A novel Alzheimer disease locus located near the gene encoding tau protein

G Jun; Carla Verbaas; M Vronskaya; JC Lambert; JW Chung; A Naj; BW Kunkle; LS (Li-San) Wang; JC Bis; C Bellenguez; D Harold; KL Lunetta; AL DeStefano; B Grenier-Boley; R Sims; GW Beecham; AV Smith; V Chouraki; KL Hamilton-Nelson; Arfan Ikram; N Fievet; N Denning; ER Martin; Heléna Schmidt; Y Kamatani; ML Dunstan; O Valladares; AR Laza; D Zelenika; A Ramirez; TM Foroud; SH Choi; A Boland; T Becker; WA Kukull; Sven van der Lee; F Pasquier; C Cruchaga; D Beekly; AL Fitzpatrick; O Hanon; M Gill; R Barber; V Gudnason; D Campion; S Love; DA Bennett; Najaf Amin; C Berr; M Tsolaki; JD Buxbaum; OL Lopez; V Deramecourt; NC Fox; LB Cantwell; L Tarraga; C Dufouil; J Hardy; PK Crane; G Eiriksdottir; D Hannequin; R Clarke; D Evans; TH Mosley; L Letenneur; C Brayne; W Maier; P Jager; V Emilsson; JF Dartigues; H Hampel; MI Kamboh; Renee Bruijn; C Tzourio; P Pastor; EB Larson; JI Rotter; MC O'Donovan; TJ Montine; MA Nalls; S Mead; EM Reiman; PV Jonsson; C Holmes; PH St George-Hyslop; M Boada; P Passmore; JR Wendland; R Schmidt; K Morgan; AR Winslow; JF Powell; M Carasquillo; SG Younkin; J Jakobsdottir; JSK Kauwe; KC Wilhelmsen; D Rujescu; MM Nothen; Bert Hofman; L Jones; JL Haines; BM Psaty; C van Broeckhoven; P Holmans; LJ (Lenore) Launer; R Mayeux; M Lathrop; AM Goate; V Escott-Price; S Seshadri; MA Pericak-Vance; P Amouyel; J Williams; Cornelia Duijn; GD Schellenberg; LA Farrer

doi:10.1038/mp.2015.23

A novel Alzheimer disease locus located near the gene encoding tau protein

G Jun, Carla Verbaas, M Vronskaya, JC Lambert, JW Chung, A Naj, BW Kunkle, LS (Li-San) Wang, JC Bis, C Bellenguez, D Harold, KL Lunetta, AL DeStefano, B Grenier-Boley, R Sims, GW Beecham, AV Smith, V Chouraki, KL Hamilton-Nelson, Arfan IkramN Fievet, N Denning, ER Martin, Heléna Schmidt, Y Kamatani, ML Dunstan, O Valladares, AR Laza, D Zelenika, A Ramirez, TM Foroud, SH Choi, A Boland, T Becker, WA Kukull, Sven van der Lee, F Pasquier, C Cruchaga, D Beekly, AL Fitzpatrick, O Hanon, M Gill, R Barber, V Gudnason, D Campion, S Love, DA Bennett, Najaf Amin, C Berr, M Tsolaki, JD Buxbaum, OL Lopez, V Deramecourt, NC Fox, LB Cantwell, L Tarraga, C Dufouil, J Hardy, PK Crane, G Eiriksdottir, D Hannequin, R Clarke, D Evans, TH Mosley, L Letenneur, C Brayne, W Maier, P Jager, V Emilsson, JF Dartigues, H Hampel, MI Kamboh, Renee Bruijn, C Tzourio, P Pastor, EB Larson, JI Rotter, MC O'Donovan, TJ Montine, MA Nalls, S Mead, EM Reiman, PV Jonsson, C Holmes, PH St George-Hyslop, M Boada, P Passmore, JR Wendland, R Schmidt, K Morgan, AR Winslow, JF Powell, M Carasquillo, SG Younkin, J Jakobsdottir, JSK Kauwe, KC Wilhelmsen, D Rujescu, MM Nothen, Bert Hofman, L Jones, JL Haines, BM Psaty, C van Broeckhoven, P Holmans, LJ (Lenore) Launer, R Mayeux, M Lathrop, AM Goate, V Escott-Price, S Seshadri, MA Pericak-Vance, P Amouyel, J Williams, Cornelia Duijn, GD Schellenberg, LA Farrer

