A NOVEL ALZHEIMER DISEASE LOCUS LOCATED NEAR THE GENE ENCODING TAU PROTEIN

Gyungah Jun; Carla A. Ibrahim-Verbaas; Maria Vronskaya; Jean-Charles Lambert; Jaeyoon Chung; Adam C. Naj; Brian W. Kunkle; Li-San Wang; Joshua C. Bis; Céline Bellenguez; Denise Harold; Kathryn L. Lunetta; Anita L. Destefano; Benjamin Grenier-Boley; Rebecca Sims; Gary W. Beecham; Albert V. Smith; Vincent Chouraki; Kara L. Hamilton-Nelson; M. Arfan Ikram; Nathalie Fievet; Nicola Denning; Eden R. Martin; Helena Schmidt; Yochiro Kamatani; Melanie L Dunstan; Otto Valladares; Agustin Ruiz Laza; Diana Zelenika; Alfredo Ramirez; Tatiana M. Foroud; Seung-Hoan Choi; Anne Boland; Tim Becker; Walter A. Kukull; Sven J. van der Lee; Florence Pasquier; Carlos Cruchaga; Duane Beekly; Annette L. Fitzpatrick; Oliver Hanon; Michael Gill; Robert Barber; Vilmundur Gudnason; Dominique Campion; Seth Love; David A. Bennett; Najaf Amin; Claudine Berr; Magda Tsolaki; Joseph D. Buxbaum; Oscar L. Lopez; Vincent Deramecourt; Nick C Fox; Laura B. Cantwell; Lluis Tárraga; Carole Dufouil; John Hardy; Paul K. Crane; Gudny Eiriksdottir; Didier Hannequin; Robert Clarke; Denis Evans; Thomas H. Mosley; Luc Letenneur; Carol Brayne; Wolfgang Maier; Philip De Jager; Valur Emilsson; Jean-François Dartigues; Harald Hampel; M. Ilyas Kamboh; Renee F.A.G. de Bruijn; Christophe Tzourio; Pau Pastor; Eric B. Larson; Jerome I. Rotter; Michael C O’Donovan; Thomas J. Montine; Michael A. Nalls; Simon Mead; Eric M. Reiman; Palmi V. Jonsson; Clive Holmes; Peter H. St George-Hyslop; Mercè Boada; Peter Passmore; Jens R. Wendland; Reinhold Schmidt; Kevin Morgan; Ashley R. Winslow; John F Powell; Minerva Carasquillo; Steven G. Younkin; Jóhanna Jakobsdóttir; John SK Kauwe; Kirk C. Wilhelmsen; Dan Rujescu; Markus M Nöthen; Albert Hofman; Lesley Jones; Jonathan L. Haines; Bruce M. Psaty; Christine Van Broeckhoven; Peter Holmans; Lenore J. Launer; Richard Mayeux; Mark Lathrop; Alison M. Goate; Valentina Escott-Price; Sudha Seshadri; Margaret A. Pericak-Vance; Philippe Amouyel; Julie Williams; Cornelia M. van Duijn; Gerard D. Schellenberg; IGAP Consortium; Lindsay A. Farrer; Panos Deloukas

doi:10.1038/mp.2015.23

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A NOVEL ALZHEIMER DISEASE LOCUS LOCATED NEAR THE GENE ENCODING TAU PROTEIN

Journal article

Peer reviewed

A NOVEL ALZHEIMER DISEASE LOCUS LOCATED NEAR THE GENE ENCODING TAU PROTEIN

Gyungah Jun, Carla A. Ibrahim-Verbaas, Maria Vronskaya, Jean-Charles Lambert, Jaeyoon Chung, Adam C. Naj, Brian W. Kunkle, Li-San Wang, Joshua C. Bis, Céline Bellenguez, …

Molecular psychiatry, Vol.21(1), pp.108-117

01/01/2016

DOI: https://doi.org/10.1038/mp.2015.23

PMID: 25778476

Abstract

APOE ε4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer’s Project (IGAP) Consortium in APOE ε4+ (10,352 cases and 9,207 controls) and APOE ε4− (7,184 cases and 26,968 controls) subgroups as well as in the total sample testing for interaction between a SNP and APOE ε4 status. Suggestive associations (P<1x10 −4 ) in stage 1 were evaluated in an independent sample (stage 2) containing 4,203 subjects ( APOE ε4+: 1,250 cases and 536 controls; APOE ε4-: 718 cases and 1,699 controls). Among APOE ε4− subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT ) in a meta-analysis of the stage 1 and stage 2 datasets (best SNP, rs2732703, P=5·8x10 −9 ). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100 kilobase region that includes MAPT . Except for previously identified AD loci showing stronger association in APOE ε4+ subjects ( CR1 and CLU ) or APOE ε4− subjects ( MS4A6A/MS4A4A/ MS4A6E ), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6x10 −7 ) is noteworthy because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P≤1.3x10 −8 ), frontal cortex (P≤1.3x10 −9 ), and temporal cortex (P≤1.2x10 −11 ). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2x10 −6 ) and temporal cortex (P=2.6x10 −6 ). Our APOE -stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ε4 compared to persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted.

