title: Late-onset Alzheimer disease risk variants mark brain regulatory loci.
abstract: OBJECTIVE
  To investigate the top late-onset Alzheimer disease (LOAD) risk loci detected or confirmed by the International Genomics of Alzheimer's Project for association with brain gene expression levels to identify variants that influence Alzheimer disease (AD) risk through gene expression regulation.
  
  
  METHODS
  Expression levels from the cerebellum (CER) and temporal cortex (TCX) were obtained using Illumina whole-genome cDNA-mediated annealing, selection, extension, and ligation assay (WG-DASL) for ∼400 autopsied patients (∼200 with AD and ∼200 with non-AD pathologies). We tested 12 significant LOAD genome-wide association study (GWAS) index single nucleotide polymorphisms (SNPs) for cis association with levels of 34 genes within ±100 kb. We also evaluated brain levels of 14 LOAD GWAS candidate genes for association with 1,899 cis-SNPs. Significant associations were validated in a subset of TCX samples using next-generation RNA sequencing (RNAseq).
  
  
  RESULTS
  We identified strong associations of brain CR1, HLA-DRB1, and PILRB levels with LOAD GWAS index SNPs. We also detected other strong cis-SNPs for LOAD candidate genes MEF2C, ZCWPW1, and SLC24A4. MEF2C and SLC24A4, but not ZCWPW1 cis-SNPs, also associate with LOAD risk, independent of the index SNPs. The TCX expression associations could be validated with RNAseq for CR1, HLA-DRB1, ZCWPW1, and SLC24A4.
  
  
  CONCLUSIONS
  Our results suggest that some LOAD GWAS variants mark brain regulatory loci, nominate genes under regulation by LOAD risk variants, and annotate these variants for their brain regulatory effects.
authors.affiliation: Department of Neuroscience (M.A., M.K., M.M.C., A.K., L. Manly, J.D.B., J.S., F.Z., C.Y., C.M., T.N., L. Ma, K.M., S.L., D.W.D., S.G.Y., N.E.-T.), Department of Neurology (N.R.G.-R., N.E.-T.), and Health Sciences Research (D.S., X.W., J.C., Y.W.A.), Mayo Clinic, Jacksonville, FL; Department of Neurology (R.C.P.) and Health Sciences Research (C.W., H.S.C.), Mayo Clinic, Rochester, MN; and Department of Neurology (J.S.), Medical University of Silesia, Katowice, Poland.
authors.forename: Mariet
authors.initials: M
authors.lastname: Allen
authors.affiliation: Department of Neuroscience (M.A., M.K., M.M.C., A.K., L. Manly, J.D.B., J.S., F.Z., C.Y., C.M., T.N., L. Ma, K.M., S.L., D.W.D., S.G.Y., N.E.-T.), Department of Neurology (N.R.G.-R., N.E.-T.), and Health Sciences Research (D.S., X.W., J.C., Y.W.A.), Mayo Clinic, Jacksonville, FL; Department of Neurology (R.C.P.) and Health Sciences Research (C.W., H.S.C.), Mayo Clinic, Rochester, MN; and Department of Neurology (J.S.), Medical University of Silesia, Katowice, Poland.
authors.forename: Michaela
authors.initials: M
authors.lastname: Kachadoorian
authors.affiliation: Department of Neuroscience (M.A., M.K., M.M.C., A.K., L. Manly, J.D.B., J.S., F.Z., C.Y., C.M., T.N., L. Ma, K.M., S.L., D.W.D., S.G.Y., N.E.-T.), Department of Neurology (N.R.G.-R., N.E.-T.), and Health Sciences Research (D.S., X.W., J.C., Y.W.A.), Mayo Clinic, Jacksonville, FL; Department of Neurology (R.C.P.) and Health Sciences Research (C.W., H.S.C.), Mayo Clinic, Rochester, MN; and Department of Neurology (J.S.), Medical University of Silesia, Katowice, Poland.
