Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing

  title={Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates A$\beta$, tau, immunity and lipid processing},
  author={Brian W. Kunkle and Benjamin Grenier‐Boley and Rebecca Sims and Joshua C. Bis and Vincent Damotte and Adam C. Naj and Anne Boland and Maria V. Vronskaya and Sven J. van der Lee and Alexandre Amlie-Wolf and C{\'e}line Bellenguez and Aura Frizatti and Vincent Chouraki and Eden R. Martin and Kristel Sleegers and Nandini Badarinarayan and J{\'o}hanna Jakobsd{\'o}ttir and Kara L. Hamilton-Nelson and Sonia Moreno-Grau and Robert Olaso and Rachel Raybould and Yuning Chen and Amanda Kuzma and Mikko Hiltunen and Taniesha Morgan and Shahzad Ahmad and Badri N. Vardarajan and Jacques Epelbaum and Per Hoffmann and Merc{\`e} Boada and Gary W. Beecham and Jean-Guillaume Garnier and Denise H. Harold and Annette L Fitzpatrick and Otto Valladares and Marie-Laure Moutet and Amy Gerrish and Albert Vernon Smith and Liming Qu and Delphine Bacq and Nicola Denning and Xueqiu Jian and Yi Zhao and Maria Del Zompo and Nick C Fox and Seung Hoan Choi and Ignacio Mateo and J. Trevor Hughes and Hieab H. H. Adams and John S. Malamon and Florentino S{\'a}nchez-Garc{\'i}a and Yogen Patel and Jennifer A. Brody and Beth Dombroski and Maria Candida Deniz Naranjo and Makrina Daniilidou and Gudny Eiriksdottir and Shubhabrata Mukherjee and David Wallon and James B. Uphill and Thor Aspelund and Laura Cantwell and Fabienne Garzia and Daniela Galimberti and Edith Hofer and Mariusz Butkiewicz and Bertrand Fin and Elio Scarpini and Chlo{\'e} Sarnowski and William S. Bush and St{\'e}phane Meslage and Johannes Kornhuber and Charles C. White and Yuenjoo Song and Robert C. Barber and Sebastiaan Engelborghs and Sabrina Sordon and Dina Voijnovic and Perrie M. Adams and Rik Vandenberghe and Manuel Mayhaus and L. Adrienne Cupples and Marilyn S. Albert and Peter Paul de Deyn and Wei Gu and Jayanadra J Himali and Duane L. Beekly and Alessio Squassina and Annette M. Hartmann and Adelina Orellana and Deborah Blacker and Eloy Rodr{\'i}guez-Rodr{\'i}guez and Simon Lovestone and Melissa E. Garcia and Rachelle Doody and Carmen Munoz-Fernadez and Rebecca Sussams and Honghuang Lin and Thomas J. Fairchild and Y Aladro Benito and Clive Holmes and Hata Karamuji{\'c}‐{\vC}omi{\'c} and Matthew P. Frosch and H{\aa}kan Thonberg and Wolfgang Maier and Gena Roschupkin and Bernardino F. Ghetti and Vilmantas Giedraitis and Amit Kawalia and Shuo Li and Ryan M. Huebinger and Lena Kilander and Susanne Moebus and Isabel Hern{\'a}ndez and M. Ilyas Kamboh and Rosemarie Brundin and James Turton and Qiong Yang and Mindy Joy Katz and Letizia Concari and Jenny Lord and Alexa S. Beiser and C. Dirk Keene and S. Helisalmi and Iwona Kloszewska and Walter A Kukull and Anne Maria Koivisto and Aoibhinn Lynch and Lluı́s T{\'a}rraga and Eric B. Larson and Annakaisa Haapasalo and Brian A Lawlor and Thomas H. Mosley and Richard B. Lipton and Vincenzo Solfrizzi and Michael Gill and William T. Longstreth and Thomas Jude Montine and Vincenza Frisardi and M{\'o}nica Diez-Fairen and Fernando Rivadeneira and Ronald C. Petersen and Vincent Deramecourt and Ignacio {\'A}lvarez and Francesca Salani and Antonio Ciaramella and Eric Boerwinkle and Eric M. Reiman and Nathalie Fievet and Jerome I. Rotter and