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PMID: 22722634 Published · ppublish English Journal Article Meta-Analysis Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Novel late-onset Alzheimer disease loci variants associate with brain gene expression.

Neurology ·Vol. 79 ·No. 3 ·2012-07-17 ·Pages 221-8

Allen M, Zou F, Chai HS, Younkin CS, Crook J, Pankratz VS, Carrasquillo MM, Rowley CN, Nair AA, Middha S, Maharjan S, Nguyen T, Ma L, Malphrus KG, Palusak R, Lincoln S, Bisceglio G, Georgescu C, Schultz D, Rakhshan F, Kolbert CP, Jen J, Haines JL, Mayeux R, Pericak-Vance MA, Farrer LA, Schellenberg GD, Petersen RC, Graff-Radford NR, Dickson DW, Younkin SG, Ertekin-Taner N, Alzheimer's Disease Genetics Consortium ADGC, Apostolova LG, Arnold SE, Baldwin CT, Barber R, Barmada MM, Beach T, Beecham GW, Beekly D, Bennett DA, Bigio EH, Bird TD, Blacker D, Boeve BF, Bowen JD, Boxer A, Burke JR, Buros J, Buxbaum JD, Cairns NJ, Cantwell LB, Cao C, Carlson CS, Carney RM, Carroll SL, Chui HC, Clark DG, Corneveaux J, Cotman CW, Crane PK, Cruchaga C, Cummings JL, De Jager PL, DeCarli C, DeKosky ST, Demirci FY, Diaz-Arrastia R, Dick M, Dombroski BA, Duara R, Ellis WD, Evans D, Faber KM, Fallon KB, Farlow MR, Ferris S, Foroud TM, Frosch M, Galasko DR, Gallins PJ, Ganguli M, Gearing M, Geschwind DH, Ghetti B, Gilbert JR, Gilman S, Giordani B, Glass JD, Goate AM, Green RC, Growdon JH, Hakonarson H, Hamilton RL, Hardy J, Harrell LE, Head E, Honig LS, Huentelman MJ, Hulette CM, Hyman BT, Jarvik GP, Jicha GA, Jin LW, Jun G, Kamboh MI, Karlawish J, Karydas A, Kauwe JS, Kaye JA, Kennedy N, Kim R, Koo EH, Kowall NW, Kramer P, Kukull WA, Lah JJ, Larson EB, Levey AI, Lieberman AP, Lopez OL, Lunetta KL, Mack WJ, Marson DC, Martin ER, Martiniuk F, Mash DC, Masliah E, McCormick WC, McCurry SM, McDavid AN, McKee AC, Mesulam M, Miller BL, Miller CA, Miller JW, Montine TJ, Morris JC, Myers AJ, Naj AC, Nowotny P, Parisi JE, Perl DP, Peskind E, Poon WW, Potter H, Quinn JF, Raj A, Rajbhandary RA, Raskind M, Reiman EM, Reisberg B, Reitz C, Ringman JM, Roberson ED, Rogaeva E, Rosenberg RN, Sano M, Saykin AJ, Schneider JA, Schneider LS, Seeley W, Shelanski ML, Slifer MA, Smith CD, Sonnen JA, Spina S, St George-Hyslop P, Stern RA, Tanzi RE, Trojanowski JQ, Troncoso JC, Tsuang DW, Van Deerlin VM, Vardarajan BN, Vinters HV, Vonsattel JP, Wang LS, Weintraub S, Welsh-Bohmer KA, Williamson J, Woltjer RL

