Whole-genome sequencing suggests a chemokine gene cluster that modifies age at onset in familial Alzheimer's disease

Molecular Psychiatry
Matthew A LalliK S Kosik

Abstract

We have sequenced the complete genomes of 72 individuals affected with early-onset familial Alzheimer's disease caused by an autosomal dominant, highly penetrant mutation in the presenilin-1 (PSEN1) gene, and performed genome-wide association testing to identify variants that modify age at onset (AAO) of Alzheimer's disease. Our analysis identified a haplotype of single-nucleotide polymorphisms (SNPs) on chromosome 17 within a chemokine gene cluster associated with delayed onset of mild-cognitive impairment and dementia. Individuals carrying this haplotype had a mean AAO of mild-cognitive impairment at 51.0 ± 5.2 years compared with 41.1 ± 7.4 years for those without these SNPs. This haplotype thus appears to modify Alzheimer's AAO, conferring a large (~10 years) protective effect. The associated locus harbors several chemokines including eotaxin-1 encoded by CCL11, and the haplotype includes a missense polymorphism in this gene. Validating this association, we found plasma eotaxin-1 levels were correlated with disease AAO in an independent cohort from the University of California San Francisco Memory and Aging Center. In this second cohort, the associated haplotype disrupted the typical age-associated increase of eotaxin-1 lev...Continue Reading

References

Mar 12, 1997·JAMA : the Journal of the American Medical Association·F LoperaK S Kosik
Jan 1, 1997·Annual Review of Immunology·M BaggioliniB Moser
Apr 15, 1999·Annual Review of Neuroscience·F González-Scarano, G Baltuch
Dec 29, 1999·Human Mutation·M KrawczakD N Cooper
Mar 5, 2002·American Journal of Human Genetics·Yi-Ju LiMargaret A Pericak-Vance
Mar 7, 2002·American Journal of Physiology. Lung Cellular and Molecular Physiology·Paul E MooreStephanie A Shore
Nov 16, 2002·Archives of Neurology·Walter A KukullEric B Larson
Jun 26, 2003·Nucleic Acids Research·Pauline C Ng, Steven Henikoff
Aug 2, 2003·Annals of Neurology·Pau PastorAlison M Goate
Mar 3, 2004·Annals of Neurology·William E KlunkBengt Långström
Jan 10, 2008·European Journal of Human Genetics : EJHG·Peter M VisscherDale R Nyholt
Feb 27, 2008·Genetic Epidemiology·Frank Dudbridge, Arief Gusnanto
Jan 9, 2010·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Susanne B Haga
Apr 8, 2010·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Tomomi KiyotaTsuneya Ikezu
May 27, 2010·Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine·Dean F WongMichael J Pontecorvo
Aug 4, 2010·Journal of Neuroimmunology·Grégory ConductierCarole Rovère
Oct 1, 2011·Nature Methods·Thomas Nordahl PetersenHenrik Nielsen
Oct 4, 2011·Bioinformatics·Gustavo GlusmanJared C Roach
Jul 26, 2012·Human Mutation·Matthew A LalliFrancisco Lopera
Nov 16, 2012·The New England Journal of Medicine·Thorlakur JonssonKari Stefansson
Nov 16, 2012·The New England Journal of Medicine·Rita GuerreiroUNKNOWN Alzheimer Genetic Analysis Group
Nov 28, 2012·Nature Reviews. Neurology·Dimitrije Krstic, Irene Knuesel
Apr 24, 2013·Bioinformatics·Kenneth LangeEric M Sobel
Jun 20, 2014·Science Translational Medicine·Andrew W LoKenneth S Kosik
Sep 5, 2014·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Ye ZhangJian Qian Wu
Mar 21, 2015·Lancet Neurology·Michael T HenekaMarkus P Kummer

❮ Previous
Next ❯

Citations

Dec 15, 2015·BioMed Research International·Vincenza PreconeValeria D'Argenio
Apr 7, 2016·Annual Review of Neuroscience·Carlo Sala Frigerio, Bart De Strooper
Mar 27, 2016·Alzheimer's & Dementia : the Journal of the Alzheimer's Association·Rita CacaceChristine Van Broeckhoven
Apr 27, 2017·PloS One·Pietro Paolo SannaCeline Lefebvre
Oct 19, 2017·Genes, Brain, and Behavior·E E BlueE M Wijsman
Mar 29, 2019·Journal of Applied Microbiology·M Bostanciklioğlu
Nov 11, 2016·Nature·Tony Wyss-Coray
Jul 28, 2016·Alzheimer's & Dementia : Diagnosis, Assessment & Disease Monitoring·Brianne M BettcherJoel H Kramer
Feb 24, 2017·Biomolecular Concepts·Marta BolósJesús Avila
Nov 7, 2019·Nature Medicine·Joseph F Arboleda-VelasquezYakeel T Quiroz
Apr 6, 2020·Journal of Neural Transmission·Jochen OhnmachtRejko Krüger
Oct 21, 2015·Genome Medicine·Rita Guerreiro, Jose Bras
Apr 25, 2020·Neurological Sciences : Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology·I PiaceriB Nacmias
Oct 21, 2016·Alzheimer's Research & Therapy·Rinko GrewalMaj-Linda B Selenica
Apr 3, 2020·International Journal of Molecular Sciences·Chen-Ling GanTae Ho Lee
Dec 15, 2020·Neurochemistry International·Michael VoronkovJeffry B Stock
Dec 16, 2020·Acta Neuropathologica·Diego Sepulveda-FallaMarkus Glatzel
Mar 1, 2019·Current Genetic Medicine Reports·Shea J AndrewsAlison Goate
Apr 16, 2021·Neurological Sciences : Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology·Gamze GuvenBasar Bilgic
Aug 22, 2021·Brain, Behavior, and Immunity·Gaia ScabiaUNKNOWN “Train the Brain” Consortium
Nov 25, 2020·Current Gene Therapy·Md Sahab UddinGhulam Md Ashraf

❮ Previous
Next ❯

Methods Mentioned

BETA
exome sequencing
transfection
genotyping

Software Mentioned

ANNOVAR
Complete Genomics
Mendel
SAS
SIFT
Complete
Discover Workbench
PLINK
CADD

Related Concepts

Related Feeds

Alzheimer's Disease: Genetics

Alzheimer's disease is a neurodegenerative disease. Discover genetic and epigenetic aspects of Alzheimer’s disease, including genetic markers and genomic structural variations with this feed.

Related Papers

Dementia and Geriatric Cognitive Disorders
Takanori IshizukaAkira Sano
Neurological Sciences : Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology
Sandro MariniBenedetta Nacmias
Neurología : publicación oficial de la Sociedad Española de Neurología
A LladóJ L Molinuevo
© 2021 Meta ULC. All rights reserved