caffarra P, Panza F, Bullido M, Clarimon J, Sánchez-Juan P, Coto E, Sanchez-Garcia F, Graff C, Ingelsson M, Bellenguez C, Castaño EM, Kairiyama C, Politis DG, Kochen S, Scaro H, Maier W, Jessen F, Mangone CA, Lambert JC, Morelli L, Ramirez A. Dalmasso MC, et al. Transl Psychiatry. 2019 Jan 31;9(1):55. doi: 10.1038/s41398-019-0394-9. Transl Psychiatry. 2019. PMID: 30705288 Free PMC article.
  • ABI3 and PLCG2 missense variants as risk factors for neurodegenerative diseases in Caucasians and African Americans.
    Conway OJ, Carrasquillo MM, Wang X, Bredenberg JM, Reddy JS, Strickland SL, Younkin CS, Burgess JD, Allen M, Lincoln SJ, Nguyen T, Malphrus KG, Soto AI, Walton RL, Boeve BF, Petersen RC, Lucas JA, Ferman TJ, Cheshire WP, van Gerpen JA, Uitti RJ, Wszolek ZK, Ross OA, Dickson DW, Graff-Radford NR, Ertekin-Taner N. Conway OJ, et al. Mol Neurodegener. 2018 Oct 11;13(1):53. doi: 10.1186/s13024-018-0289-x. Mol Neurodegener. 2018. PMID: 30326945 Free PMC article.
  • TREM2 variants in Alzheimer's disease.
    Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, Cruchaga C, Sassi C, Kauwe JS, Younkin S, Hazrati L, Collinge J, Pocock J, Lashley T, Williams J, Lambert JC, Amouyel P, Goate A, Rademakers R, Morgan K, Powell J, St George-Hyslop P, Singleton A, Hardy J; Alzheimer Genetic Analysis Group. Guerreiro R, et al. N Engl J Med. 2013 Jan 10;368(2):117-27. doi: 10.1056/NEJMoa1211851. Epub 2012 Nov 14. N Engl J Med. 2013. PMID: 23150934 Free PMC article.
  • TREM2 and the neuroimmunology of Alzheimer's disease.
    Hickman SE, El Khoury J. Hickman SE, et al. Biochem Pharmacol. 2014 Apr 15;88(4):495-8. doi: 10.1016/j.bcp.2013.11.021. Epub 2013 Dec 16. Biochem Pharmacol. 2014. PMID: 24355566 Free PMC article. Review.
  • The role of TREM2 in Alzheimer's disease and other neurodegenerative disorders.
    Carmona S, Zahs K, Wu E, Dakin K, Bras J, Guerreiro R. Carmona S, et al. Lancet Neurol. 2018 Aug;17(8):721-730. doi: 10.1016/S1474-4422(18)30232-1. Epub 2018 Jul 17. Lancet Neurol. 2018. PMID: 30033062 Review.
See all similar articles

Cited by 166 articles

See all "Cited by" articles

MeSH terms

Grant support

LinkOut - more resources

Feedback