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• Genetic variation in PCDH11X is associated with susceptibility to late-onset Alzheimer's disease.
• Citation:
  Carrasquillo M, Zou F, Pankratz V, Wilcox S, Ma L, Walker L, Younkin S, Younkin C, Younkin L, Bisceglio G, Ertekin-Taner N, Crook J, Dickson D, Petersen R, Graff-Radford N, Younkin S
  

  Genetic variation in PCDH11X is associated with susceptibility to late-onset Alzheimer's disease.

  Nature genetics. 2009 Feb;41(2):192-8
  [PubMed] [Alzforum]
• Supporting:
  • The PCDH11X gene was previously found to be a genetic determinant of AD in GWAS; however, none of the SNPs in the PCDH11X locus reached a suggestive level of significance in the French cohort, suggesting that this locus may also contribute to the Alzheimer’s disease risk but not as significantly as CLU or CR1.

    SHOW Details   Supporting(1)     Genes/Proteins: (1)

    Experimental Approach: Genetics
    Pathogenic Narrative Tags: Initial condition
    Supporting Evidence
    

    • Carrasquillo M, Zou F, Pankratz V, Wilcox S, Ma L, Walker L, Younkin S, Younkin C, Younkin L, Bisceglio G, Ertekin-Taner N, Crook J, Dickson D, Petersen R, Graff-Radford N, Younkin S
      Genetic variation in PCDH11X is associated with susceptibility to late-onset Alzheimer's disease.
      Nature genetics. 2009 Feb;41(2):192-8

    Genes/Proteins
    

    • Gene: PCDH11X protocadherin 11 X-linked [Homo sapiens]
  • All previous genome-wide association studies (GWAS) which have all included fewer than 1,100 cases have identified strong evidence for Alzheimer’s disease risk association to APOE but have found less convincing evidence implicating other genes.

    SHOW Details   Supporting(9)     Genes/Proteins: (1)

    Experimental Approach: Genetics
    Pathogenic Narrative Tags: Initial condition
    Supporting Evidence
    

    • Coon K, Myers A, Craig D, Webster J, Pearson J, Lince D, Zismann V, Beach T, Leung D, Bryden L, Halperin R, Marlowe L, Kaleem M, Walker D, Ravid R, Heward C, Rogers J, Papassotiropoulos A, Reiman E, Hardy J, Stephan D
      A high-density whole-genome association study reveals that APOE is the major susceptibility gene for sporadic late-onset Alzheimer's disease.
      The Journal of clinical psychiatry. 2007 Apr;68(4):613-8
    • 
      Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls.
      Nature. 2007 Jun 7;447(7145):661-78
    • Carrasquillo M, Zou F, Pankratz V, Wilcox S, Ma L, Walker L, Younkin S, Younkin C, Younkin L, Bisceglio G, Ertekin-Taner N, Crook J, Dickson D, Petersen R, Graff-Radford N, Younkin S
      Genetic variation in PCDH11X is associated with susceptibility to late-onset Alzheimer's disease.
