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

Mariet Allen, Fanggeng Zou, High Seng Chai, Curtis S. Younkin, Juliana Crook, V. Shane Pankratz, Minerva M Carrasquillo, Christopher N. Rowley, Asha A. Nair, Sumit Middha, Sooraj Maharjan, Thuy Nguyen, Li Ma, Kimberly G. Malphrus, Ryan Palusak, Sarah Lincoln, Gina Bisceglio, Constantin Georgescu, Debra Schultz, Fariborz RakhshanChristopher P. Kolbert, Jin Jen, Jonathan L. Haines, Richard Mayeux, Margaret A. Pericak-Vance, Lindsay A. Farrer, Gerard D. Schellenberg, Ronald Carl Petersen, Neill R Graff Radford, Dennis W Dickson, Steven G Younkin, Nilufer Taner

Research output: Contribution to journalArticle

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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 nfluence 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 evels 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.

Original languageEnglish (US)
Pages (from-to)221-228
Number of pages8
JournalNeurology
Volume79
Issue number3
DOIs
StatePublished - Jul 17 2012

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Alzheimer Disease
Gene Expression
Brain
Single Nucleotide Polymorphism
Genes
Temporal Lobe
Onset
Alzheimer's Disease
Locus
Genome-Wide Association Study
Cerebellum
Alleles
Gene
Pathology

ASJC Scopus subject areas

  • Clinical Neurology
  • Arts and Humanities (miscellaneous)

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Novel late-onset Alzheimer disease loci variants associate with brain gene expression. / Allen, Mariet; Zou, Fanggeng; Chai, High Seng; Younkin, Curtis S.; Crook, Juliana; Shane Pankratz, V.; 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 Carl; Graff Radford, Neill R; Dickson, Dennis W; Younkin, Steven G; Taner, Nilufer.

In: Neurology, Vol. 79, No. 3, 17.07.2012, p. 221-228.

Research output: Contribution to journalArticle

Allen, M, Zou, F, Chai, HS, Younkin, CS, Crook, J, Shane Pankratz, V, 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 & Taner, N 2012, 'Novel late-onset Alzheimer disease loci variants associate with brain gene expression', Neurology, vol. 79, no. 3, pp. 221-228. https://doi.org/10.1212/WNL.0b013e3182605801
Allen, Mariet ; Zou, Fanggeng ; Chai, High Seng ; Younkin, Curtis S. ; Crook, Juliana ; Shane Pankratz, V. ; 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 Carl ; Graff Radford, Neill R ; Dickson, Dennis W ; Younkin, Steven G ; Taner, Nilufer. / Novel late-onset Alzheimer disease loci variants associate with brain gene expression. In: Neurology. 2012 ; Vol. 79, No. 3. pp. 221-228.
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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 nfluence 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 evels 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.",
author = "Mariet Allen and Fanggeng Zou and Chai, {High Seng} and Younkin, {Curtis S.} and Juliana Crook and {Shane Pankratz}, V. and Carrasquillo, {Minerva M} and Rowley, {Christopher N.} and Nair, {Asha A.} and Sumit Middha and Sooraj Maharjan and Thuy Nguyen and Li Ma and Malphrus, {Kimberly G.} and Ryan Palusak and Sarah Lincoln and Gina Bisceglio and Constantin Georgescu and Debra Schultz and Fariborz Rakhshan and Kolbert, {Christopher P.} and Jin Jen and Haines, {Jonathan L.} and Richard Mayeux and Pericak-Vance, {Margaret A.} and Farrer, {Lindsay A.} and Schellenberg, {Gerard D.} and Petersen, {Ronald Carl} and {Graff Radford}, {Neill R} and Dickson, {Dennis W} and Younkin, {Steven G} and Nilufer Taner",
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T1 - Novel late-onset Alzheimer disease loci variants associate with brain gene expression

AU - Allen, Mariet

AU - Zou, Fanggeng

AU - Chai, High Seng

AU - Younkin, Curtis S.

AU - Crook, Juliana

AU - Shane Pankratz, V.

AU - Carrasquillo, Minerva M

AU - Rowley, Christopher N.

AU - Nair, Asha A.

AU - Middha, Sumit

AU - Maharjan, Sooraj

AU - Nguyen, Thuy

AU - Ma, Li

AU - Malphrus, Kimberly G.

AU - Palusak, Ryan

AU - Lincoln, Sarah

AU - Bisceglio, Gina

AU - Georgescu, Constantin

AU - Schultz, Debra

AU - Rakhshan, Fariborz

AU - Kolbert, Christopher P.

AU - Jen, Jin

AU - Haines, Jonathan L.

AU - Mayeux, Richard

AU - Pericak-Vance, Margaret A.

AU - Farrer, Lindsay A.

AU - Schellenberg, Gerard D.

AU - Petersen, Ronald Carl

AU - Graff Radford, Neill R

AU - Dickson, Dennis W

AU - Younkin, Steven G

AU - Taner, Nilufer

PY - 2012/7/17

Y1 - 2012/7/17

N2 - 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 nfluence 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 evels 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.

AB - 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 nfluence 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 evels 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.

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