title: Overrepresentation of glutamate signaling in Alzheimer's disease: network-based pathway enrichment using meta-analysis of genome-wide association studies.
abstract: Genome-wide association studies (GWAS) have successfully identified several risk loci for Alzheimer's disease (AD). Nonetheless, these loci do not explain the entire susceptibility of the disease, suggesting that other genetic contributions remain to be identified. Here, we performed a meta-analysis combining data of 4,569 individuals (2,540 cases and 2,029 healthy controls) derived from three publicly available GWAS in AD and replicated a broad genomic region (>248,000 bp) associated with the disease near the APOE/TOMM40 locus in chromosome 19. To detect minor effect size contributions that could help to explain the remaining genetic risk, we conducted network-based pathway analyses either by extracting gene-wise p-values (GW), defined as the single strongest association signal within a gene, or calculated a more stringent gene-based association p-value using the extended Simes (GATES) procedure. Comparison of these strategies revealed that ontological sub-networks (SNs) involved in glutamate signaling were significantly overrepresented in AD (p<2.7×10(-11), p<1.9×10(-11); GW and GATES, respectively). Notably, glutamate signaling SNs were also found to be significantly overrepresented (p<5.1×10(-8)) in the Alzheimer's disease Neuroimaging Initiative (ADNI) study, which was used as a targeted replication sample. Interestingly, components of the glutamate signaling SNs are coordinately expressed in disease-related tissues, which are tightly related to known pathological hallmarks of AD. Our findings suggest that genetic variation within glutamate signaling contributes to the remaining genetic risk of AD and support the notion that functional biological networks should be targeted in future therapies aimed to prevent or treat this devastating neurological disorder.
authors.affiliation: Center for Biomedical Research and FONDAP Center for Genome Regulation, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello, Santiago, Chile.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Pérez-Palma
authors.affiliation: Center for Biomedical Research and FONDAP Center for Genome Regulation, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello, Santiago, Chile.
authors.forename: Bernabé I
authors.initials: BI
authors.lastname: Bustos
authors.affiliation: Center for Biomedical Research and FONDAP Center for Genome Regulation, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello, Santiago, Chile.
authors.forename: Camilo F
authors.initials: CF
authors.lastname: Villamán
authors.affiliation: Center for Biomedical Research and FONDAP Center for Genome Regulation, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello, Santiago, Chile; Faculty of Biological Sciences, Universidad de Concepción, Concepción, Chile.
authors.forename: Marcelo A
authors.initials: MA
authors.lastname: Alarcón
authors.affiliation: Center for Biomedical Research and FONDAP Center for Genome Regulation, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello, Santiago, Chile; Faculty of Biological Sciences, Universidad de Concepción, Concepción, Chile.
authors.forename: Miguel E
authors.initials: ME
authors.lastname: Avila
authors.affiliation: Center for Biomedical Research and FONDAP Center for Genome Regulation, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello, Santiago, Chile.
authors.forename: Giorgia D
authors.initials: GD
authors.lastname: Ugarte
authors.affiliation: Center for Biomedical Research and FONDAP Center for Genome Regulation, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello, Santiago, Chile.
authors.forename: Ariel E
authors.initials: AE
authors.lastname: Reyes
authors.affiliation: Oxidation Biology Laboratory, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Australia.
authors.forename: Carlos
authors.initials: C
authors.lastname: Opazo
authors.affiliation: Center for Biomedical Research and FONDAP Center for Genome Regulation, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello, Santiago, Chile.
authors.forename: Giancarlo V
authors.initials: GV
authors.lastname: De Ferrari
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D063990:Gene Ontology; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study; D005971:Glutamates / Q000378:metabolism*; D006801:Humans; D059906:Neuroimaging; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000235:genetics*; D013569:Synapses / Q000378:metabolism
chemical_list: D005971:Glutamates
references.citation: Nat Protoc. 2007;2(10):2366-82
references.pmid: 17947979
references.citation: Neurosurg Focus. 2010 Jan;28(1):E2
references.pmid: 20043717
references.citation: Hum Mol Genet. 2009 Jun 1;18(11):2078-90
references.pmid: 19286671
references.citation: Arch Neurol. 2012 Oct;69(10):1270-9
references.pmid: 22869155
references.citation: Neurology. 1993 Aug;43(8):1467-72
references.pmid: 8350998
references.citation: Nat Genet. 2009 Oct;41(10):1094-9
references.pmid: 19734903
references.citation: Control Clin Trials. 1986 Sep;7(3):177-88
references.pmid: 3802833