      Nature genetics. 2009 Feb;41(2):192-8
    • Li H, Wetten S, Li L, St Jean P, Upmanyu R, Surh L, Hosford D, Barnes M, Briley J, Borrie M, Coletta N, Delisle R, Dhalla D, Ehm M, Feldman H, Fornazzari L, Gauthier S, Goodgame N, Guzman D, Hammond S, Hollingworth P, Hsiung G, Johnson J, Kelly D, Keren R, Kertesz A, King K, Lovestone S, Loy-English I, Matthews P, Owen M, Plumpton M, Pryse-Phillips W, Prinjha R, Richardson J, Saunders A, Slater A, St George-Hyslop P, Stinnett S, Swartz J, Taylor R, Wherrett J, Williams J, Yarnall D, Gibson R, Irizarry M, Middleton L, Roses A
      Candidate single-nucleotide polymorphisms from a genomewide association study of Alzheimer disease.
      Archives of neurology. 2008 Jan;65(1):45-53
    • Beecham G, Martin E, Li Y, Slifer M, Gilbert J, Haines J, Pericak-Vance M
      Genome-wide association study implicates a chromosome 12 risk locus for late-onset Alzheimer disease.
      American journal of human genetics. 2009 Jan;84(1):35-43
    • Reiman E, Webster J, Myers A, Hardy J, Dunckley T, Zismann V, Joshipura K, Pearson J, Hu-Lince D, Huentelman M, Craig D, Coon K, Liang W, Herbert R, Beach T, Rohrer K, Zhao A, Leung D, Bryden L, Marlowe L, Kaleem M, Mastroeni D, Grover A, Heward C, Ravid R, Rogers J, Hutton M, Melquist S, Petersen R, Alexander G, Caselli R, Kukull W, Papassotiropoulos A, Stephan D
      GAB2 alleles modify Alzheimer's risk in APOE epsilon4 carriers.
      Neuron. 2007 Jun 7;54(5):713-20
    • Bertram L, Lange C, Mullin K, Parkinson M, Hsiao M, Hogan M, Schjeide B, Hooli B, Divito J, Ionita I, Jiang H, Laird N, Moscarillo T, Ohlsen K, Elliott K, Wang X, Hu-Lince D, Ryder M, Murphy A, Wagner S, Blacker D, Becker K, Tanzi R
      Genome-wide association analysis reveals putative Alzheimer's disease susceptibility loci in addition to APOE.
      American journal of human genetics. 2008 Nov;83(5):623-32
    • Grupe A, Abraham R, Li Y, Rowland C, Hollingworth P, Morgan A, Jehu L, Segurado R, Stone D, Schadt E, Karnoub M, Nowotny P, Tacey K, Catanese J, Sninsky J, Brayne C, Rubinsztein D, Gill M, Lawlor B, Lovestone S, Holmans P, O'Donovan M, Morris J, Thal L, Goate A, Owen M, Williams J
      Evidence for novel susceptibility genes for late-onset Alzheimer's disease from a genome-wide association study of putative functional variants.
      Human molecular genetics. 2007 Apr 15;16(8):865-73
    • Abraham R, Moskvina V, Sims R, Hollingworth P, Morgan A, Georgieva L, Dowzell K, Cichon S, Hillmer A, O'Donovan M, Williams J, Owen M, Kirov G
      A genome-wide association study for late-onset Alzheimer's disease using DNA pooling.
      BMC medical genomics. 2008;1:44

