New insights into the genetic etiology of Alzheimer’s disease and related dementias

doi:10.1038/s41588-022-01024-z

New insights into the genetic etiology of Alzheimer’s disease and related dementias

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Producción científica: Article › revisión exhaustiva

1767 Citas (Scopus)

Resumen

Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.

Idioma original	English
Páginas (desde-hasta)	412-436
Número de páginas	25
Publicación	Nature Genetics
Volumen	54
N.º	4
DOI	https://doi.org/10.1038/s41588-022-01024-z
Estado	Published - abr 1 2022

Nota bibliográfica

Publisher Copyright:
© 2022, The Author(s).

Financiación

We thank the many study participants, researchers and staff for collecting and contributing to the data, the high-performance computing service at the University of Lille and the staff at CEA-CNRGH for their help with sample preparation and genotyping and excellent technical assistance. We thank Antonio Pardinas for his help. We thank the Netherlands Brain Bank. This research was conducted using the UKBB resource (application number 61054). This work was funded by a grant (EADB) from the EU Joint Programme – Neurodegenerative Disease Research. INSERM UMR1167 is also funded by the INSERM, Institut Pasteur de Lille, Lille Métropole Communauté Urbaine and French government’s LABEX DISTALZ program (development of innovative strategies for a transdisciplinary approach to AD). Full consortium acknowledgements and funding are in the Supplementary Note.

Financiadores	Número del financiador
Institut national de la santé et de la recherche médicale
EU Joint Programme – Neurodegenerative Disease Research
Institute Pasteur De Lille
EADB
U.S. Department of Health & Human Services \| NIH \| National Institute on Aging (U.S. National Institute on Aging)	R01AG033193, RF1AG061872, RF1AG061351, R01AG035137, RC2AG036650, P30AG053760, R01AG013616, R56AG055824, R01AG062622, RC2AG036528, RF1AG059421, P30AG013854, P30AG028383, U24AG056270, P50AG016582, P50AG023501, U01AG006786, R01AG041797, P01AG066597, RF1AG057473, R01AG036042, R01AG041718, R37AG015473, R21AG063130, R01AG026916, P01AG019724, R01AG054076, U01AG006781, RF1AG057519, P50AG033514, R01AG028786, P30AG010133, U01AG049505, R01AG036836, R01AG017917, P30AG066530, R01AG023651, P01AG002219, R01AG033040, P01AG003949, U01AG032984, RC2AG036547, K08AG065463, R01AG049607, U01AG068880, P30AG062715, R01AG054005, R01AG032990, U24AG026395, P30AG010124, P30AG012300, U24AG072122, P30AG019610, P30AG010129, P30AG008051, R01AG020098, P50AG005144, R01AG023629, P50AG005146, R01AG048927, P50AG005142, K99AG066849, R01AG022018, P01AG026276, P30AG066509, U24AG021886, U01AG024904, R01AG019085, U01AG046139, R01AG025259, P30AG066514, U01AG016976, P30AG066512, P30AG066511, P01AG010491, F99AG073565, U01AG058654, P50AG025711, R01AG048015, P50AG005133, R01AG042437, P50AG005134, R01AG012101, P30AG072980, P50AG005131, P01AG017216, R01AG037985, U01AG052409, R01AG027944, P30AG062422, P30AG072976, P30AG066462, P30AG072977, P50AG005136, R01AG022374, P50AG025688, P50AG005138, P30AG072979, R01AG041232, P30AG072972, R01AG011101, R01AG021547, U01AG046161, P50AG005681, P01AG017586, U01AG061356, P30AG028377, R56AG057191, R01AG030146, R01AG037212, P50AG016573, P50AG016574, P30AG013846, R01AG030653, P50AG016570, R01AG009029, R01AG015819, RC2AG036502, R01AG019757, R01AG020688, R01AG018023, U19AG062418, ZIAAG007270, U01AG046152, R01AG017173, P30AG008017, R01AG031581, R01AG009956, P30AG010161, U24AG041689, P01AG003991, P30AG066444, U19AG068753, P50AG008702
National Heart, Lung, and Blood Institute (NHLBI)	U01HL080295, R01HL105756, R01HL085083, R01HL120393, R01HL103612, U01HL130114, R01HL087652
Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke Council	U24NS072026, UH2NS100605, R01NS017950, R01NS080820, R01NS059873, R01NS118146, P50NS039764
National Institute of Mental Health, National Institutes of Health	R01MH080295
National Center for Research Resources	KL2RR024151, UL1RR029893
Nederlandse Hersenbank	61054
National Childhood Cancer Registry – National Cancer Institute	R01CA129769
National Human Genome Research Institute	U01HG008657, U01HG006375, U01HG004610
UK Medical Research Council, Engineering and Physical Sciences Research Council	MR/K013041/1, MR/L501529/1, MR/L501517/1
National Center for Advancing Translational Sciences (NCATS)	UL1TR001445
National Institute on Minority Health and Disparities	P20MD000546
National Institute of Diabetes and Digestive and Kidney Diseases	P30DK063491
???publication-publication-funding-organisation-not-added???	R10HL025195
National Eye Institute/National Institutes of Health	T32EY007157

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10.1038/s41588-022-01024-z

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title = "New insights into the genetic etiology of Alzheimer{\textquoteright}s disease and related dementias",

abstract = "Characterization of the genetic landscape of Alzheimer{\textquoteright}s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/{\textquoteleft}proxy{\textquoteright} AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.",

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doi = "10.1038/s41588-022-01024-z",

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N2 - Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.

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New insights into the genetic etiology of Alzheimer’s disease and related dementias

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Nota bibliográfica

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