authors.forename: Minerva M
authors.initials: MM
authors.lastname: Carrasquillo
authors.affiliation: Department of Neuroscience (M.A., M.K., M.M.C., A.K., L. Manly, J.D.B., J.S., F.Z., C.Y., C.M., T.N., L. Ma, K.M., S.L., D.W.D., S.G.Y., N.E.-T.), Department of Neurology (N.R.G.-R., N.E.-T.), and Health Sciences Research (D.S., X.W., J.C., Y.W.A.), Mayo Clinic, Jacksonville, FL; Department of Neurology (R.C.P.) and Health Sciences Research (C.W., H.S.C.), Mayo Clinic, Rochester, MN; and Department of Neurology (J.S.), Medical University of Silesia, Katowice, Poland.
authors.forename: Aditya
authors.initials: A
authors.lastname: Karhade
authors.affiliation: Department of Neuroscience (M.A., M.K., M.M.C., A.K., L. Manly, J.D.B., J.S., F.Z., C.Y., C.M., T.N., L. Ma, K.M., S.L., D.W.D., S.G.Y., N.E.-T.), Department of Neurology (N.R.G.-R., N.E.-T.), and Health Sciences Research (D.S., X.W., J.C., Y.W.A.), Mayo Clinic, Jacksonville, FL; Department of Neurology (R.C.P.) and Health Sciences Research (C.W., H.S.C.), Mayo Clinic, Rochester, MN; and Department of Neurology (J.S.), Medical University of Silesia, Katowice, Poland.
authors.forename: Lester
authors.initials: L
authors.lastname: Manly
authors.affiliation: Department of Neuroscience (M.A., M.K., M.M.C., A.K., L. Manly, J.D.B., J.S., F.Z., C.Y., C.M., T.N., L. Ma, K.M., S.L., D.W.D., S.G.Y., N.E.-T.), Department of Neurology (N.R.G.-R., N.E.-T.), and Health Sciences Research (D.S., X.W., J.C., Y.W.A.), Mayo Clinic, Jacksonville, FL; Department of Neurology (R.C.P.) and Health Sciences Research (C.W., H.S.C.), Mayo Clinic, Rochester, MN; and Department of Neurology (J.S.), Medical University of Silesia, Katowice, Poland.
authors.forename: Jeremy D
authors.initials: JD
authors.lastname: Burgess
authors.affiliation: Department of Neuroscience (M.A., M.K., M.M.C., A.K., L. Manly, J.D.B., J.S., F.Z., C.Y., C.M., T.N., L. Ma, K.M., S.L., D.W.D., S.G.Y., N.E.-T.), Department of Neurology (N.R.G.-R., N.E.-T.), and Health Sciences Research (D.S., X.W., J.C., Y.W.A.), Mayo Clinic, Jacksonville, FL; Department of Neurology (R.C.P.) and Health Sciences Research (C.W., H.S.C.), Mayo Clinic, Rochester, MN; and Department of Neurology (J.S.), Medical University of Silesia, Katowice, Poland.
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Neuroscience (M.A., M.K., M.M.C., A.K., L. Manly, J.D.B., J.S., F.Z., C.Y., C.M., T.N., L. Ma, K.M., S.L., D.W.D., S.G.Y., N.E.-T.), Department of Neurology (N.R.G.-R., N.E.-T.), and Health Sciences Research (D.S., X.W., J.C., Y.W.A.), Mayo Clinic, Jacksonville, FL; Department of Neurology (R.C.P.) and Health Sciences Research (C.W., H.S.C.), Mayo Clinic, Rochester, MN; and Department of Neurology (J.S.), Medical University of Silesia, Katowice, Poland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Serie
authors.affiliation: Department of Neuroscience (M.A., M.K., M.M.C., A.K., L. Manly, J.D.B., J.S., F.Z., C.Y., C.M., T.N., L. Ma, K.M., S.L., D.W.D., S.G.Y., N.E.-T.), Department of Neurology (N.R.G.-R., N.E.-T.), and Health Sciences Research (D.S., X.W., J.C., Y.W.A.), Mayo Clinic, Jacksonville, FL; Department of Neurology (R.C.P.) and Health Sciences Research (C.W., H.S.C.), Mayo Clinic, Rochester, MN; and Department of Neurology (J.S.), Medical University of Silesia, Katowice, Poland.