    Genes/Proteins
    

    • Gene: APOE apolipoprotein E [Homo sapiens]
  • Genome-wide significant evidence for association with AD was reached at the APOE, CLU and PICALM loci, as well as for two novel loci on chromosomes 2 (rs744373, within 30 kb of the gene bridging integrator 1 (BIN1)) and 19 (rs597668) resulting from an international, racially restricted, 3-stage meta-analysis of several of the largest AD GWAS studies that includes CHARGE Consortium, Translational Genomics Research Institute (TGEN) public release database and the Mayo AD GWAS.

    SHOW Details   Supporting(6)   Consistent(7)     Genes/Proteins: (4)

    Experimental Approach: Genetics
    Pathogenic Narrative Tags: Initial condition
    Supporting Evidence
    

    • Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere M, Pahwa J, Moskvina V, Dowzell K, Williams A, Jones N, Thomas C, Stretton A, Morgan A, Lovestone S, Powell J, Proitsi P, Lupton M, Brayne C, Rubinsztein D, Gill M, Lawlor B, Lynch A, Morgan K, Brown K, Passmore P, Craig D, McGuinness B, Todd S, Holmes C, Mann D, Smith A, Love S, Kehoe P, Hardy J, Mead S, Fox N, Rossor M, Collinge J, Maier W, Jessen F, Schürmann B, van den Bussche H, Heuser I, Kornhuber J, Wiltfang J, Dichgans M, Frölich L, Hampel H, Hüll M, Rujescu D, Goate A, Kauwe J, Cruchaga C, Nowotny P, Morris J, Mayo K, Sleegers K, Bettens K, Engelborghs S, De Deyn P, Van Broeckhoven C, Livingston G, Bass N, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw C, Tsolaki M, Singleton A, Guerreiro R, Mühleisen T, Nöthen M, Moebus S, Jöckel K, Klopp N, Wichmann H, Carrasquillo M, Pankratz V, Younkin S, Holmans P, O'Donovan M, Owen M, Williams J
      Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease.
      Nature genetics. 2009 Oct;41(10):1088-93
    • Lambert J, Heath S, Even G, Campion D, Sleegers K, Hiltunen M, Combarros O, Zelenika D, Bullido M, Tavernier B, Letenneur L, Bettens K, Berr C, Pasquier F, Fiévet N, Barberger-Gateau P, Engelborghs S, De Deyn P, Mateo I, Franck A, Helisalmi S, Porcellini E, Hanon O, de Pancorbo M, Lendon C, Dufouil C, Jaillard C, Leveillard T, Alvarez V, Bosco P, Mancuso M, Panza F, Nacmias B, Bossù P, Piccardi P, Annoni G, Seripa D, Galimberti D, Hannequin D, Licastro F, Soininen H, Ritchie K, Blanché H, Dartigues J, Tzourio C, Gut I, Van Broeckhoven C, Alpérovitch A, Lathrop M, Amouyel P
      Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease.
      Nature genetics. 2009 Oct;41(10):1094-9
    • Carrasquillo M, Zou F, Pankratz V, Wilcox S, Ma L, Walker L, Younkin S, Younkin C, Younkin L, Bisceglio G, Ertekin-Taner N, Crook J, Dickson D, Petersen R, Graff-Radford N, Younkin S
      Genetic variation in PCDH11X is associated with susceptibility to late-onset Alzheimer's disease.
      Nature genetics. 2009 Feb;41(2):192-8
    • Seshadri S, Fitzpatrick A, Ikram M, DeStefano A, Gudnason V, Boada M, Bis J, Smith A, Carassquillo M, Lambert J, Harold D, Schrijvers E, Ramirez-Lorca R, Debette S, Longstreth W, Janssens A, Pankratz V, Dartigues J, Hollingworth P, Aspelund T, Hernandez I, Beiser A, Kuller L, Koudstaal P, Dickson D, Tzourio C, Abraham R, Antunez C, Du Y, Rotter J, Aulchenko Y, Harris T, Petersen R, Berr C, Owen M, Lopez-Arrieta J, Varadarajan B, Becker J, Rivadeneira F, Nalls M, Graff-Radford N, Campion D, Auerbach S, Rice K, Hofman A, Jonsson P, Schmidt H, Lathrop M, Mosley T, Au R, Psaty B, Uitterlinden A, Farrer L, Lumley T, Ruiz A, Williams J, Amouyel P, Younkin S, Wolf P, Launer L, Lopez O, van Duijn C, Breteler M
      Genome-wide analysis of genetic loci associated with Alzheimer disease.
      JAMA : the journal of the American Medical Association. 2010 May 12;303(18):1832-40
    • Reiman E, Webster J, Myers A, Hardy J, Dunckley T, Zismann V, Joshipura K, Pearson J, Hu-Lince D, Huentelman M, Craig D, Coon K, Liang W, Herbert R, Beach T, Rohrer K, Zhao A, Leung D, Bryden L, Marlowe L, Kaleem M, Mastroeni D, Grover A, Heward C, Ravid R, Rogers J, Hutton M, Melquist S, Petersen R, Alexander G, Caselli R, Kukull W, Papassotiropoulos A, Stephan D
      GAB2 alleles modify Alzheimer's risk in APOE epsilon4 carriers.
      Neuron. 2007 Jun 7;54(5):713-20
    • Psaty B, O'Donnell C, Gudnason V, Lunetta K, Folsom A, Rotter J, Uitterlinden A, Harris T, Witteman J, Boerwinkle E
      Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium: Design of prospective meta-analyses of genome-wide association studies from 5 cohorts.
      Circulation. Cardiovascular genetics. 2009 Feb;2(1):73-80

