Meta-analysis of genetic association with diagnosed Alzheimer’s disease identifies novel risk loci and implicates Abeta, Tau, immunity and lipid processing
Authors: Kunkle BW , Grenier-Boley B , Sims R , Bis JC , 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 , Aloso 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 , Zompo MD , Fox NC , Grove ML , Choi SH , Mateo I , Hughes JT , Adams HH , Malamon J , Garcia FS , Patel Y , Brody JA , Dombroski B , Naranjo MCD , Daniilidou M , Eiriksdottir G , Mukherjee S , Wallon D , Uphill J , Aspelund T , Cantwell LB , Garzia F , Galimberti D , Hofer E , Butkiewics M , Fin B , Scarpini E , Sarnowski C , Bush W , Meslage S , Kornhuber J , White CC , Song Y , Barber RC , Engelborghs S , Pichler 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 , Fernadez CM , Sussams R , Lin H , Fairchild TJ , Benito YA , Holmes C , Comic H , Frosch MP , Thonberg H , Maier W , Roschupkin 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 , Montine TJ , Frisardi V , Ortega-Cubero S , Rivadeneira F , Petersen RC , Deramecourt V , Ciaramella A , Boerwinkle E , Reiman EM , Fievet N , Caltagirone C , Rotter JI , Reisch JS , Hanon O , Cupidi C , Uitterlinden AG , Royall DR , Dufouil C , Maletta RG , Moreno-Grau S , Sano M , Brice A , Cecchetti R , St George-Hyslop P , 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 , Baldwin CT , Lannfelt L , Rubinsztein DC , Barnes LL , Pasquier F , Frölich L , Barral S , McGuinness B , Beach TG , Johnston JI , 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 JK , 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 , Cribbs DH , 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 , 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 G , Jin LW , Leonenko G , Jun G , 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 , Coto E , Olichney JM , Alvarez V , Parisi JE , Singleton AB , Paulson HL , Collinge J , Perry W , Mead S , Peskind E , Rosser M , Pierce A , Ryan N , Poon WW , Nacmias B , Potter H , Sorbi S , Quinn JF , Sacchinelli E , Raj A , Spalletta G , Raskind M , Bossù P , 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 , Seeley WW , Smith AG , Sonnen JA , Spina S , Stern RA , Swerdlow RH , 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 ,   Alzheimer Disease Genetics Consortium (ADGC),   The European Alzheimer’s Disease Initiative (EADI),   Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (CHARGE),   Genetic and Environmental Risk in AD/Defining Genetic, Polygenic and Environmental Risk for Alzheimer’s Disease Consortium (GERAD/PERADES), Crane PK , Bennett DA , Boccardi V , De Jager PL , Warner N , Lopez OL , McDonough S , 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 , Campion D , Tschanz J , Schmidt H , Hakonarson H , 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 , Ruiz A , Ramirez A , Wang LS , van Duijn CM , Holmans PA , Seshadri S , Williams J , Amouyel P , Schellenberg GD , Lambert JC , Pericak-Vance MA 
Published: April 2018

IntroductionLate-onset Alzheimer’s disease (LOAD, onset age > 60 years) is the most prevalent dementia in the elderly1, and risk is partially driven by genetics2. Many of the loci responsible for this genetic risk were identified by genome-wide association studies (GWAS)3–8. To identify additional LOAD risk loci, the we performed the largest GWAS to date (89,769 individuals), analyzing both common and rare variants. We confirm 20 previous LOAD risk loci and identify four new genome-wide loci (IQCK, ACE, ADAM10, and ADAMTS1). Pathway analysis of these data implicates the immune system and lipid metabolism, and for the first time tau binding proteins and APP metabolism. These findings show that genetic variants affecting APP and Aβ processing are not only associated with early-onset autosomal dominant AD but also with LOAD. Analysis of AD risk genes and pathways show enrichment for rare variants (P = 1.32 × 10−7) indicating that additional rare variants remain to be identified.