Joan S. Reisch and Olivier Hanon and Chiara Cupidi and A G Andre Uitterlinden and Donald R Royall and Carole Dufouil and Raffaele Maletta and Itziar de Rojas and Mary Sano and Alexis Brice and Roberta Cecchetti and Peter St. George-Hyslop and Karen Ritchie and Magda Tsolaki and Debby W. Tsuang and Bruno Dubois and David Craig and Chuang-Kuo Wu and Hilkka Soininen and Despoina Avramidou and Roger L. Albin and Laura Fratiglioni and Antonia Germanou and Liana G. Apostolova and Lina Keller and Maria Koutroumani and Steven E. Arnold and Francesco Panza and Olymbia Gkatzima and Sanjay Asthana and Didier Hannequin and Patrice L. Whitehead and Craig S Atwood and Paolo Caffarra and Harald Hampel and In{\'e}s Quintela and {\'A}ngel Carracedo and Lars Lannfelt and David C. Rubinsztein and Lisa L. Barnes and Florence Pasquier and Lutz Fr{\"o}lich and Sandra Barral and Bernadette McGuinness and Thomas G Beach and Janet A. Johnston and James T. Becker and Peter Passmore and Eileen H. Bigio and Jonathan M. Schott and Thomas D. Bird and Jason D. Warren and Bradley F. Boeve and Michelle K Lupton and James D Bowen and Petra Proitsi and Adam L. Boxer and John Powell and James R Burke and John S. K. Kauwe and Jeffrey M. Burns and Michelangelo Mancuso and Joseph D. Buxbaum and Ubaldo Bonuccelli and Nigel J Cairns and Andrew McQuillin and Chuanhai Cao and Gill Livingston and Christopher S. Carlson and Nicholas J Bass and Cynthia M Carlsson and John Hardy and Regina M. Carney and Jose T Bras and Minerva M. Carrasquillo and Rita Guerreiro and Mariet Allen and Helena Chui and Elizabeth M. C. Fisher and Carlo Masullo and Elizabeth A. Crocco and Charles DeCarli and Gina D. Bisceglio and Malcolm C. Dick and Li Ma and Ranjan Duara and Neill R. Graff-Radford and Denis A. Evans and Angela K. Hodges and Kelley M. Faber and Martin Scherer and Kenneth B. Fallon and Matthias Riemenschneider and David W. Fardo and Reinhard Heun and Martin R. Farlow and Heike K{\"o}lsch and Steven Ferris and Markus Leber and Tatiana M Foroud and Isabella Heuser and Douglas R. Galasko and Ina Giegling and Marla Gearing and Michael H{\"u}ll and Daniel H. Geschwind and John R. Gilbert and John C. Morris and Robert C. Green and Kevin Mayo and John Growdon and Thomas Feulner and Ronald L. Hamilton and Lindy E. Harrell and Dmitriy Drichel and Lawrence S. Honig and Thomas D. Cushion and Matthew J. Huentelman and Paul Hollingworth and Christine M. Hulette and Bradley T. Hyman and Rachel Marshall and Gail P. Jarvik and A. B. Meggy and Erin L. Abner and Georgina E. Menzies and Lee‐way Jin and Ganna Leonenko and Luis Miguel Real and Gyungah R. Jun and C. T. Baldwin and Detelina Grozeva and Anna M. Karydas and Giancarlo Russo and Jeffrey A. Kaye and Ronald C. Kim and Frank Jessen and Neil W. Kowall and Bruno Vellas and Joel H. Kramer and Emma R.L.C. Vardy and Frank M LaFerla and Karl-Heinz J{\"o}ckel and James J. Lah and Martin Dichgans and James B. Leverenz and David M A Mann and Allan I. Levey and Stuart Pickering-Brown and Andrew P. Lieberman and Norman Klopp and Kathryn L. Lunetta and Heinz-Erich Wichmann and Constantine G Lyketsos and Kevin Morgan and Daniel Marson and Kristelle S. Brown and Frank T. Martiniuk and Christopher William Medway and Deborah C. Mash and Markus M. N{\"o}then and Eliezer Masliah and Nigel M. Hooper and Wayne C. McCormick