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Title: A NOVEL ALZHEIMER DISEASE LOCUS LOCATED NEAR THE GENE ENCODING TAU PROTEIN
Creators - without role: Gyungah Jun - McGill University and Génome Québec Innovation Centre
Carla A. Ibrahim-Verbaas - McGill University and Génome Québec Innovation Centre
Maria Vronskaya - McGill University and Génome Québec Innovation Centre
Jean-Charles Lambert - McGill University and Génome Québec Innovation Centre
Jaeyoon Chung - McGill University and Génome Québec Innovation Centre
Adam C. Naj - McGill University and Génome Québec Innovation Centre
Brian W. Kunkle - McGill University and Génome Québec Innovation Centre
Li-San Wang - McGill University and Génome Québec Innovation Centre
Joshua C. Bis - McGill University and Génome Québec Innovation Centre
Céline Bellenguez - McGill University and Génome Québec Innovation Centre
Denise Harold - McGill University and Génome Québec Innovation Centre
Kathryn L. Lunetta - McGill University and Génome Québec Innovation Centre
Anita L. Destefano - McGill University and Génome Québec Innovation Centre
Benjamin Grenier-Boley - McGill University and Génome Québec Innovation Centre
Rebecca Sims - McGill University and Génome Québec Innovation Centre
Gary W. Beecham - McGill University and Génome Québec Innovation Centre
Albert V. Smith - McGill University and Génome Québec Innovation Centre
Vincent Chouraki - McGill University and Génome Québec Innovation Centre
Kara L. Hamilton-Nelson - McGill University and Génome Québec Innovation Centre
M. Arfan Ikram - McGill University and Génome Québec Innovation Centre
Nathalie Fievet - McGill University and Génome Québec Innovation Centre
Nicola Denning - McGill University and Génome Québec Innovation Centre
Eden R. Martin - McGill University and Génome Québec Innovation Centre
Helena Schmidt - McGill University and Génome Québec Innovation Centre
Yochiro Kamatani - McGill University and Génome Québec Innovation Centre
Melanie L Dunstan - McGill University and Génome Québec Innovation Centre
Otto Valladares - McGill University and Génome Québec Innovation Centre
Agustin Ruiz Laza - McGill University and Génome Québec Innovation Centre
Diana Zelenika - McGill University and Génome Québec Innovation Centre
Alfredo Ramirez - McGill University and Génome Québec Innovation Centre
Tatiana M. Foroud - McGill University and Génome Québec Innovation Centre
Seung-Hoan Choi - McGill University and Génome Québec Innovation Centre
Anne Boland - McGill University and Génome Québec Innovation Centre
Tim Becker - McGill University and Génome Québec Innovation Centre
Walter A. Kukull - McGill University and Génome Québec Innovation Centre
Sven J. van der Lee - McGill University and Génome Québec Innovation Centre
Florence Pasquier - McGill University and Génome Québec Innovation Centre
Carlos Cruchaga - McGill University and Génome Québec Innovation Centre
Duane Beekly - McGill University and Génome Québec Innovation Centre
Annette L. Fitzpatrick - McGill University and Génome Québec Innovation Centre
Oliver Hanon - McGill University and Génome Québec Innovation Centre
Michael Gill - McGill University and Génome Québec Innovation Centre
Robert Barber - McGill University and Génome Québec Innovation Centre
Vilmundur Gudnason - McGill University and Génome Québec Innovation Centre
Dominique Campion - McGill University and Génome Québec Innovation Centre
Seth Love - McGill University and Génome Québec Innovation Centre
David A. Bennett - McGill University and Génome Québec Innovation Centre
Najaf Amin - McGill University and Génome Québec Innovation Centre
Claudine Berr - McGill University and Génome Québec Innovation Centre
Magda Tsolaki - McGill University and Génome Québec Innovation Centre
Joseph D. Buxbaum - McGill University and Génome Québec Innovation Centre
Oscar L. Lopez - McGill University and Génome Québec Innovation Centre
Vincent Deramecourt - McGill University and Génome Québec Innovation Centre
Nick C Fox - McGill University and Génome Québec Innovation Centre
Laura B. Cantwell - McGill University and Génome Québec Innovation Centre
Lluis Tárraga - McGill University and Génome Québec Innovation Centre
Carole Dufouil - McGill University and Génome Québec Innovation Centre
John Hardy - McGill University and Génome Québec Innovation Centre
Paul K. Crane - McGill University and Génome Québec Innovation Centre