Abstract

Recent genome-wide association studies (GWAS) of late-onset Alzheimer disease (LOAD) identified 9 novel risk loci. Discovery of functional variants within genes at these loci is required to confirm their role in Alzheimer disease (AD). Single nucleotide polymorphisms that influence gene expression (eSNPs) constitute an important class of functional variants. We therefore investigated the influence of the novel LOAD risk loci on human brain gene expression. We measured gene expression levels in the cerebellum and temporal cortex of autopsied AD subjects and those with other brain pathologies (∼400 total subjects). To determine whether any of the novel LOAD risk variants are eSNPs, we tested their cis-association with expression of 6 nearby LOAD candidate genes detectable in human brain (ABCA7, BIN1, CLU, MS4A4A, MS4A6A, PICALM) and an additional 13 genes ±100 kb of these SNPs. To identify additional eSNPs that influence brain gene expression levels of the novel candidate LOAD genes, we identified SNPs ±100 kb of their location and tested for cis-associations. CLU rs11136000 (p = 7.81 × 10(-4)) and MS4A4A rs2304933/rs2304935 (p = 1.48 × 10(-4)-1.86 × 10(-4)) significantly influence temporal cortex expression levels of these genes. The LOAD-protective CLU and risky MS4A4A locus alleles associate with higher brain levels of these genes. There are other cis-variants that significantly influence brain expression of CLU and ABCA7 (p = 4.01 × 10(-5)-9.09 × 10(-9)), some of which also associate with AD risk (p = 2.64 × 10(-2)-6.25 × 10(-5)). CLU and MS4A4A eSNPs may at least partly explain the LOAD risk association at these loci. CLU and ABCA7 may harbor additional strong eSNPs. These results have implications in the search for functional variants at the novel LOAD risk loci.

MeSH Terms

Aged Alleles Alzheimer Disease/genetics Apolipoprotein E4/genetics Autopsy Brain Chemistry/genetics Female Gene Dosage Gene Expression/physiology Genetic Predisposition to Disease Genotype Humans Linear Models Male Polymorphism, Single Nucleotide RNA/genetics,isolation & purification Risk Factors Temporal Lobe/metabolism

Chemicals

Apolipoprotein E4 RNA

Authors & Affiliations

183 authors, click to expand affiliations / ORCID

Allen Mariet

Department of Neuroscience, Biostatistics Unit, Mayo Clinic Florida, Jacksonville, FL, USA.

Zou Fanggeng

Chai High Seng

Younkin Curtis S

Crook Julia

Pankratz V Shane

Carrasquillo Minerva M

Rowley Christopher N

Nair Asha A

Middha Sumit

Maharjan Sooraj

Nguyen Thuy

Ma Li

Malphrus Kimberly G

Palusak Ryan

Lincoln Sarah

Bisceglio Gina

Georgescu Constantin

Schultz Debra

Rakhshan Fariborz

Kolbert Christopher P

Jen Jin

Haines Jonathan L

Mayeux Richard

Pericak-Vance Margaret A

Farrer Lindsay A

Schellenberg Gerard D

Petersen Ronald C

Graff-Radford Neill R

Dickson Dennis W

Younkin Steven G

Ertekin-Taner Nilüfer

Alzheimer's Disease Genetics Consortium (ADGC)

