BACKGROUND: Rare variants in PLCG2 (p.P522R), ABI3 (p.S209F), and TREM2 (p.R47H, p.R62H) have been associated with late onset Alzheimer's disease (LOAD) risk in Caucasians. After the initial report, several studies have found positive results in cohorts of different ethnic background and with different phenotype. OBJECTIVE: In this study, we aim to evaluate the association of rare coding variants in PLCG2, ABI3, and TREM2 with LOAD risk and their effect at different time points of the disease. METHODS: We used a European American cohort to assess the association of the variants prior onset (using CSF Aβ42, tau, and pTau levels, and amyloid imaging as endophenotypes) and after onset (measured as rate of memory decline). RESULTS: We confirm the association with LOAD risk of TREM2 p.R47H, p.R62H and ABI3 p.S209F variants, and the protective effect of PLCG2 p.P522R. In addition, ABI3 and TREM2 gene-sets showed significant association with LOAD risk. TREM2 p.R47H and PLCG2 p.P522R variants were also statistically associated with increase of amyloid imaging and AD progression, respectively. We did not observe any association of ABI3 p.S209F with any of the other AD endophenotypes. CONCLUSION: The results of this study highlight the importance of including biomarkers and alternative phenotypes to better understand the role of novel candidate genes with the disease.
BACKGROUND: Rare variants in PLCG2 (p.P522R), ABI3 (p.S209F), and TREM2 (p.R47H, p.R62H) have been associated with late onset Alzheimer's disease (LOAD) risk in Caucasians. After the initial report, several studies have found positive results in cohorts of different ethnic background and with different phenotype. OBJECTIVE: In this study, we aim to evaluate the association of rare coding variants in PLCG2, ABI3, and TREM2 with LOAD risk and their effect at different time points of the disease. METHODS: We used a European American cohort to assess the association of the variants prior onset (using CSF Aβ42, tau, and pTau levels, and amyloid imaging as endophenotypes) and after onset (measured as rate of memory decline). RESULTS: We confirm the association with LOAD risk of TREM2p.R47H, p.R62H and ABI3p.S209F variants, and the protective effect of PLCG2p.P522R. In addition, ABI3 and TREM2 gene-sets showed significant association with LOAD risk. TREM2p.R47H and PLCG2p.P522R variants were also statistically associated with increase of amyloid imaging and AD progression, respectively. We did not observe any association of ABI3p.S209F with any of the other AD endophenotypes. CONCLUSION: The results of this study highlight the importance of including biomarkers and alternative phenotypes to better understand the role of novel candidate genes with the disease.
Entities:
Keywords:
ABI3; PLCG2; TREM2; endophenotypes; late onset Alzheimer’s disease; progression
Authors: Basavaraj V Hooli; Antonio R Parrado; Kristina Mullin; Wai-Ki Yip; Tian Liu; Johannes T Roehr; Dandi Qiao; Frank Jessen; Oliver Peters; Tim Becker; Alfredo Ramirez; Christoph Lange; Lars Bertram; Rudolph E Tanzi Journal: Neurology Date: 2014-09-03 Impact factor: 9.910
Authors: John S K Kauwe; Carlos Cruchaga; Sarah Bertelsen; Kevin Mayo; Wayne Latu; Petra Nowotny; Anthony L Hinrichs; Anne M Fagan; David M Holtzman; Alison M Goate Journal: J Alzheimers Dis Date: 2010 Impact factor: 4.472
