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

被引：125

作者：

Allen, Mariet ^{[1
]}

Zou, Fanggeng ^{[1
]}

Chai, High Seng ^{[4
]}

Younkin, Curtis S. ^{[1
]}

Crook, Julia ^{[2
]}

Pankratz, V. Shane ^{[4
]}

Carrasquillo, Minerva M. ^{[1
]}

Rowley, Christopher N. ^{[1
]}

Nair, Asha A. ^{[4
]}

Middha, Sumit ^{[4
]}

Maharjan, Sooraj ^{[4
]}

Thuy Nguyen ^{[1
]}

Ma, Li ^{[1
]}

Malphrus, Kimberly G. ^{[1
]}

Palusak, Ryan ^{[1
]}

Lincoln, Sarah ^{[1
]}

Bisceglio, Gina ^{[1
]}

Georgescu, Constantin ^{[1
]}

Schultz, Debra ^{[5
]}

Rakhshan, Fariborz ^{[5
]}

Kolbert, Christopher P. ^{[5
]}

Jen, Jin ^{[5
]}

Haines, Jonathan L. ^{[7
,8
]}

Mayeux, Richard ^{[9
,10
]}

Pericak-Vance, Margaret A. ^{[11
,12
]}

Farrer, Lindsay A. ^{[13
,14
,15
,16
]}

Schellenberg, Gerard D. ^{[17
]}

Petersen, Ronald C. ^{[6
]}

Graff-Radford, Neill R. ^{[3
]}

Dickson, Dennis W. ^{[1
]}

Younkin, Steven G. ^{[1
]}

Ertekin-Taner, Niluefer ^{[1
,3
]}

机构：

[1] Mayo Clin Florida, Dept Neurosci, Jacksonville, FL 32224 USA

[2] Mayo Clin Florida, Biostat Unit, Jacksonville, FL USA

[3] Mayo Clin Florida, Dept Neurol, Jacksonville, FL USA

[4] Mayo Clin Minnesota, Dept Biostat, Rochester, MN USA

[5] Mayo Clin Minnesota, Gene Express Core, Adv Genome Technol Ctr, Rochester, MN USA

[6] Mayo Clin Minnesota, Dept Neurol, Rochester, MN USA

[7] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA

[8] Vanderbilt Univ, Vanderbilt Ctr Human Genet Res, Nashville, TN USA

[9] Columbia Univ, Gertrude H Sergievsky Ctr, Dept Neurol, New York, NY 10027 USA

[10] Columbia Univ, Taub Inst Alzheimers Dis & Aging Brain, New York, NY USA

[11] Univ Miami, John P Hussman Inst Human Genom, Miami, FL USA

[12] Univ Miami, Dept Human Genet, Dr John T MacDonald Fdn, Miami, FL USA

[13] Boston Univ, Dept Biostat, Genet Program, Boston, MA 02215 USA

[14] Boston Univ, Dept Ophthalmol, Boston, MA 02215 USA

[15] Boston Univ, Dept Neurol, Boston, MA 02215 USA

[16] Boston Univ, Dept Epidemiol, Boston, MA 02215 USA

[17] Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA 19104 USA

来源：

NEUROLOGY | 2012年 / 79卷 / 03期

基金：

美国国家卫生研究院;

关键词：

GENOME-WIDE ASSOCIATION; IDENTIFIES VARIANTS; COMMON VARIANTS; ABCA7; ENDOPHENOTYPES; DISCOVERY; CD2AP; EPHA1; CD33; CLU;

D O I：

10.1212/WNL.0b013e3182605801

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

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 (similar to 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 x 10(-4)) and MS4A4A rs2304933/rs2304935 (p = 1.48 x 10(-4)-1.86 x 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 x 10(-5)-9.09 x 10(-9)), some of which also associate with AD risk (p = 2.64 x 10(-2)-6.25 x 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. Neurology(R) 2012;79:221-228

引用

页码：221 / 228

页数：8

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