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


ABSTRACT:

Objective

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.

Methods

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.

Results

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)).

Conclusions

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.

SUBMITTER: Allen M 

PROVIDER: S-EPMC3398432 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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

Allen Mariet M   Zou Fanggeng F   Chai High Seng HS   Younkin Curtis S CS   Crook Julia J   Pankratz V Shane VS   Carrasquillo Minerva M MM   Rowley Christopher N CN   Nair Asha A AA   Middha Sumit S   Maharjan Sooraj S   Nguyen Thuy T   Ma Li L   Malphrus Kimberly G KG   Palusak Ryan R   Lincoln Sarah S   Bisceglio Gina G   Georgescu Constantin C   Schultz Debra D   Rakhshan Fariborz F   Kolbert Christopher P CP   Jen Jin J   Haines Jonathan L JL   Mayeux Richard R   Pericak-Vance Margaret A MA   Farrer Lindsay A LA   Schellenberg Gerard D GD   Petersen Ronald C RC   Graff-Radford Neill R NR   Dickson Dennis W DW   Younkin Steven G SG   Ertekin-Taner Nilüfer N   Apostolova Liana G LG   Arnold Steven E SE   Baldwin Clinton T CT   Barber Robert R   Barmada Michael M MM   Beach Thomas T   Beecham Gary W GW   Beekly Duane D   Bennett David A DA   Bigio Eileen H EH   Bird Thomas D TD   Blacker Deborah D   Boeve Bradley F BF   Bowen James D JD   Boxer Adam A   Burke James R JR   Buros Jacqueline J   Buxbaum Joseph D JD   Cairns Nigel J NJ   Cantwell Laura B LB   Cao Chuanhai C   Carlson Chris S CS   Carney Regina M RM   Carroll Steven L SL   Chui Helena C HC   Clark David G DG   Corneveaux Jason J   Cotman Carl W CW   Crane Paul K PK   Cruchaga Carlos C   Cummings Jeffrey L JL   De Jager Philip L PL   DeCarli Charles C   DeKosky Steven T ST   Demirci F Yesim FY   Diaz-Arrastia Ramon R   Dick Malcolm M   Dombroski Beth A BA   Duara Ranjan R   Ellis William D WD   Evans Denis D   Faber Kelley M KM   Fallon Kenneth B KB   Farlow Martin R MR   Ferris Steven S   Foroud Tatiana M TM   Frosch Matthew M   Galasko Douglas R DR   Gallins Paul J PJ   Ganguli Mary M   Gearing Marla M   Geschwind Daniel H DH   Ghetti Bernardino B   Gilbert John R JR   Gilman Sid S   Giordani Bruno B   Glass Jonathan D JD   Goate Alison M AM   Green Robert C RC   Growdon John H JH   Hakonarson Hakon H   Hamilton Ronald L RL   Hardy John J   Harrell Lindy E LE   Head Elizabeth E   Honig Lawrence S LS   Huentelman Matthew J MJ   Hulette Christine M CM   Hyman Bradley T BT   Jarvik Gail P GP   Jicha Gregory A GA   Jin Lee-Way LW   Jun Gyungah G   Kamboh M Ilyas MI   Karlawish Jason J   Karydas Anna A   Kauwe John S K JS   Kaye Jeffrey A JA   Kennedy Nancy N   Kim Ronald R   Koo Edward H EH   Kowall Neil W NW   Kramer Patricia P   Kukull Walter A WA   Lah James J JJ   Larson Eric B EB   Levey Allan I AI   Lieberman Andrew P AP   Lopez Oscar L OL   Lunetta Kathryn L KL   Mack Wendy J WJ   Marson Daniel C DC   Martin Eden R ER   Martiniuk Frank F   Mash Deborah C DC   Masliah Eliezer E   McCormick Wayne C WC   McCurry Susan M SM   McDavid Andrew N AN   McKee Ann C AC   Mesulam Marsel M   Miller Bruce L BL   Miller Carol A CA   Miller Joshua W JW   Montine Thomas J TJ   Morris John C JC   Myers Amanda J AJ   Naj Adam C AC   Nowotny Petra P   Parisi Joseph E JE   Perl Daniel P DP   Peskind Elaine E   Poon Wayne W WW   Potter Huntington H   Quinn Joseph F JF   Raj Ashok A   Rajbhandary Ruchita A RA   Raskind Murray M   Reiman Eric M EM   Reisberg Barry B   Reitz Christiane C   Ringman John M JM   Roberson Erik D ED   Rogaeva Ekaterina E   Rosenberg Roger N RN   Sano Mary M   Saykin Andrew J AJ   Schneider Julie A JA   Schneider Lon S LS   Seeley William W   Shelanski Michael L ML   Slifer Michael A MA   Smith Charles D CD   Sonnen Joshua A JA   Spina Salvatore S   St George-Hyslop Peter P   Stern Robert A RA   Tanzi Rudolph E RE   Trojanowski John Q JQ   Troncoso Juan C JC   Tsuang Debby W DW   Van Deerlin Vivianna M VM   Vardarajan Badri Narayan BN   Vinters Harry V HV   Vonsattel Jean Paul JP   Wang Li-San LS   Weintraub Sandra S   Welsh-Bohmer Kathleen A KA   Williamson Jennifer J   Woltjer Randall L RL  

Neurology 20120620 3


<h4>Objective</h4>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.<h4>Methods</h4>We mea  ...[more]

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