Apostolova Liana G

Arnold Steven E

Baldwin Clinton T

Barber Robert

Barmada Michael M

Beach Thomas

Beecham Gary W

Beekly Duane

Bennett David A

Bigio Eileen H

Bird Thomas D

Blacker Deborah

Boeve Bradley F

Bowen James D

Boxer Adam

Burke James R

Buros Jacqueline

Buxbaum Joseph D

Cairns Nigel J

Cantwell Laura B

Cao Chuanhai

Carlson Chris S

Carney Regina M

Carroll Steven L

Chui Helena C

Clark David G

Corneveaux Jason

Cotman Carl W

Crane Paul K

Cruchaga Carlos

Cummings Jeffrey L

De Jager Philip L

DeCarli Charles

DeKosky Steven T

Demirci F Yesim

Diaz-Arrastia Ramon

Dick Malcolm

Dombroski Beth A

Duara Ranjan

Ellis William D

Evans Denis

Faber Kelley M

Fallon Kenneth B

Farlow Martin R

Ferris Steven

Foroud Tatiana M

Frosch Matthew

Galasko Douglas R

Gallins Paul J

Ganguli Mary

Gearing Marla

Geschwind Daniel H

Ghetti Bernardino

Gilbert John R

Gilman Sid

Giordani Bruno

Glass Jonathan D

Goate Alison M

Green Robert C

Growdon John H

Hakonarson Hakon

Hamilton Ronald L

Hardy John

Harrell Lindy E

Head Elizabeth

Honig Lawrence S

Huentelman Matthew J

Hulette Christine M

Hyman Bradley T

Jarvik Gail P

Jicha Gregory A

Jin Lee-Way

Jun Gyungah

Kamboh M Ilyas

Karlawish Jason

Karydas Anna

Kauwe John S K

Kaye Jeffrey A

Kennedy Nancy

Kim Ronald

Koo Edward H

Kowall Neil W

Kramer Patricia

Kukull Walter A

Lah James J

Larson Eric B

Levey Allan I

Lieberman Andrew P

Lopez Oscar L

Lunetta Kathryn L

Mack Wendy J

Marson Daniel C

Martin Eden R

Martiniuk Frank

Mash Deborah C

Masliah Eliezer

McCormick Wayne C

McCurry Susan M

McDavid Andrew N

McKee Ann C

Mesulam Marsel

Miller Bruce L

Miller Carol A

Miller Joshua W

Montine Thomas J

Morris John C

Myers Amanda J

Naj Adam C

Nowotny Petra

Parisi Joseph E

Perl Daniel P

Peskind Elaine

Poon Wayne W

Potter Huntington

Quinn Joseph F

Raj Ashok

Rajbhandary Ruchita A

Raskind Murray

Reiman Eric M

Reisberg Barry

Reitz Christiane

Ringman John M

Roberson Erik D

Rogaeva Ekaterina

Rosenberg Roger N

Sano Mary

Saykin Andrew J

Schneider Julie A

Schneider Lon S

Seeley William

Shelanski Michael L

Slifer Michael A

Smith Charles D

Sonnen Joshua A

Spina Salvatore

St George-Hyslop Peter

Stern Robert A

Tanzi Rudolph E

Trojanowski John Q

Troncoso Juan C

Tsuang Debby W

Van Deerlin Vivianna M

Vardarajan Badri Narayan

Vinters Harry V

Vonsattel Jean Paul

Wang Li-San

Weintraub Sandra

Welsh-Bohmer Kathleen A

Williamson Jennifer

Woltjer Randall L

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Article Info

Journal

Neurology

Abbr.

Neurology

ISSN

1526-632X

DOI

10.1212/WNL.0b013e3182605801

Published

2012-07-17

Epub

2012-00-20

Pages

221-8

Language

English

Region

United States

NLM ID

0401060

PMCID

PMC3398432

Subset

Grants

NIA NIH HHS · U01 AG006576 · United States

NHGRI NIH HHS · U01 HG006375 · United States

NIA NIH HHS · R01 AG018023 · United States

NIA NIH HHS · U01 AG032984 · United States

NIA NIH HHS · U01 AG016976 · United States

NIA NIH HHS · P30 AG012300 · United States

NIA NIH HHS · R01 AG032990 · United States

NIA NIH HHS · R01 AG041797 · United States

NIA NIH HHS · AG017216 · United States

PHS HHS · R01 032990 · United States

NCRR NIH HHS · KL2 RR024151 · United States

NIA NIH HHS · U24 AG021886 · United States

NIA NIH HHS · AG003949 · United States

NIA NIH HHS · P50 AG016574 · United States

NIA NIH HHS · P30 AG013846 · United States

NIA NIH HHS · U24 AG056270 · United States

NIA NIH HHS · AG025711 · United States

Corrections

CommentIn

PMID: 22722635

External Links

PubMed source DOI: 10.1212/WNL.0b013e3182605801 PMC Full Text View journal details

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Novel late-onset Alzheimer disease loci variants associate with brain gene expression.

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