    Consistent statements
    

    • GWAS analysis identified two loci associated at a genome-wide level of significance including the APOE locus on chromosome 19, CLU (which encodes clusterin) on chromosome 8, and PICALM on chromosome 11 with meta-analysis of combined datasets producing highly significant evidence of AD risk association. Harold D  Abraham R  Hollingworth P  Sims R  Gerrish A  Hamshere M  Pahwa J  Moskvina V  Dowzell K  Williams A  Jones N  Thomas C  Stretton A  Morgan A  Lovestone S  Powell J  Proitsi P  Lupton M  Brayne C  Rubinsztein D  Gill M  Lawlor B  Lynch A  Morgan K  Brown K  Passmore P  Craig D  McGuinness B  Todd S  Holmes C  Mann D  Smith A  Love S  Kehoe P  Hardy J  Mead S  Fox N  Rossor M  Collinge J  Maier W  Jessen F  Schürmann B  van den Bussche H  Heuser I  Kornhuber J  Wiltfang J  Dichgans M  Frölich L  Hampel H  Hüll M  Rujescu D  Goate A  Kauwe J  Cruchaga C  Nowotny P  Morris J  Mayo K  Sleegers K  Bettens K  Engelborghs S  De Deyn P  Van Broeckhoven C  Livingston G  Bass N  Gurling H  McQuillin A  Gwilliam R  Deloukas P  Al-Chalabi A  Shaw C  Tsolaki M  Singleton A  Guerreiro R  Mühleisen T  Nöthen M  Moebus S  Jöckel K  Klopp N  Wichmann H  Carrasquillo M  Pankratz V  Younkin S  Holmans P  O'Donovan M  Owen M  Williams J 
    • Clusterin (ApoJ) and phosphatidylinositol binding clathrin assembly protein gene (PICALM) genes are associated with Late Onset AD. Harold D  Abraham R  Hollingworth P  Sims R  Gerrish A  Hamshere M  Pahwa J  Moskvina V  Dowzell K  Williams A  Jones N  Thomas C  Stretton A  Morgan A  Lovestone S  Powell J  Proitsi P  Lupton M  Brayne C  Rubinsztein D  Gill M  Lawlor B  Lynch A  Morgan K  Brown K  Passmore P  Craig D  McGuinness B  Todd S  Holmes C  Mann D  Smith A  Love S  Kehoe P  Hardy J  Mead S  Fox N  Rossor M  Collinge J  Maier W  Jessen F  Schürmann B  van den Bussche H  Heuser I  Kornhuber J  Wiltfang J  Dichgans M  Frölich L  Hampel H  Hüll M  Rujescu D  Goate A  Kauwe J  Cruchaga C  Nowotny P  Morris J  Mayo K  Sleegers K  Bettens K  Engelborghs S  De Deyn P  Van Broeckhoven C  Livingston G  Bass N  Gurling H  McQuillin A  Gwilliam R  Deloukas P  Al-Chalabi A  Shaw C  Tsolaki M  Singleton A  Guerreiro R  Mühleisen T  Nöthen M  Moebus S  Jöckel K  Klopp N  Wichmann H  Carrasquillo M  Pankratz V  Younkin S  Holmans P  O'Donovan M  Owen M  Williams J 
    • Outside of APOE, one marker (rs11136000) within CLU on chromosome 8p21-p12 showed statistical significance in the GWAS test that has also been noted in meta-analysis of linkage studies of Alzheimer Disease. Lambert J  Heath S  Even G  Campion D  Sleegers K  Hiltunen M  Combarros O  Zelenika D  Bullido M  Tavernier B  Letenneur L  Bettens K  Berr C  Pasquier F  Fiévet N  Barberger-Gateau P  Engelborghs S  De Deyn P  Mateo I  Franck A  Helisalmi S  Porcellini E  Hanon O  de Pancorbo M  Lendon C  Dufouil C  Jaillard C  Leveillard T  Alvarez V  Bosco P  Mancuso M  Panza F  Nacmias B  Bossù P  Piccardi P  Annoni G  Seripa D  Galimberti D  Hannequin D  Licastro F  Soininen H  Ritchie K  Blanché H  Dartigues J  Tzourio C  Gut I  Van Broeckhoven C  Alpérovitch A  Lathrop M  Amouyel P 
