New insights into the genetic etiology of Alzheimer?s disease and related dementia

BELLENGUEZ, C; KUCUCALLI, F; JANSEN, I; KLEINEIDAM, L; MORENO-GRAU, SONIA; AMIN, N; NAJ, AC; CAMPOS MARTIN, R; DALMASSO, MC; RUIZ A; RAMIREZ, A; LAMBERT, J-C

NATURE GENETICS

NATURE PUBLISHING GROUP

Lugar: Londres; Año: 2022

1061-4036

Deciphering thegenetic landscape of Alzheimer?s disease (AD) is a unique opportunity to betterunderstand pathophysiological processes of the disease. We performed agenome-wide association study (GWAS) on a new dataset including 20,464clinically-diagnosed AD cases and 22,244 controls, and completed ameta-analysis with existing GWAS, totaling 39,106 clinically-diagnosed AD cases,46,828 proxy-AD cases and 401,577 controls. The most promising signals were followed-up in25,392 clinically-diagnosed AD cases and 276,086 controls. We report 75 risk loci for AD,including 42 novel ones. Pathway-enrichment analyses confirm the involvementof amyloid/Tau pathways and highlight microglia implication. Systematicgene prioritization in novel loci prioritized 32 genes that imply newgenetically-associated processes including TNF-apathway through LUBAC complex. We generated a novel genetic risk score(GRS) associated with the risk of future AD/dementia or progression from mildcognitive impairment to AD/dementia. The cumulative improvements in riskprediction by this GRS lead to anadditional 1.6 to 1.9-fold increase in AD risk from the lowest to the highestdecile on top of effects of age and APOEe4 allele. In conclusion, by more than doubling thenumber of loci associated with AD risk, our study offers new insights into theAD pathophysiological processes and offers additionaltherapeutic entry-points and tools for translational genomics.@font-face{font-family:Helvetica;panose-1:0 0 0 0 0 0 0 0 0 0;mso-font-charset:0;mso-generic-font-family:auto;mso-font-pitch:variable;mso-font-signature:-536870145 1342208091 0 0 415 0;}@font-face{font-family:"Cambria Math";panose-1:2 4 5 3 5 4 6 3 2 4;mso-font-charset:0;mso-generic-font-family:roman;mso-font-pitch:variable;mso-font-signature:-536870145 1107305727 0 0 415 0;}@font-face{font-family:Calibri;panose-1:2 15 5 2 2 2 4 3 2 4;mso-font-charset:204;mso-generic-font-family:swiss;mso-font-pitch:variable;mso-font-signature:-536858881 -1073732485 9 0 511 0;}p.MsoNormal, li.MsoNormal, div.MsoNormal{mso-style-unhide:no;mso-style-qformat:yes;mso-style-parent:"";margin-top:0cm;margin-right:0cm;margin-bottom:10.0pt;margin-left:0cm;line-height:115%;mso-pagination:widow-orphan;mso-hyphenate:none;font-size:11.0pt;font-family:"Calibri",sans-serif;mso-ascii-font-family:Calibri;mso-ascii-theme-font:minor-latin;mso-fareast-font-family:Calibri;mso-fareast-theme-font:minor-latin;mso-hansi-font-family:Calibri;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:Calibri;mso-bidi-theme-font:minor-bidi;mso-ansi-language:FR;mso-fareast-language:EN-US;}.MsoChpDefault{mso-style-type:export-only;mso-default-props:yes;font-size:10.0pt;mso-ansi-font-size:10.0pt;mso-bidi-font-size:11.0pt;font-family:"Calibri",sans-serif;mso-ascii-font-family:Calibri;mso-ascii-theme-font:minor-latin;mso-fareast-font-family:Calibri;mso-fareast-theme-font:minor-latin;mso-hansi-font-family:Calibri;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:Calibri;mso-bidi-theme-font:minor-bidi;mso-ansi-language:FR;mso-fareast-language:EN-US;}.MsoPapDefault{mso-style-type:export-only;mso-hyphenate:none;}div.WordSection1{page:WordSection1;}