authors.forename: Xue
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Neuroscience (M.A., M.K., M.M.C., A.K., L. Manly, J.D.B., J.S., F.Z., C.Y., C.M., T.N., L. Ma, K.M., S.L., D.W.D., S.G.Y., N.E.-T.), Department of Neurology (N.R.G.-R., N.E.-T.), and Health Sciences Research (D.S., X.W., J.C., Y.W.A.), Mayo Clinic, Jacksonville, FL; Department of Neurology (R.C.P.) and Health Sciences Research (C.W., H.S.C.), Mayo Clinic, Rochester, MN; and Department of Neurology (J.S.), Medical University of Silesia, Katowice, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Siuda
authors.affiliation: Department of Neuroscience (M.A., M.K., M.M.C., A.K., L. Manly, J.D.B., J.S., F.Z., C.Y., C.M., T.N., L. Ma, K.M., S.L., D.W.D., S.G.Y., N.E.-T.), Department of Neurology (N.R.G.-R., N.E.-T.), and Health Sciences Research (D.S., X.W., J.C., Y.W.A.), Mayo Clinic, Jacksonville, FL; Department of Neurology (R.C.P.) and Health Sciences Research (C.W., H.S.C.), Mayo Clinic, Rochester, MN; and Department of Neurology (J.S.), Medical University of Silesia, Katowice, Poland.
authors.forename: Fanggeng
authors.initials: F
authors.lastname: Zou
authors.affiliation: Department of Neuroscience (M.A., M.K., M.M.C., A.K., L. Manly, J.D.B., J.S., F.Z., C.Y., C.M., T.N., L. Ma, K.M., S.L., D.W.D., S.G.Y., N.E.-T.), Department of Neurology (N.R.G.-R., N.E.-T.), and Health Sciences Research (D.S., X.W., J.C., Y.W.A.), Mayo Clinic, Jacksonville, FL; Department of Neurology (R.C.P.) and Health Sciences Research (C.W., H.S.C.), Mayo Clinic, Rochester, MN; and Department of Neurology (J.S.), Medical University of Silesia, Katowice, Poland.
authors.forename: High Seng
authors.initials: HS
authors.lastname: Chai
authors.affiliation: Department of Neuroscience (M.A., M.K., M.M.C., A.K., L. Manly, J.D.B., J.S., F.Z., C.Y., C.M., T.N., L. Ma, K.M., S.L., D.W.D., S.G.Y., N.E.-T.), Department of Neurology (N.R.G.-R., N.E.-T.), and Health Sciences Research (D.S., X.W., J.C., Y.W.A.), Mayo Clinic, Jacksonville, FL; Department of Neurology (R.C.P.) and Health Sciences Research (C.W., H.S.C.), Mayo Clinic, Rochester, MN; and Department of Neurology (J.S.), Medical University of Silesia, Katowice, Poland.
authors.forename: Curtis
authors.initials: C
authors.lastname: Younkin
authors.affiliation: Department of Neuroscience (M.A., M.K., M.M.C., A.K., L. Manly, J.D.B., J.S., F.Z., C.Y., C.M., T.N., L. Ma, K.M., S.L., D.W.D., S.G.Y., N.E.-T.), Department of Neurology (N.R.G.-R., N.E.-T.), and Health Sciences Research (D.S., X.W., J.C., Y.W.A.), Mayo Clinic, Jacksonville, FL; Department of Neurology (R.C.P.) and Health Sciences Research (C.W., H.S.C.), Mayo Clinic, Rochester, MN; and Department of Neurology (J.S.), Medical University of Silesia, Katowice, Poland.