    • Additional and larger GWAS may be required to identify remaining susceptibility variants for Alzheimer’s disease since many SNPs were observed which, although failing to reach this level of statistical significance, might still reflect true associations with Alzheimer’s disease: for example, variants at the CR1 locus. Harold D  Abraham R  Hollingworth P  Sims R  Gerrish A  Hamshere M  Pahwa J  Moskvina V  Dowzell K  Williams A  Jones N  Thomas C  Stretton A  Morgan A  Lovestone S  Powell J  Proitsi P  Lupton M  Brayne C  Rubinsztein D  Gill M  Lawlor B  Lynch A  Morgan K  Brown K  Passmore P  Craig D  McGuinness B  Todd S  Holmes C  Mann D  Smith A  Love S  Kehoe P  Hardy J  Mead S  Fox N  Rossor M  Collinge J  Maier W  Jessen F  Schürmann B  van den Bussche H  Heuser I  Kornhuber J  Wiltfang J  Dichgans M  Frölich L  Hampel H  Hüll M  Rujescu D  Goate A  Kauwe J  Cruchaga C  Nowotny P  Morris J  Mayo K  Sleegers K  Bettens K  Engelborghs S  De Deyn P  Van Broeckhoven C  Livingston G  Bass N  Gurling H  McQuillin A  Gwilliam R  Deloukas P  Al-Chalabi A  Shaw C  Tsolaki M  Singleton A  Guerreiro R  Mühleisen T  Nöthen M  Moebus S  Jöckel K  Klopp N  Wichmann H  Carrasquillo M  Pankratz V  Younkin S  Holmans P  O'Donovan M  Owen M  Williams J 
    • Clusterin (ApoJ) and Complement component receptor CR1 genes are associated with Late Onset AD. Lambert J  Heath S  Even G  Campion D  Sleegers K  Hiltunen M  Combarros O  Zelenika D  Bullido M  Tavernier B  Letenneur L  Bettens K  Berr C  Pasquier F  Fiévet N  Barberger-Gateau P  Engelborghs S  De Deyn P  Mateo I  Franck A  Helisalmi S  Porcellini E  Hanon O  de Pancorbo M  Lendon C  Dufouil C  Jaillard C  Leveillard T  Alvarez V  Bosco P  Mancuso M  Panza F  Nacmias B  Bossù P  Piccardi P  Annoni G  Seripa D  Galimberti D  Hannequin D  Licastro F  Soininen H  Ritchie K  Blanché H  Dartigues J  Tzourio C  Gut I  Van Broeckhoven C  Alpérovitch A  Lathrop M  Amouyel P 
    • APOE may account for as much as 50% of genetic susceptibility of late onset AD. Lambert J  Heath S  Even G  Campion D  Sleegers K  Hiltunen M  Combarros O  Zelenika D  Bullido M  Tavernier B  Letenneur L  Bettens K  Berr C  Pasquier F  Fiévet N  Barberger-Gateau P  Engelborghs S  De Deyn P  Mateo I  Franck A  Helisalmi S  Porcellini E  Hanon O  de Pancorbo M  Lendon C  Dufouil C  Jaillard C  Leveillard T  Alvarez V  Bosco P  Mancuso M  Panza F  Nacmias B  Bossù P  Piccardi P  Annoni G  Seripa D  Galimberti D  Hannequin D  Licastro F  Soininen H  Ritchie K  Blanché H  Dartigues J  Tzourio C  Gut I  Van Broeckhoven C  Alpérovitch A  Lathrop M  Amouyel P 
    • Genome-wide significant evidence for association with AD was reached at the APOE, CLU and PICALM loci, as well as for two novel loci on chromosomes 2 (rs744373, within 30 kb of the gene bridging integrator 1 (BIN1)) and 19 (rs597668) resulting from an international, racially restricted, 3-stage meta-analysis of several of the largest AD GWAS studies that includes CHARGE Consortium, Translational Genomics Research Institute (TGEN) public release database and the Mayo AD GWAS. Seshadri S  Fitzpatrick A  Ikram M  DeStefano A  Gudnason V  Boada M  Bis J  Smith A  Carassquillo M  Lambert J  Harold D  Schrijvers E  Ramirez-Lorca R  Debette S  Longstreth W  Janssens A  Pankratz V  Dartigues J  Hollingworth P  Aspelund T  Hernandez I  Beiser A  Kuller L  Koudstaal P  Dickson D  Tzourio C  Abraham R  Antunez C  Du Y  Rotter J  Aulchenko Y  Harris T  Petersen R  Berr C  Owen M  Lopez-Arrieta J  Varadarajan B  Becker J  Rivadeneira F  Nalls M  Graff-Radford N  Campion D  Auerbach S  Rice K  Hofman A  Jonsson P  Schmidt H  Lathrop M  Mosley T  Au R  Psaty B  Uitterlinden A  Farrer L  Lumley T  Ruiz A  Williams J  Amouyel P  Younkin S  Wolf P  Launer L  Lopez O  van Duijn C  Breteler M 

    Genes/Proteins
    

    • Gene: BIN1 bridging integrator 1 [Homo sapiens]
    • Gene: APOE apolipoprotein E [Homo sapiens]
    • Gene: PICALM phosphatidylinositol binding clathrin assembly protein [Homo sapiens]
    • Gene: CLU clusterin [Homo sapiens]
• Created On: Wed, Mar 03 14:53:10 EST 2010
• Last Modified On: Wed Mar 03 14:53:10 EST 2010