Gudny Eiriksdottir - McGill University and Génome Québec Innovation Centre
Didier Hannequin - McGill University and Génome Québec Innovation Centre
Robert Clarke - McGill University and Génome Québec Innovation Centre
Denis Evans - McGill University and Génome Québec Innovation Centre
Thomas H. Mosley - McGill University and Génome Québec Innovation Centre
Luc Letenneur - McGill University and Génome Québec Innovation Centre
Carol Brayne - McGill University and Génome Québec Innovation Centre
Wolfgang Maier - McGill University and Génome Québec Innovation Centre
Philip De Jager - McGill University and Génome Québec Innovation Centre
Valur Emilsson - McGill University and Génome Québec Innovation Centre
Jean-François Dartigues - McGill University and Génome Québec Innovation Centre
Harald Hampel - McGill University and Génome Québec Innovation Centre
M. Ilyas Kamboh - McGill University and Génome Québec Innovation Centre
Renee F.A.G. de Bruijn - McGill University and Génome Québec Innovation Centre
Christophe Tzourio - McGill University and Génome Québec Innovation Centre
Pau Pastor - McGill University and Génome Québec Innovation Centre
Eric B. Larson - McGill University and Génome Québec Innovation Centre
Jerome I. Rotter - McGill University and Génome Québec Innovation Centre
Michael C O’Donovan - McGill University and Génome Québec Innovation Centre
Thomas J. Montine - McGill University and Génome Québec Innovation Centre
Michael A. Nalls - McGill University and Génome Québec Innovation Centre
Simon Mead - McGill University and Génome Québec Innovation Centre
Eric M. Reiman - McGill University and Génome Québec Innovation Centre
Palmi V. Jonsson - McGill University and Génome Québec Innovation Centre
Clive Holmes - McGill University and Génome Québec Innovation Centre
Peter H. St George-Hyslop - McGill University and Génome Québec Innovation Centre
Mercè Boada - McGill University and Génome Québec Innovation Centre
Peter Passmore - McGill University and Génome Québec Innovation Centre
Jens R. Wendland - McGill University and Génome Québec Innovation Centre
Reinhold Schmidt - McGill University and Génome Québec Innovation Centre
Kevin Morgan - McGill University and Génome Québec Innovation Centre
Ashley R. Winslow - McGill University and Génome Québec Innovation Centre
John F Powell - McGill University and Génome Québec Innovation Centre
Minerva Carasquillo - McGill University and Génome Québec Innovation Centre
Steven G. Younkin - McGill University and Génome Québec Innovation Centre
Jóhanna Jakobsdóttir - McGill University and Génome Québec Innovation Centre
John SK Kauwe - McGill University and Génome Québec Innovation Centre
Kirk C. Wilhelmsen - McGill University and Génome Québec Innovation Centre
Dan Rujescu - McGill University and Génome Québec Innovation Centre
Markus M Nöthen - McGill University and Génome Québec Innovation Centre
Albert Hofman - McGill University and Génome Québec Innovation Centre
Lesley Jones - McGill University and Génome Québec Innovation Centre
Jonathan L. Haines - McGill University and Génome Québec Innovation Centre
Bruce M. Psaty - McGill University and Génome Québec Innovation Centre
Christine Van Broeckhoven - McGill University and Génome Québec Innovation Centre
Peter Holmans - McGill University and Génome Québec Innovation Centre
Lenore J. Launer - McGill University and Génome Québec Innovation Centre
Richard Mayeux - McGill University and Génome Québec Innovation Centre
Mark Lathrop - McGill University and Génome Québec Innovation Centre
Alison M. Goate - McGill University and Génome Québec Innovation Centre
Valentina Escott-Price - McGill University and Génome Québec Innovation Centre
Sudha Seshadri - McGill University and Génome Québec Innovation Centre
Margaret A. Pericak-Vance - McGill University and Génome Québec Innovation Centre
Philippe Amouyel - McGill University and Génome Québec Innovation Centre
Julie Williams - McGill University and Génome Québec Innovation Centre
Cornelia M. van Duijn - McGill University and Génome Québec Innovation Centre
Gerard D. Schellenberg - McGill University and Génome Québec Innovation Centre
IGAP Consortium
Lindsay A. Farrer - McGill University and Génome Québec Innovation Centre
Panos Deloukas - King Abdulaziz University
Publication Details: Molecular psychiatry, Vol.21(1), pp.108-117
Identifiers: 9936685008331
Academic Unit: King Abdulaziz University
Language: English
Resource Type: Journal article