references.citation: Ann Hum Genet. 2004 Jul;68(Pt 4):381-404
references.pmid: 15225164
references.citation: Nat Genet. 2013 Dec;45(12):1452-8
references.pmid: 24162737
references.citation: BMC Bioinformatics. 2011 Aug 04;12:322
references.pmid: 21816037
references.citation: Adv Pharmacol. 2012;64:303-25
references.pmid: 22840751
references.citation: Genetics. 2005 Oct;171(2):813-23
references.pmid: 16020784
references.citation: Nat Genet. 1998 Aug;19(4):321-2
references.pmid: 9697689
references.citation: Nat Genet. 2007 Oct;39(10):1181-6
references.pmid: 17898773
references.citation: Arch Neurol. 2008 Nov;65(11):1518-26
references.pmid: 19001172
references.citation: PLoS Med. 2009 Jul 21;6(7):e1000097
references.pmid: 19621072
references.citation: Nucleic Acids Res. 2004 Jan 1;32(Database issue):D258-61
references.pmid: 14681407
references.citation: Nat Genet. 2011 May;43(5):429-35
references.pmid: 21460840
references.citation: Nat Genet. 2009 Oct;41(10):1088-93
references.pmid: 19734902
references.citation: Bioinformatics. 2007 Nov 15;23(22):3024-31
references.pmid: 17848398
references.citation: Neurobiol Dis. 2005 Nov;20(2):187-98
references.pmid: 16242627
references.citation: J Psychiatry Neurosci. 2013 Jan;38(1):6-23
references.pmid: 22894822
references.citation: Brain Imaging Behav. 2012 Dec;6(4):634-48
references.pmid: 22865056
references.citation: Schizophr Bull. 2012 Sep;38(5):927-35
references.pmid: 22532703
references.citation: Science. 2002 Jul 19;297(5580):353-6
references.pmid: 12130773
references.citation: Apoptosis. 2009 Apr;14(4):455-68
references.pmid: 19130231
references.citation: PLoS Genet. 2011 Feb;7(2):e1001308
references.pmid: 21379329
references.citation: Nucleic Acids Res. 2004 Jan 1;32(Database issue):D493-6
references.pmid: 14681465
references.citation: Genomics. 2008 Nov;92(5):265-72
references.pmid: 18722519
references.citation: Bioinformatics. 2004 Nov 22;20(17):3246-8
references.pmid: 15180930
references.citation: Nature. 2005 Oct 27;437(7063):1299-320
references.pmid: 16255080
references.citation: Genet Epidemiol. 2010 Dec;34(8):816-34
references.pmid: 21058334
references.citation: Genome Biol. 2012 Jul 18;13(7):R62
references.pmid: 22809392
references.citation: Neurology. 2011 Jan 25;76(4):397-404
references.pmid: 21263141
references.citation: Nature. 2012 Sep 20;489(7416):391-399
references.pmid: 22996553
references.citation: Neuron. 2007 Jun 7;54(5):713-20
references.pmid: 17553421
references.citation: Nucleic Acids Res. 2010 Jul;38(Web Server issue):W214-20
references.pmid: 20576703
references.citation: Neurobiol Aging. 2012 Mar;33(3):437-56
references.pmid: 20594621
references.citation: Trends Cell Biol. 2011 Oct;21(10):594-603
references.pmid: 21840719
references.citation: J Neurosci. 2007 Mar 14;27(11):2866-75
references.pmid: 17360908
references.citation: J Neurol Neurosurg Psychiatry. 2005 Sep;76(9):1286-8
references.pmid: 16107369
references.citation: In Silico Biol. 2005;5(4):419-23
references.pmid: 16268787
references.citation: PLoS One. 2011 Feb 24;6(2):e16616
references.pmid: 21390209
references.citation: Nucleic Acids Res. 2011 Jan;39(Database issue):D561-8
references.pmid: 21045058
references.citation: PLoS Genet. 2012 Jul;8(7):e1002812
references.pmid: 22792080
references.citation: Mech Ageing Dev. 2011 Aug;132(8-9):405-11
references.pmid: 21729715
references.citation: J Clin Psychiatry. 2007 Apr;68(4):613-8
references.pmid: 17474819
references.citation: Am J Hum Genet. 2011 Mar 11;88(3):283-93
references.pmid: 21397060
references.citation: Am J Hum Genet. 2007 Sep;81(3):559-75
references.pmid: 17701901
references.citation: Neurology. 2009 Sep 15;73(11):847-53
references.pmid: 19752451
references.citation: Nat Rev Neurol. 2012 Mar 13;8(4):189-202
references.pmid: 22410582
references.citation: J Clin Epidemiol. 1991;44(2):127-39
references.pmid: 1995774
references.citation: Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1977-81
references.pmid: 8446617
references.citation: Pharmacogenomics J. 2010 Oct;10(5):375-84
references.pmid: 20029386
references.citation: Med Decis Making. 2005 Nov-Dec;25(6):646-54
references.pmid: 16282215
references.citation: Nat Genet. 2006 Aug;38(8):904-9
references.pmid: 16862161
references.citation: Alzheimers Dement. 2010 May;6(3):239-46
references.pmid: 20451872
references.citation: Nat Genet. 2007 Jan;39(1):17-23
references.pmid: 17192785
references.citation: Arch Neurol. 2011 Aug;68(8):1013-9
references.pmid: 21825236
references.citation: Genome Med. 2011 May 31;3(5):33
references.pmid: 21627779
references.citation: Bioinformatics. 2002;18 Suppl 1:S233-40
references.pmid: 12169552
references.citation: Nucleic Acids Res. 2000 Jan 1;28(1):27-30
references.pmid: 10592173
references.citation: Adv Genet. 2010;72:141-79
references.pmid: 21029852
references.citation: Hum Mol Genet. 2010 Apr 15;19(R1):R4-R11
references.pmid: 20388643
references.citation: J Alzheimers Dis. 2011;23(1):49-59
references.pmid: 20930298
references.citation: World J Gastroenterol. 2009 Nov 21;15(43):5377-96
references.pmid: 19916168
references.citation: Ann N Y Acad Sci. 2008 Nov;1144:97-112
references.pmid: 19076369