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

Abstract

Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. We thank Drs. D. Stephen Snyder and Marilyn Miller from NIA who are ex-officio ADGC members. EADI. This work has been developed and supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease) including funding from MEL (Metropole européenne de Lille), ERDF (European Regional Development Fund) and Conseil Régional Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The authors are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. The generation and management of GWAS genotype data for the Rotterdam Study (RS-I, RS-II, RS-III) was executed by the Human Genotyping Facility of the Genetic Laboratory of the

“Amyloid‐beta accumulation cycle” as a prevention and/or therapy target for Alzheimer's disease

“…The genes include 21 previously identified loci: ABCA7, BIN1, CASS4, SORL1, CD33, CD2AP, CELF1, CLU, CR1, DSG2, EPHA1, FERMT2, HLA‐DRB5/HLA‐DRB1, INPP5D, MEF2C, MS4M6A, MS4A4E, NME8, PTK2B/PYK2, SLC24A4, and ZCWPW1. In addition, ADAM10, ACE, NYAP1, SPI1, and ECHDC3 were identified through a recent meta‐analysis (Kunkle et al, ). ADAMTS4, HESX1, CLNK, TREM2, CNTAP2, APH1B, KAT8, SCIMP, ABI3, SUZ12P1, ALPK2, and BZRAP‐AS1 were identified with international transethnic cohorts (Jun et al, ) (Table ).…”

“…Analyzing AD brains in a comprehensive and hypothesis-free manner with a combination of various -omics, imaging, and other biomarker analysis techniques has been proposed by the "Alzheimer Precision Medicine Initiative (APMI)" to advance understanding of AD, to identify dysfunctional systems and predictive markers, and to develop remedies against neurodegenerative disorders (Hampel, Toschi, et al, 2018;Hampel, Vergallo, et al, 2018). Genome sequencing projects of human AD patients and meta-analysis of the reports have revealed genes/loci that are frequently mutated in AD patients, that is, AD genetic risk loci (Beecham et al, 2014;Carrasquillo et al, 2015;Chouraki & Seshadri, 2014;Jansen et al, 2019;Kim, 2018;Kunkle et al, 2019;Lambert et al, 2013;Van Cauwenberghe, Broeckhoven, & Sleegers, 2016;Zhang, Gaiteri, et al, 2013), in addition to known familial AD mutations, such as PSEN1/2, APP, and APOE variants. The genes include 21 previously identified loci: ABCA7, BIN1, CASS4, SORL1, CD33, CD2AP, CELF1, CLU, CR1, DSG2, EPHA1, FERMT2, HLA-DRB5/HLA-DRB1, INPP5D, MEF2C, MS4M6A, MS4A4E, NME8, PTK2B/PYK2, SLC24A4, and ZCWPW1.…”

Human iPSC‐derived microglia: A growing toolset to study the brain's innate immune cells

“…As a multitude of microglial genes have recently been implicated in modulating AD risk (Efthymiou & Goate, 2017;Guerreiro, Wojtas, et al, 2013;Hansen, Hanson, & Sheng, 2018;Huang et al, 2017;Jansen et al, 2019;Jonsson et al, 2013;Kunkle et al, 2019;Lambert et al, 2013;Sims et al, 2017), studies that carefully analyze these risk genes will be critical for enhancing our understanding of AD pathogenesis. Therefore, it is not surprising that some of the first iMG studies examined functions related to AD neuropathology.…”

Single-cell analysis of antiviral neuroinflammatory responses in the mouse dorsal raphe nucleus

“…Neuroinflammatory processes are increasingly recognized for their importance in the etiology of neurological and psychiatric disorders. Recent studies have found significant associations between genes with known immune functions and diseases that include Alzheimer's Disease and schizophrenia [1][2][3][4] . Microglia, the predominant resident immune cells of the central nervous system (CNS), express many of these disease-associated genes, and undergo transcriptional changes and diversification in both acute and chronic models of inflammation, aging, and neurodegeneration [5][6][7][8] .…”