Authors: Deana Finelli; Sara Rollinson; Jenny Harris; Matthew Jones; Anna Richardson; Alex Gerhard; Julie Snowden; David Mann; Stuart Pickering-Brown Journal: Neurobiol Aging Date: 2014-08-27 Impact factor: 4.673
Authors: Monkol Lek; Konrad J Karczewski; Eric V Minikel; Kaitlin E Samocha; Eric Banks; Timothy Fennell; Anne H O'Donnell-Luria; James S Ware; Andrew J Hill; Beryl B Cummings; Taru Tukiainen; Daniel P Birnbaum; Jack A Kosmicki; Laramie E Duncan; Karol Estrada; Fengmei Zhao; James Zou; Emma Pierce-Hoffman; Joanne Berghout; David N Cooper; Nicole Deflaux; Mark DePristo; Ron Do; Jason Flannick; Menachem Fromer; Laura Gauthier; Jackie Goldstein; Namrata Gupta; Daniel Howrigan; Adam Kiezun; Mitja I Kurki; Ami Levy Moonshine; Pradeep Natarajan; Lorena Orozco; Gina M Peloso; Ryan Poplin; Manuel A Rivas; Valentin Ruano-Rubio; Samuel A Rose; Douglas M Ruderfer; Khalid Shakir; Peter D Stenson; Christine Stevens; Brett P Thomas; Grace Tiao; Maria T Tusie-Luna; Ben Weisburd; Hong-Hee Won; Dongmei Yu; David M Altshuler; Diego Ardissino; Michael Boehnke; John Danesh; Stacey Donnelly; Roberto Elosua; Jose C Florez; Stacey B Gabriel; Gad Getz; Stephen J Glatt; Christina M Hultman; Sekar Kathiresan; Markku Laakso; Steven McCarroll; Mark I McCarthy; Dermot McGovern; Ruth McPherson; Benjamin M Neale; Aarno Palotie; Shaun M Purcell; Danish Saleheen; Jeremiah M Scharf; Pamela Sklar; Patrick F Sullivan; Jaakko Tuomilehto; Ming T Tsuang; Hugh C Watkins; James G Wilson; Mark J Daly; Daniel G MacArthur Journal: Nature Date: 2016-08-18 Impact factor: 49.962
Authors: Perry G Ridge; Kaitlyn B Hoyt; Kevin Boehme; Shubhabrata Mukherjee; Paul K Crane; Jonathan L Haines; Richard Mayeux; Lindsay A Farrer; Margaret A Pericak-Vance; Gerard D Schellenberg; John S K Kauwe Journal: Neurobiol Aging Date: 2016-03-03 Impact factor: 4.673
Authors: J C Lambert; C A Ibrahim-Verbaas; D Harold; A C Naj; R Sims; C Bellenguez; A L DeStafano; J C Bis; G W Beecham; B Grenier-Boley; G Russo; T A Thorton-Wells; N Jones; A V Smith; V Chouraki; C Thomas; M A Ikram; D Zelenika; B N Vardarajan; Y Kamatani; C F Lin; A Gerrish; H Schmidt; B Kunkle; M L Dunstan; A Ruiz; M T Bihoreau; S H Choi; C Reitz; F Pasquier; C Cruchaga; D Craig; N Amin; C Berr; O L Lopez; P L De Jager; V Deramecourt; J A Johnston; D Evans; S Lovestone; L Letenneur; F J Morón; D C Rubinsztein; G Eiriksdottir; K Sleegers; A M Goate; N Fiévet; M W Huentelman; M Gill; K Brown; M I Kamboh; L Keller; P Barberger-Gateau; B McGuiness; E B Larson; R Green; A J Myers; C Dufouil; S Todd; D Wallon; S Love; E Rogaeva; J Gallacher; P St George-Hyslop; J Clarimon; A Lleo; A Bayer; D W Tsuang; L Yu; M Tsolaki; P Bossù; G Spalletta; P Proitsi; J Collinge; S Sorbi; F Sanchez-Garcia; N C Fox; J Hardy; M C Deniz Naranjo; P Bosco; R Clarke; C Brayne; D Galimberti; M Mancuso; F Matthews; S Moebus; P Mecocci; M Del Zompo; W Maier; H Hampel; A Pilotto; M Bullido; F Panza; P Caffarra; B Nacmias; J R Gilbert; M Mayhaus; L Lannefelt; H Hakonarson; S Pichler; M M Carrasquillo; M Ingelsson; D Beekly; V Alvarez; F Zou; O Valladares; S G Younkin; E Coto; K L Hamilton-Nelson; W Gu; C Razquin; P Pastor; I Mateo; M J Owen; K M Faber; P V Jonsson; O Combarros; M C O'Donovan; L B Cantwell; H Soininen; D Blacker; S Mead; T H Mosley; D A Bennett; T B Harris; L Fratiglioni; C Holmes; R F de Bruijn; P Passmore; T J Montine; K Bettens; J I Rotter; A Brice; K