and Antonio Daniele and Susan M. McCurry and Anthony J. Bayer and Andrew N. McDavid and John E. Gallacher and Ann C. McKee and Hendrik van den Bussche and Marsel M. Mesulam and Carol Brayne and Bruce L. Miller and Steffi G. Riedel-Heller and Carol A Miller and Joshua W. Miller and Ammar Al-Chalabi and John C. Morris and Christopher E. Shaw and Amanda Myers and Jens Wiltfang and Sid E. O'Bryant and John M. Olichney and Victoria {\'A}lvarez and Joseph E. Parisi and Andrew B. Singleton and Henry L. Paulson and John Collinge and William R. Perry and Simon Mead and Elaine Peskind and David H. Cribbs and Martin N. Rossor and Aimee L Pierce and Natalie Sarah Ryan and Wayne W. Poon and Benedetta Nacmias and Huntington Potter and Sandro Sorbi and Joseph F. Quinn and Eleonora Sacchinelli and Ashok Raj and Gianfranco Spalletta and Murray Raskind and Carlo Caltagirone and Paola Boss{\`u} and Maria Donata Orfei and Barry Reisberg and Robert J. Clarke and Christiane Reitz and A. David Smith and John M. Ringman and Donald R. Warden and Erik D. Roberson and Gordon Wilcock and Ekaterina Rogaeva and Amalia Cecilia Bruni and Howard J. Rosen and Maura Gallo and Roger N. Rosenberg and Yoav Ben-Shlomo and Mark A. Sager and Patrizia Mecocci and Andrew J. Saykin and Pau P{\'a}stor and Michael L Cuccaro and Jeffery M. Vance and Julie A. Schneider and Lori S Schneider and Susan H. Slifer and William W. Seeley and Amanda G. Smith and J.A. Sonnen and Salvatore Spina and Robert A. Stern and Russell H Swerdlow and Mitchell Tang and Rudolph E. Tanzi and John Q. Trojanowski and Juan C. Troncoso and Vivianna M. Van Deerlin and Linda J Van Eldik and Harry V. Vinters and Jean Paul G. Vonsattel and Sandra Weintraub and Kathleen Welsh-Bohmer and Kirk C. Wilhelmsen and Jennifer Williamson and Thomas S. Wingo and Randall L. Woltjer and Clinton B. Wright and Chang-En Yu and Lei Yu and Yasaman Saba and Alberto Pilotto and Maria Jesus Bullido and Oliver Peters and Paul K. Crane and David A. Bennett and Paola Bosco and Eliecer Coto and Virginia Boccardi and Philip Lawrence De Jager and Alberto Lle{\'o} and Nick Warner and Oscar L. Lopez and Martin Ingelsson and Panagiotis Deloukas and Carlos Cruchaga and Caroline Graff and Rhian Gwilliam and Myriam Fornage and Alison M. Goate and Pascual S{\'a}nchez-Juan and Patrick Gavin Kehoe and Najaf Amin and Nilifur Ertekin-Taner and Claudine Berr and St{\'e}phanie Debette and Seth Love and Lenore J. Launer and Steven G. Younkin and Jean-François Dartigues and Chris D Corcoran and M. Arfan Ikram and Dennis W. Dickson and Ga{\"e}l Nicolas and Dominique Campion and JoAnn T. Tschanz and Helena Schmidt and Hakon H. Hakonarson and Jordi Clarim{\'o}n and Ronald G. Munger and Reinhold Schmidt and Lindsay A. Farrer and Christine van Broeckhoven and Michael C O'Donovan and Anita L. DeStefano and Lesley Jones and Jonathan L. Haines and Jean-François Deleuze and Michael J. Owen and Vilmundur G. Gudnason and Richard Mayeux and Valentina Escott-Price and Bruce M. Psaty and Alfredo Ram{\'i}rez and Li-San Wang and A. Ruiz and Cornelia M. van Duijn and Peter A Holmans and Sudha Seshadri and Julie Williams and Phillippe Amouyel and Gerard D. Schellenberg and Jean-Charles Lambert and Margaret A. Pericak-Vance},
  journal={Nature Genetics},
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… 

