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

Authors:
Sumit Middha, PhD
Sumit Middha, PhD
MSKCC
Principal Computational Biologist
next-gen sequencing NGS, bioinformatics, genomics
United States
Mariet Allen Fanggeng Zou High Seng Chai Curtis S Younkin Julia Crook V Shane Pankratz Minerva M Carrasquillo Christopher N Rowley Asha A Nair Sooraj Maharjan Thuy Nguyen Li Ma Kimberly G Malphrus Ryan Palusak Sarah Lincoln Gina Bisceglio Constantin Georgescu Debra Schultz Fariborz Rakhshan Christopher P Kolbert Jin Jen Jonathan L Haines Richard Mayeux Margaret A Pericak-Vance Lindsay A Farrer Gerard D Schellenberg Ronald C Petersen Neill R Graff-Radford Dennis W Dickson Steven G Younkin Nilüfer Ertekin-Taner Liana G Apostolova Steven E Arnold Clinton T Baldwin Robert Barber Michael M Barmada Thomas Beach Gary W Beecham Duane Beekly David A Bennett Eileen H Bigio Thomas D Bird Deborah Blacker Bradley F Boeve James D Bowen Adam Boxer James R Burke Jacqueline Buros Joseph D Buxbaum Nigel J Cairns Laura B Cantwell Chuanhai Cao Chris S Carlson Regina M Carney Steven L Carroll Helena C Chui David G Clark Jason Corneveaux Carl W Cotman Paul K Crane Carlos Cruchaga Jeffrey L Cummings Philip L De Jager Charles DeCarli Steven T DeKosky F Yesim Demirci Ramon Diaz-Arrastia Malcolm Dick Beth A Dombroski Ranjan Duara William D Ellis Denis Evans Kelley M Faber Kenneth B Fallon Martin R Farlow Steven Ferris Tatiana M Foroud Matthew Frosch Douglas R Galasko Paul J Gallins Mary Ganguli Marla Gearing Daniel H Geschwind Bernardino Ghetti John R Gilbert Sid Gilman Bruno Giordani Jonathan D Glass Alison M Goate Robert C Green John H Growdon Hakon Hakonarson Ronald L Hamilton John Hardy Lindy E Harrell Elizabeth Head Lawrence S Honig Matthew J Huentelman Christine M Hulette Bradley T Hyman Gail P Jarvik Gregory A Jicha Lee-Way Jin Gyungah Jun M Ilyas Kamboh Jason Karlawish Anna Karydas John S K Kauwe Jeffrey A Kaye Nancy Kennedy Ronald Kim Edward H Koo Neil W Kowall Patricia Kramer Walter A Kukull James J Lah Eric B Larson Allan I Levey Andrew P Lieberman Oscar L Lopez Kathryn L Lunetta Wendy J Mack Daniel C Marson Eden R Martin Frank Martiniuk Deborah C Mash Eliezer Masliah Wayne C McCormick Susan M McCurry Andrew N McDavid Ann C McKee Marsel Mesulam Bruce L Miller Carol A Miller Joshua W Miller Thomas J Montine John C Morris Amanda J Myers Adam C Naj Petra Nowotny Joseph E Parisi Daniel P Perl Elaine Peskind Wayne W Poon Huntington Potter Joseph F Quinn Ashok Raj Ruchita A Rajbhandary Murray Raskind Eric M Reiman Barry Reisberg Christiane Reitz John M Ringman Erik D Roberson Ekaterina Rogaeva Roger N Rosenberg Mary Sano Andrew J Saykin Julie A Schneider Lon S Schneider William Seeley Michael L Shelanski Michael A Slifer Charles D Smith Joshua A Sonnen Salvatore Spina Peter St George-Hyslop Robert A Stern Rudolph E Tanzi John Q Trojanowski Juan C Troncoso Debby W Tsuang Vivianna M Van Deerlin Badri Narayan Vardarajan Harry V Vinters Jean Paul Vonsattel Li-San Wang Sandra Weintraub Kathleen A Welsh-Bohmer Jennifer Williamson Randall L Woltjer

Neurology 2012 Jul 20;79(3):221-8. Epub 2012 Jun 20.

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

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.

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Source
http://dx.doi.org/10.1212/WNL.0b013e3182605801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3398432PMC
July 2012
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