Morgan; T M Foroud; W A Kukull; D Hannequin; J F Powell; M A Nalls; K Ritchie; K L Lunetta; J S Kauwe; E Boerwinkle; M Riemenschneider; M Boada; M Hiltuenen; E R Martin; R Schmidt; D Rujescu; L S Wang; J F Dartigues; R Mayeux; C Tzourio; A Hofman; M M Nöthen; C Graff; B M Psaty; L Jones; J L Haines; P A Holmans; M Lathrop; M A Pericak-Vance; L J Launer; L A Farrer; C M van Duijn; C Van Broeckhoven; V Moskvina; S Seshadri; J Williams; G D Schellenberg; P Amouyel Journal: Nat Genet Date: 2013-10-27 Impact factor: 38.330
Authors: Catherine F Slattery; Jonathan A Beck; Lorna Harper; Gary Adamson; Zeinab Abdi; James Uphill; Tracy Campbell; Ron Druyeh; Colin J Mahoney; Jonathan D Rohrer; Janna Kenny; Jessica Lowe; Kelvin K Leung; Josephine Barnes; Shona L Clegg; Melanie Blair; Jennifer M Nicholas; Rita J Guerreiro; James B Rowe; Claudia Ponto; Inga Zerr; Hans Kretzschmar; Pierluigi Gambetti; Sebastian J Crutch; Jason D Warren; Martin N Rossor; Nick C Fox; John Collinge; Jonathan M Schott; Simon Mead Journal: Alzheimers Dement Date: 2014-08-23 Impact factor: 21.566
Authors: Joshua C Bis; Xueqiu Jian; Brian W Kunkle; Yuning Chen; Adam C Naj; Myriam Fornage; Lindsay A Farrer; Kara L Hamilton-Nelson; William S Bush; William J Salerno; Daniel Lancour; Yiyi Ma; Alan E Renton; Edoardo Marcora; John J Farrell; Yi Zhao; Liming Qu; Shahzad Ahmad; Najaf Amin; Philippe Amouyel; Gary W Beecham; Jennifer E Below; Dominique Campion; Laura Cantwell; Camille Charbonnier; Jaeyoon Chung; Paul K Crane; Carlos Cruchaga; L Adrienne Cupples; Jean-François Dartigues; Stéphanie Debette; Jean-François Deleuze; Lucinda Fulton; Stacey B Gabriel; Emmanuelle Genin; Richard A Gibbs; Alison Goate; Benjamin Grenier-Boley; Namrata Gupta; Jonathan L Haines; Aki S Havulinna; Seppo Helisalmi; Mikko Hiltunen; Daniel P Howrigan; M Arfan Ikram; Jaakko Kaprio; Jan Konrad; Amanda Kuzma; Eric S Lander; Mark Lathrop; Terho Lehtimäki; Honghuang Lin; Kari Mattila; Richard Mayeux; Donna M Muzny; Waleed Nasser; Benjamin Neale; Kwangsik Nho; Gaël Nicolas; Devanshi Patel; Margaret A Pericak-Vance; Markus Perola; Bruce M Psaty; Olivier Quenez; Farid Rajabli; Richard Redon; Christiane Reitz; Anne M Remes; Veikko Salomaa; Chloe Sarnowski; Helena Schmidt; Michael Schmidt; Reinhold Schmidt; Hilkka Soininen; Timothy A Thornton; Giuseppe Tosto; Christophe Tzourio; Sven J van der Lee; Cornelia M van Duijn; Otto Valladares; Badri Vardarajan; Li-San Wang; Weixin Wang; Ellen Wijsman; Richard K Wilson; Daniela Witten; Kim C Worley; Xiaoling Zhang; Celine Bellenguez; Jean-Charles Lambert; Mitja I Kurki; Aarno Palotie; Mark Daly; Eric Boerwinkle; Kathryn L Lunetta; Anita L Destefano; Josée Dupuis; Eden R Martin; Gerard D Schellenberg; Sudha Seshadri Journal: Mol Psychiatry Date: 2018-08-14 Impact factor: 15.992
Authors: Hande Karahan; Daniel C Smith; Byungwook Kim; Luke C Dabin; Md Mamun Al-Amin; H R Sagara Wijeratne; Taylor Pennington; Gonzalo Viana di Prisco; Brianne McCord; Peter Bor-Chian Lin; Yuxin Li; Junmin Peng; Adrian L Oblak; Shaoyou Chu; Brady K Atwood; Jungsu Kim Journal: Sci Adv Date: 2021-11-03 Impact factor: 14.136
Authors: Andy P Tsai; Chuanpeng Dong; Peter Bor-Chian Lin; Evan J Messenger; Brad T Casali; Miguel Moutinho; Yunlong Liu; Adrian L Oblak; Bruce T Lamb; Gary E Landreth; Stephanie J Bissel; Kwangsik Nho Journal: Genome Med Date: 2022-02-18 Impact factor: 11.117