Research output: Contribution to journal › Article › Academic › peer-review

200 Citations (Scopus)

Abstract

APOE epsilon 4, 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 epsilon 4+ (10 352 cases and 9207 controls) and APOE epsilon 4 - (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE e4 status. Suggestive associations (P < 1x10(-4)) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE epsilon 4+: 1250 cases and 536 controls; APOE epsilon 4 -: 718 cases and 1699 controls). Among APOE epsilon 4 - 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 data sets (best SNP, rs2732703, P = 5.8 x 10(-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 epsilon 4+ subjects (CR1 and CLU) or APOE epsilon 4 - 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 = 1.6 x 10(-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 <= 1.3 x 10(-8)), frontal cortex (P <= 1.3 x 10(-9)) and temporal cortex (P <= 1.2 x 10(-11)). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P = 9.2 x 10(-6)) and temporal cortex (P = 2.6 x 10(-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 epsilon 4 compared with 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.

Original language	Undefined/Unknown
Pages (from-to)	108-117
Number of pages	10
Journal	Molecular Psychiatry
Volume	21
Issue number	1
DOIs	https://doi.org/10.1038/mp.2015.23
Publication status	Published - 2016

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10.1038/mp.2015.23

Cite this

Jun, G., Verbaas, C., Vronskaya, M., Lambert, JC., Chung, JW., Naj, A., Kunkle, BW., Wang, LS., Bis, JC., Bellenguez, C., Harold, D., Lunetta, KL., DeStefano, AL., Grenier-Boley, B., Sims, R., Beecham, GW., Smith, AV., Chouraki, V., Hamilton-Nelson, KL., ... Farrer, LA. (2016). A novel Alzheimer disease locus located near the gene encoding tau protein. Molecular Psychiatry, 21(1), 108-117. https://doi.org/10.1038/mp.2015.23

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title = "A novel Alzheimer disease locus located near the gene encoding tau protein",

abstract = "APOE epsilon 4, 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 epsilon 4+ (10 352 cases and 9207 controls) and APOE epsilon 4 - (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE e4 status. Suggestive associations (P < 1x10(-4)) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE epsilon 4+: 1250 cases and 536 controls; APOE epsilon 4 -: 718 cases and 1699 controls). Among APOE epsilon 4 - 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 data sets (best SNP, rs2732703, P = 5.8 x 10(-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 epsilon 4+ subjects (CR1 and CLU) or APOE epsilon 4 - 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 = 1.6 x 10(-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 <= 1.3 x 10(-8)), frontal cortex (P <= 1.3 x 10(-9)) and temporal cortex (P <= 1.2 x 10(-11)). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P = 9.2 x 10(-6)) and temporal cortex (P = 2.6 x 10(-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 epsilon 4 compared with 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.",

author = "G Jun and Carla Verbaas and M Vronskaya and JC Lambert and JW Chung and A Naj and BW Kunkle and Wang, {LS (Li-San)} and JC Bis and C Bellenguez and D Harold and KL Lunetta and AL DeStefano and B Grenier-Boley and R Sims and GW Beecham and AV Smith and V Chouraki and KL Hamilton-Nelson and Arfan Ikram and N Fievet and N Denning and ER Martin and Hel{\'e}na Schmidt and Y Kamatani and ML Dunstan and O Valladares and AR Laza and D Zelenika and A Ramirez and TM Foroud and SH Choi and A Boland and T Becker and WA Kukull and {van der Lee}, Sven and F Pasquier and C Cruchaga and D Beekly and AL Fitzpatrick and O Hanon and M Gill and R Barber and V Gudnason and D Campion and S Love and DA Bennett and Najaf Amin and C Berr and M Tsolaki and JD Buxbaum and OL Lopez and V Deramecourt and NC Fox and LB Cantwell and L Tarraga and C Dufouil and J Hardy and PK Crane and G Eiriksdottir and D Hannequin and R Clarke and D Evans and TH Mosley and L Letenneur and C Brayne and W Maier and P Jager and V Emilsson and JF Dartigues and H Hampel and MI Kamboh and Renee Bruijn and C Tzourio and P Pastor and EB Larson and JI Rotter and MC O'Donovan and TJ Montine and MA Nalls and S Mead and EM Reiman and PV Jonsson and C Holmes and {St George-Hyslop}, PH and M Boada and P Passmore and JR Wendland and R Schmidt and K Morgan and AR Winslow and JF Powell and M Carasquillo and SG Younkin and J Jakobsdottir and JSK Kauwe and KC Wilhelmsen and D Rujescu and MM Nothen and Bert Hofman and L Jones and JL Haines and BM Psaty and {van Broeckhoven}, C and P Holmans and Launer, {LJ (Lenore)} and R Mayeux and M Lathrop and AM Goate and V Escott-Price and S Seshadri and MA Pericak-Vance and P Amouyel and J Williams and Cornelia Duijn and GD Schellenberg and LA Farrer",

