Genome-wide, high-content siRNA screening identifies the Alzheimer’s genetic risk factor FERMT2 as a major modulator of APP metabolism

ADGC, Alzheimer’s Disease Neuroimaging Initiative

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Genome-wide association studies (GWASs) have identified 19 susceptibility loci for Alzheimer’s disease (AD). However, understanding how these genes are involved in the pathophysiology of AD is one of the main challenges of the “post-GWAS” era. At least 123 genes are located within the 19 susceptibility loci; hence, a conventional approach (studying the genes one by one) would not be time- and cost-effective. We therefore developed a genome-wide, high-content siRNA screening approach and used it to assess the functional impact of gene under-expression on APP metabolism. We found that 832 genes modulated APP metabolism. Eight of these genes were located within AD susceptibility loci. Only FERMT2 (a β3-integrin co-activator) was also significantly associated with a variation in cerebrospinal fluid Aβ peptide levels in 2886 AD cases. Lastly, we showed that the under-expression of FERMT2 increases Aβ peptide production by raising levels of mature APP at the cell surface and facilitating its recycling. Taken as a whole, our data suggest that FERMT2 modulates the AD risk by regulating APP metabolism and Aβ peptide production.

Original languageEnglish (US)
Pages (from-to)955-966
Number of pages12
JournalActa Neuropathologica
Volume133
Issue number6
DOIs
StatePublished - Jun 1 2017

Fingerprint

Small Interfering RNA
Alzheimer Disease
Genome
Genes
Genome-Wide Association Study
Peptides
Disease Susceptibility
Recycling
Integrins
Cerebrospinal Fluid
Gene Expression
Costs and Cost Analysis

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Genome-wide, high-content siRNA screening identifies the Alzheimer’s genetic risk factor FERMT2 as a major modulator of APP metabolism. / ADGC, Alzheimer’s Disease Neuroimaging Initiative.

In: Acta Neuropathologica, Vol. 133, No. 6, 01.06.2017, p. 955-966.

Research output: Contribution to journalArticle

@article{932d329284c345e0bc407f82e9581f8e,
title = "Genome-wide, high-content siRNA screening identifies the Alzheimer’s genetic risk factor FERMT2 as a major modulator of APP metabolism",
abstract = "Genome-wide association studies (GWASs) have identified 19 susceptibility loci for Alzheimer’s disease (AD). However, understanding how these genes are involved in the pathophysiology of AD is one of the main challenges of the “post-GWAS” era. At least 123 genes are located within the 19 susceptibility loci; hence, a conventional approach (studying the genes one by one) would not be time- and cost-effective. We therefore developed a genome-wide, high-content siRNA screening approach and used it to assess the functional impact of gene under-expression on APP metabolism. We found that 832 genes modulated APP metabolism. Eight of these genes were located within AD susceptibility loci. Only FERMT2 (a β3-integrin co-activator) was also significantly associated with a variation in cerebrospinal fluid Aβ peptide levels in 2886 AD cases. Lastly, we showed that the under-expression of FERMT2 increases Aβ peptide production by raising levels of mature APP at the cell surface and facilitating its recycling. Taken as a whole, our data suggest that FERMT2 modulates the AD risk by regulating APP metabolism and Aβ peptide production.",
author = "{ADGC, Alzheimer’s Disease Neuroimaging Initiative} and Julien Chapuis and Amandine Flaig and Benjamin Grenier-Boley and Fanny Eysert and Virginie Pottiez and Gaspard Deloison and Alexandre Vandeputte and Ayral, {Anne Marie} and Tiago Mendes and Shruti Desai and Goate, {Alison M.} and Kauwe, {John S.K.} and Florence Leroux and Adrien Herledan and Florie Demiautte and Charlotte Bauer and Fr{\'e}deric Checler and Petersen, {Ronald Carl} and Kaj Blennow and Henrik Zetterberg and Lennart Minthon and {Van Deerlin}, {Vivianna M.} and Lee, {Virginia Man Yee} and Shaw, {Leslie M.} and Trojanowski, {John Q.} and Marilyn Albert and Abhay Moghekar and Richard O’Brien and Peskind, {Elaine R.} and Nicolas Malmanche and Schellenberg, {Gerard D.} and Pierre Dourlen and Song, {Ok Ryul} and Carlos Cruchaga and Philippe Amouyel and Benoit Deprez and Priscille Brodin and Lambert, {Jean Charles}",
year = "2017",
month = "6",
day = "1",
doi = "10.1007/s00401-016-1652-z",
language = "English (US)",
volume = "133",
pages = "955--966",
journal = "Acta Neuropathologica",
issn = "0001-6322",
publisher = "Springer Verlag",
number = "6",