Genome-wide association study of brain biochemical phenotypes reveals distinct genetic architecture of Alzheimer’s Disease related proteins

The novel approach of deep brain biochemical endophenotype GWAS has implications for pathophysiology of proteostasis in AD that can guide therapeutic discovery efforts focused on these proteins.

Novel Alzheimer’s disease risk variants identified based on whole-genome sequencing of APOE ε4 carriers

This study demonstrates that APOE -stratified analysis is important for understanding the genetic background of AD in different populations.

Genome-wide meta-analysis for Alzheimer’s disease cerebrospinal fluid biomarkers

Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD.

Prediction of clinical diagnosis of Alzheimer’s disease, vascular, mixed, and all-cause dementia by a polygenic risk score and APOE status in a community-based cohort prospectively followed over 17 years

The PRS enriched the ability of APOE to discern AD with stronger associations than to VD, MD, or all-cause dementia in a prospective community-based cohort.

Shared Genetic Background Between Cerebrospinal Fluid Biomarkers and Risk for Alzheimer's Disease: A Two-Sample Mendelian Randomization Study.

The results suggest that the etiology of LOAD involves multiple biological processes, including the pathways of Aβ and tau proteins.

Genetically regulated expression in late-onset Alzheimer’s disease implicates risk genes within known and novel loci

GReX-based meta-analysis in LOAD identifies 216 genes (including 72 novel genes), illuminating the role of gene regulatory models in LOads, and reveals eight additional genes significantly associated with LOAD.

Manifestations of genetic risk for Alzheimer’s Disease in the blood: a cross-sectional multi-omic analysis in healthy adults aged 18-90+

A phenome-wide association study on clinical, proteomic, and metabolic blood-based analytes obtained from 2,831 cognitively normal adult clients of a consumer-based scientific wellness company uncovered statistically significant SNP-analyte associations for five genetic variants after correction for multiple testing.

Associations of Alzheimer’s disease risk variants with gene expression, amyloidosis, tauopathy, and neurodegeneration

Genetic variants might play functional roles and suggest potential mechanisms in AD pathogenesis, which opens doors to uncover novel targets for AD treatment.

A comprehensive analysis of methods for assessing polygenic burden on Alzheimer’s disease pathology and risk beyond APOE

Polygenic scores were associated beyond APOE with clinical diagnosis, CSF-tau levels and, to a minor degree, with progressive atrophy, and the results demonstrate that incomplete adjustment for the APOE locus can lead to overestimated effects of polygenic scores due to APOE-ε4 homozygous participants.



Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease

In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10−8) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.

Genome-wide analysis of genetic loci associated with Alzheimer disease.

Although CLU and PICALM were confirmed to be associated with AD in this independent sample, they did not improve the ability of a model that included age, sex, and APOE to predict incident AD.

Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease

A large genome-wide association study of 2,032 individuals from France with Alzheimer's disease and 5,328 controls identified other risk loci, which support roles of CLU and CR1 in the clearance of β amyloid (Aβ) peptide, the principal constituent of amyloids plaques, which are one of the major brain lesions of individuals with Alzheimer’s disease.

A multi-center study of ACE and the risk of late-onset Alzheimer's disease.

Previously reported associations of ACE variants with LOAD will be diminished following this study because at best, ACE variants have modest effect sizes, which are likely part of a complex interaction between genetic, phenotypic and pharmacological effects that would be undetected in traditional case-control studies.

Genome-Wide Association Study of CSF Levels of 59 Alzheimer's Disease Candidate Proteins: Significant Associations with Proteins Involved in Amyloid Processing and Inflammation

The genetic associations reported here are novel and suggest mechanisms for genetic control of CSF and plasma levels of these disease-related proteins/pathways may be valuable therapeutic targets for AD.

Polygenic Overlap Between C-Reactive Protein, Plasma Lipids, and Alzheimer Disease

Genetic overlap between AD, C-reactive protein, and plasma lipids is demonstrated and novel AD susceptibility loci are identified, including 2 genome-wide significant variants conferring increased risk for AD.

Variant of TREM2 associated with the risk of Alzheimer's disease.

These findings strongly implicate variant TREM2 in the pathogenesis of Alzheimer's disease and find that carriers of rs75932628-T between the ages of 80 and 100 years without Alzheimer’s disease had poorer cognitive function than noncarriers.

Whole exome sequencing study identifies novel rare and common Alzheimer’s-Associated variants involved in immune response and transcriptional regulation

The Alzheimer’s Disease Sequencing Project undertook whole exome sequencing in 5,740 late-onset Alzheimer disease cases and 5,096 cognitively normal controls primarily of European ancestry, identifying novel and predicted functional genetic variants in genes previously associated with AD.

Potential late-onset Alzheimer's disease-associated mutations in the ADAM10 gene attenuate {alpha}-secretase activity.

The first evidence of ADAM10 as a candidate AD susceptibility gene is provided, and two potentially pathogenic mutations with incomplete penetrance for late-onset familial AD are reported.