year = "2016",

doi = "10.1038/mp.2015.23",

language = "Undefined/Unknown",

volume = "21",

pages = "108--117",

journal = "Molecular Psychiatry",

issn = "1359-4184",

publisher = "Springer Nature",

number = "1",

}

Jun, G, Verbaas, C, Vronskaya, M, Lambert, JC, Chung, JW, Naj, A, Kunkle, BW, Wang, LS, Bis, JC, Bellenguez, C, Harold, D, Lunetta, KL, DeStefano, AL, Grenier-Boley, B, Sims, R, Beecham, GW, Smith, AV, Chouraki, V, Hamilton-Nelson, KL, Ikram, A, Fievet, N, Denning, N, Martin, ER, Schmidt, H, Kamatani, Y, Dunstan, ML, Valladares, O, Laza, AR, Zelenika, D, Ramirez, A, Foroud, TM, Choi, SH, Boland, A, Becker, T, Kukull, WA, van der Lee, S, Pasquier, F, Cruchaga, C, Beekly, D, Fitzpatrick, AL, Hanon, O, Gill, M, Barber, R, Gudnason, V, Campion, D, Love, S, Bennett, DA, Amin, N, Berr, C, Tsolaki, M, Buxbaum, JD, Lopez, OL, Deramecourt, V, Fox, NC, Cantwell, LB, Tarraga, L, Dufouil, C, Hardy, J, Crane, PK, Eiriksdottir, G, Hannequin, D, Clarke, R, Evans, D, Mosley, TH, Letenneur, L, Brayne, C, Maier, W, Jager, P, Emilsson, V, Dartigues, JF, Hampel, H, Kamboh, MI, Bruijn, R, Tzourio, C, Pastor, P, Larson, EB, Rotter, JI, O'Donovan, MC, Montine, TJ, Nalls, MA, Mead, S, Reiman, EM, Jonsson, PV, Holmes, C, St George-Hyslop, PH, Boada, M, Passmore, P, Wendland, JR, Schmidt, R, Morgan, K, Winslow, AR, Powell, JF, Carasquillo, M, Younkin, SG, Jakobsdottir, J, Kauwe, JSK, Wilhelmsen, KC, Rujescu, D, Nothen, MM, Hofman, B, Jones, L, Haines, JL, Psaty, BM, van Broeckhoven, C, Holmans, P, Launer, LJ, Mayeux, R, Lathrop, M, Goate, AM, Escott-Price, V, Seshadri, S, Pericak-Vance, MA, Amouyel, P, Williams, J, Duijn, C, Schellenberg, GD & Farrer, LA 2016, 'A novel Alzheimer disease locus located near the gene encoding tau protein', Molecular Psychiatry, vol. 21, no. 1, pp. 108-117. https://doi.org/10.1038/mp.2015.23

TY - JOUR

T1 - A novel Alzheimer disease locus located near the gene encoding tau protein

AU - Jun, G

AU - Verbaas, Carla

AU - Vronskaya, M

AU - Lambert, JC

AU - Chung, JW

AU - Naj, A

AU - Kunkle, BW

AU - Wang, LS (Li-San)