}

TY - JOUR

T1 - Genome-wide, high-content siRNA screening identifies the Alzheimer’s genetic risk factor FERMT2 as a major modulator of APP metabolism

AU - ADGC, Alzheimer’s Disease Neuroimaging Initiative

AU - Chapuis, Julien

AU - Flaig, Amandine

AU - Grenier-Boley, Benjamin

AU - Eysert, Fanny

AU - Pottiez, Virginie

AU - Deloison, Gaspard

AU - Vandeputte, Alexandre

AU - Ayral, Anne Marie

AU - Mendes, Tiago

AU - Desai, Shruti

AU - Goate, Alison M.

AU - Kauwe, John S.K.

AU - Leroux, Florence

AU - Herledan, Adrien

AU - Demiautte, Florie

AU - Bauer, Charlotte

AU - Checler, Fréderic

AU - Petersen, Ronald Carl

AU - Blennow, Kaj

AU - Zetterberg, Henrik

AU - Minthon, Lennart

AU - Van Deerlin, Vivianna M.

AU - Lee, Virginia Man Yee

AU - Shaw, Leslie M.

AU - Trojanowski, John Q.

AU - Albert, Marilyn

AU - Moghekar, Abhay

AU - O’Brien, Richard

AU - Peskind, Elaine R.

AU - Malmanche, Nicolas

AU - Schellenberg, Gerard D.

AU - Dourlen, Pierre

AU - Song, Ok Ryul

AU - Cruchaga, Carlos

AU - Amouyel, Philippe

AU - Deprez, Benoit

AU - Brodin, Priscille

AU - Lambert, Jean Charles

PY - 2017/6/1

Y1 - 2017/6/1

N2 - Genome-wide association studies (GWASs) have identified 19 susceptibility loci for Alzheimer’s disease (AD). However, understanding how these genes are involved in the pathophysiology of AD is one of the main challenges of the “post-GWAS” era. At least 123 genes are located within the 19 susceptibility loci; hence, a conventional approach (studying the genes one by one) would not be time- and cost-effective. We therefore developed a genome-wide, high-content siRNA screening approach and used it to assess the functional impact of gene under-expression on APP metabolism. We found that 832 genes modulated APP metabolism. Eight of these genes were located within AD susceptibility loci. Only FERMT2 (a β3-integrin co-activator) was also significantly associated with a variation in cerebrospinal fluid Aβ peptide levels in 2886 AD cases. Lastly, we showed that the under-expression of FERMT2 increases Aβ peptide production by raising levels of mature APP at the cell surface and facilitating its recycling. Taken as a whole, our data suggest that FERMT2 modulates the AD risk by regulating APP metabolism and Aβ peptide production.

AB - Genome-wide association studies (GWASs) have identified 19 susceptibility loci for Alzheimer’s disease (AD). However, understanding how these genes are involved in the pathophysiology of AD is one of the main challenges of the “post-GWAS” era. At least 123 genes are located within the 19 susceptibility loci; hence, a conventional approach (studying the genes one by one) would not be time- and cost-effective. We therefore developed a genome-wide, high-content siRNA screening approach and used it to assess the functional impact of gene under-expression on APP metabolism. We found that 832 genes modulated APP metabolism. Eight of these genes were located within AD susceptibility loci. Only FERMT2 (a β3-integrin co-activator) was also significantly associated with a variation in cerebrospinal fluid Aβ peptide levels in 2886 AD cases. Lastly, we showed that the under-expression of FERMT2 increases Aβ peptide production by raising levels of mature APP at the cell surface and facilitating its recycling. Taken as a whole, our data suggest that FERMT2 modulates the AD risk by regulating APP metabolism and Aβ peptide production.

UR - http://www.scopus.com/inward/record.url?scp=85028025956&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85028025956&partnerID=8YFLogxK

U2 - 10.1007/s00401-016-1652-z

DO - 10.1007/s00401-016-1652-z

M3 - Article

C2 - 27933404

AN - SCOPUS:85028025956

VL - 133

SP - 955

EP - 966

JO - Acta Neuropathologica

JF - Acta Neuropathologica

SN - 0001-6322

IS - 6

ER -