authors.forename: Julia
authors.initials: J
authors.lastname: Crook
authors.affiliation: Department of Neuroscience (M.A., M.K., M.M.C., A.K., L. Manly, J.D.B., J.S., F.Z., C.Y., C.M., T.N., L. Ma, K.M., S.L., D.W.D., S.G.Y., N.E.-T.), Department of Neurology (N.R.G.-R., N.E.-T.), and Health Sciences Research (D.S., X.W., J.C., Y.W.A.), Mayo Clinic, Jacksonville, FL; Department of Neurology (R.C.P.) and Health Sciences Research (C.W., H.S.C.), Mayo Clinic, Rochester, MN; and Department of Neurology (J.S.), Medical University of Silesia, Katowice, Poland.
authors.forename: Christopher
authors.initials: C
authors.lastname: Medway
authors.affiliation: Department of Neuroscience (M.A., M.K., M.M.C., A.K., L. Manly, J.D.B., J.S., F.Z., C.Y., C.M., T.N., L. Ma, K.M., S.L., D.W.D., S.G.Y., N.E.-T.), Department of Neurology (N.R.G.-R., N.E.-T.), and Health Sciences Research (D.S., X.W., J.C., Y.W.A.), Mayo Clinic, Jacksonville, FL; Department of Neurology (R.C.P.) and Health Sciences Research (C.W., H.S.C.), Mayo Clinic, Rochester, MN; and Department of Neurology (J.S.), Medical University of Silesia, Katowice, Poland.
authors.forename: Thuy
authors.initials: T
authors.lastname: Nguyen
authors.affiliation: Department of Neuroscience (M.A., M.K., M.M.C., A.K., L. Manly, J.D.B., J.S., F.Z., C.Y., C.M., T.N., L. Ma, K.M., S.L., D.W.D., S.G.Y., N.E.-T.), Department of Neurology (N.R.G.-R., N.E.-T.), and Health Sciences Research (D.S., X.W., J.C., Y.W.A.), Mayo Clinic, Jacksonville, FL; Department of Neurology (R.C.P.) and Health Sciences Research (C.W., H.S.C.), Mayo Clinic, Rochester, MN; and Department of Neurology (J.S.), Medical University of Silesia, Katowice, Poland.
authors.forename: Li
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Neuroscience (M.A., M.K., M.M.C., A.K., L. Manly, J.D.B., J.S., F.Z., C.Y., C.M., T.N., L. Ma, K.M., S.L., D.W.D., S.G.Y., N.E.-T.), Department of Neurology (N.R.G.-R., N.E.-T.), and Health Sciences Research (D.S., X.W., J.C., Y.W.A.), Mayo Clinic, Jacksonville, FL; Department of Neurology (R.C.P.) and Health Sciences Research (C.W., H.S.C.), Mayo Clinic, Rochester, MN; and Department of Neurology (J.S.), Medical University of Silesia, Katowice, Poland.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Malphrus
authors.affiliation: Department of Neuroscience (M.A., M.K., M.M.C., A.K., L. Manly, J.D.B., J.S., F.Z., C.Y., C.M., T.N., L. Ma, K.M., S.L., D.W.D., S.G.Y., N.E.-T.), Department of Neurology (N.R.G.-R., N.E.-T.), and Health Sciences Research (D.S., X.W., J.C., Y.W.A.), Mayo Clinic, Jacksonville, FL; Department of Neurology (R.C.P.) and Health Sciences Research (C.W., H.S.C.), Mayo Clinic, Rochester, MN; and Department of Neurology (J.S.), Medical University of Silesia, Katowice, Poland.
authors.forename: Sarah
authors.initials: S
authors.lastname: Lincoln
authors.affiliation: Department of Neuroscience (M.A., M.K., M.M.C., A.K., L. Manly, J.D.B., J.S., F.Z., C.Y., C.M., T.N., L. Ma, K.M., S.L., D.W.D., S.G.Y., N.E.-T.), Department of Neurology (N.R.G.-R., N.E.-T.), and Health Sciences Research (D.S., X.W., J.C., Y.W.A.), Mayo Clinic, Jacksonville, FL; Department of Neurology (R.C.P.) and Health Sciences Research (C.W., H.S.C.), Mayo Clinic, Rochester, MN; and Department of Neurology (J.S.), Medical University of Silesia, Katowice, Poland.