AU - Bis, JC

AU - Bellenguez, C

AU - Harold, D

AU - Lunetta, KL

AU - DeStefano, AL

AU - Grenier-Boley, B

AU - Sims, R

AU - Beecham, GW

AU - Smith, AV

AU - Chouraki, V

AU - Hamilton-Nelson, KL

AU - Ikram, Arfan

AU - Fievet, N

AU - Denning, N

AU - Martin, ER

AU - Schmidt, Heléna

AU - Kamatani, Y

AU - Dunstan, ML

AU - Valladares, O

AU - Laza, AR

AU - Zelenika, D

AU - Ramirez, A

AU - Foroud, TM

AU - Choi, SH

AU - Boland, A

AU - Becker, T

AU - Kukull, WA

AU - van der Lee, Sven

AU - Pasquier, F

AU - Cruchaga, C

AU - Beekly, D

AU - Fitzpatrick, AL

AU - Hanon, O

AU - Gill, M

AU - Barber, R

AU - Gudnason, V

AU - Campion, D

AU - Love, S

AU - Bennett, DA

AU - Amin, Najaf

AU - Berr, C

AU - Tsolaki, M

AU - Buxbaum, JD

AU - Lopez, OL

AU - Deramecourt, V

AU - Fox, NC

AU - Cantwell, LB

AU - Tarraga, L

AU - Dufouil, C

AU - Hardy, J

AU - Crane, PK

AU - Eiriksdottir, G

AU - Hannequin, D

AU - Clarke, R

AU - Evans, D

AU - Mosley, TH

AU - Letenneur, L

AU - Brayne, C

AU - Maier, W

AU - Jager, P

AU - Emilsson, V

AU - Dartigues, JF

AU - Hampel, H

AU - Kamboh, MI

AU - Bruijn, Renee

AU - Tzourio, C

AU - Pastor, P

AU - Larson, EB

AU - Rotter, JI

AU - O'Donovan, MC

AU - Montine, TJ

AU - Nalls, MA

AU - Mead, S

AU - Reiman, EM

AU - Jonsson, PV

AU - Holmes, C

AU - St George-Hyslop, PH

AU - Boada, M

AU - Passmore, P

AU - Wendland, JR

AU - Schmidt, R

AU - Morgan, K

AU - Winslow, AR

AU - Powell, JF

AU - Carasquillo, M

AU - Younkin, SG

AU - Jakobsdottir, J

AU - Kauwe, JSK

AU - Wilhelmsen, KC

AU - Rujescu, D

AU - Nothen, MM

AU - Hofman, Bert

AU - Jones, L

AU - Haines, JL

AU - Psaty, BM

AU - van Broeckhoven, C

AU - Holmans, P

AU - Launer, LJ (Lenore)

AU - Mayeux, R

AU - Lathrop, M

AU - Goate, AM

AU - Escott-Price, V

AU - Seshadri, S

AU - Pericak-Vance, MA

AU - Amouyel, P

AU - Williams, J

AU - Duijn, Cornelia

AU - Schellenberg, GD

AU - Farrer, LA

PY - 2016

Y1 - 2016

N2 - APOE epsilon 4, 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 epsilon 4+ (10 352 cases and 9207 controls) and APOE epsilon 4 - (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE e4 status. Suggestive associations (P < 1x10(-4)) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE epsilon 4+: 1250 cases and 536 controls; APOE epsilon 4 -: 718 cases and 1699 controls). Among APOE epsilon 4 - 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 data sets (best SNP, rs2732703, P = 5.8 x 10(-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 epsilon 4+ subjects (CR1 and CLU) or APOE epsilon 4 - 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 = 1.6 x 10(-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 <= 1.3 x 10(-8)), frontal cortex (P <= 1.3 x 10(-9)) and temporal cortex (P <= 1.2 x 10(-11)). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P = 9.2 x 10(-6)) and temporal cortex (P = 2.6 x 10(-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 epsilon 4 compared with 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.

AB - APOE epsilon 4, 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 epsilon 4+ (10 352 cases and 9207 controls) and APOE epsilon 4 - (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE e4 status. Suggestive associations (P < 1x10(-4)) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE epsilon 4+: 1250 cases and 536 controls; APOE epsilon 4 -: 718 cases and 1699 controls). Among APOE epsilon 4 - 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 data sets (best SNP, rs2732703, P = 5.8 x 10(-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 epsilon 4+ subjects (CR1 and CLU) or APOE epsilon 4 - 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 = 1.6 x 10(-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 <= 1.3 x 10(-8)), frontal cortex (P <= 1.3 x 10(-9)) and temporal cortex (P <= 1.2 x 10(-11)). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P = 9.2 x 10(-6)) and temporal cortex (P = 2.6 x 10(-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 epsilon 4 compared with 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.

U2 - 10.1038/mp.2015.23

DO - 10.1038/mp.2015.23

M3 - Article

C2 - 25778476

SN - 1359-4184

VL - 21

SP - 108

EP - 117

JO - Molecular Psychiatry

JF - Molecular Psychiatry

IS - 1

ER -