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Petersen
authors.affiliation: Department of Neuroscience (M.A., M.K., M.M.C., A.K., L. Manly, J.D.B., J.S., F.Z., C.Y., C.M., T.N., L. Ma, K.M., S.L., D.W.D., S.G.Y., N.E.-T.), Department of Neurology (N.R.G.-R., N.E.-T.), and Health Sciences Research (D.S., X.W., J.C., Y.W.A.), Mayo Clinic, Jacksonville, FL; Department of Neurology (R.C.P.) and Health Sciences Research (C.W., H.S.C.), Mayo Clinic, Rochester, MN; and Department of Neurology (J.S.), Medical University of Silesia, Katowice, Poland.
authors.forename: Neill R
authors.initials: NR
authors.lastname: Graff-Radford
authors.affiliation: Department of Neuroscience (M.A., M.K., M.M.C., A.K., L. Manly, J.D.B., J.S., F.Z., C.Y., C.M., T.N., L. Ma, K.M., S.L., D.W.D., S.G.Y., N.E.-T.), Department of Neurology (N.R.G.-R., N.E.-T.), and Health Sciences Research (D.S., X.W., J.C., Y.W.A.), Mayo Clinic, Jacksonville, FL; Department of Neurology (R.C.P.) and Health Sciences Research (C.W., H.S.C.), Mayo Clinic, Rochester, MN; and Department of Neurology (J.S.), Medical University of Silesia, Katowice, Poland.
authors.forename: Yan W
authors.initials: YW
authors.lastname: Asmann
authors.affiliation: Department of Neuroscience (M.A., M.K., M.M.C., A.K., L. Manly, J.D.B., J.S., F.Z., C.Y., C.M., T.N., L. Ma, K.M., S.L., D.W.D., S.G.Y., N.E.-T.), Department of Neurology (N.R.G.-R., N.E.-T.), and Health Sciences Research (D.S., X.W., J.C., Y.W.A.), Mayo Clinic, Jacksonville, FL; Department of Neurology (R.C.P.) and Health Sciences Research (C.W., H.S.C.), Mayo Clinic, Rochester, MN; and Department of Neurology (J.S.), Medical University of Silesia, Katowice, Poland.
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.affiliation: Department of Neuroscience (M.A., M.K., M.M.C., A.K., L. Manly, J.D.B., J.S., F.Z., C.Y., C.M., T.N., L. Ma, K.M., S.L., D.W.D., S.G.Y., N.E.-T.), Department of Neurology (N.R.G.-R., N.E.-T.), and Health Sciences Research (D.S., X.W., J.C., Y.W.A.), Mayo Clinic, Jacksonville, FL; Department of Neurology (R.C.P.) and Health Sciences Research (C.W., H.S.C.), Mayo Clinic, Rochester, MN; and Department of Neurology (J.S.), Medical University of Silesia, Katowice, Poland.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Younkin
authors.affiliation: Department of Neuroscience (M.A., M.K., M.M.C., A.K., L. Manly, J.D.B., J.S., F.Z., C.Y., C.M., T.N., L. Ma, K.M., S.L., D.W.D., S.G.Y., N.E.-T.), Department of Neurology (N.R.G.-R., N.E.-T.), and Health Sciences Research (D.S., X.W., J.C., Y.W.A.), Mayo Clinic, Jacksonville, FL; Department of Neurology (R.C.P.) and Health Sciences Research (C.W., H.S.C.), Mayo Clinic, Rochester, MN; and Department of Neurology (J.S.), Medical University of Silesia, Katowice, Poland.
authors.forename: Nilüfer
authors.initials: N
authors.lastname: Ertekin-Taner