title: ABCA7loss-of-function variants, expression, and neurologic disease risk.
abstract: OBJECTIVE
  To investigate and characterize putative "loss-of-function" (LOF) adenosine triphosphate-binding cassette, subfamily A member 7 (ABCA7) mutations reported to associate with Alzheimer disease (AD) risk.
  
  
  METHODS
  We genotyped 6 previously reportedABCA7putative LOF variants in 1,465 participants with AD, 381 participants with other neuropathologies (non-AD), and 1,043 controls and assessed the overall mutational burden for association with different diagnosis groups. We measured brain ABCA7 protein and messenger RNA (mRNA) levels using Western blot and quantitative PCR, respectively, in 11 carriers of the 3 most common variants, and sequenced all 47 ABCA7 exons in these participants to screen for other coding variants.
  
  
  RESULTS
  At least one of the investigated variants was identified in 45 participants with late-onset Alzheimer disease, 12 participants with other neuropathologies, and 11 elderly controls. Association analysis revealed a significantly higher burden of these variants in participants with AD (p= 5.00E-04) and those with other neuropathologies (p= 8.60E-03) when compared with controls. Concurrent analysis of brain ABCA7 mRNA and protein revealed lower protein but not mRNA in p.L1403fs carriers, lower mRNA but not protein in p.E709fs carriers, and additional deleterious mutations in some c.5570+5G>C carriers.
  
  
  CONCLUSIONS
  Our results suggest that LOF may not be a common mechanism for theseABCA7variants and expand the list of neurologic diseases enriched for them.
authors.affiliation: Form the Department of Neuroscience (M.A., S.J.L., M.C., J.O.W., M.M.C., J.S.R., J.D.B., T.N., K.M., D.W.D., N.E.-T.), Department of Neurology (N.R.G.-R., N.E.-T.), Mayo Clinic, Jacksonville, FL; and Department of Neurology (R.C.P.), Mayo Clinic, Rochester, MN.
authors.forename: Mariet
authors.initials: M
authors.lastname: Allen
authors.affiliation: Form the Department of Neuroscience (M.A., S.J.L., M.C., J.O.W., M.M.C., J.S.R., J.D.B., T.N., K.M., D.W.D., N.E.-T.), Department of Neurology (N.R.G.-R., N.E.-T.), Mayo Clinic, Jacksonville, FL; and Department of Neurology (R.C.P.), Mayo Clinic, Rochester, MN.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Lincoln
authors.affiliation: Form the Department of Neuroscience (M.A., S.J.L., M.C., J.O.W., M.M.C., J.S.R., J.D.B., T.N., K.M., D.W.D., N.E.-T.), Department of Neurology (N.R.G.-R., N.E.-T.), Mayo Clinic, Jacksonville, FL; and Department of Neurology (R.C.P.), Mayo Clinic, Rochester, MN.
authors.forename: Morgane
authors.initials: M
authors.lastname: Corda
authors.affiliation: Form the Department of Neuroscience (M.A., S.J.L., M.C., J.O.W., M.M.C., J.S.R., J.D.B., T.N., K.M., D.W.D., N.E.-T.), Department of Neurology (N.R.G.-R., N.E.-T.), Mayo Clinic, Jacksonville, FL; and Department of Neurology (R.C.P.), Mayo Clinic, Rochester, MN.
authors.forename: Jens O
authors.initials: JO
authors.lastname: Watzlawik
authors.affiliation: Form the Department of Neuroscience (M.A., S.J.L., M.C., J.O.W., M.M.C., J.S.R., J.D.B., T.N., K.M., D.W.D., N.E.-T.), Department of Neurology (N.R.G.-R., N.E.-T.), Mayo Clinic, Jacksonville, FL; and Department of Neurology (R.C.P.), Mayo Clinic, Rochester, MN.
authors.forename: Minerva M
authors.initials: MM
authors.lastname: Carrasquillo
authors.affiliation: Form the Department of Neuroscience (M.A., S.J.L., M.C., J.O.W., M.M.C., J.S.R., J.D.B., T.N., K.M., D.W.D., N.E.-T.), Department of Neurology (N.R.G.-R., N.E.-T.), Mayo Clinic, Jacksonville, FL; and Department of Neurology (R.C.P.), Mayo Clinic, Rochester, MN.
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Reddy
authors.affiliation: Form the Department of Neuroscience (M.A., S.J.L., M.C., J.O.W., M.M.C., J.S.R., J.D.B., T.N., K.M., D.W.D., N.E.-T.), Department of Neurology (N.R.G.-R., N.E.-T.), Mayo Clinic, Jacksonville, FL; and Department of Neurology (R.C.P.), Mayo Clinic, Rochester, MN.
authors.forename: Jeremy D
authors.initials: JD
authors.lastname: Burgess
authors.affiliation: Form the Department of Neuroscience (M.A., S.J.L., M.C., J.O.W., M.M.C., J.S.R., J.D.B., T.N., K.M., D.W.D., N.E.-T.), Department of Neurology (N.R.G.-R., N.E.-T.), Mayo Clinic, Jacksonville, FL; and Department of Neurology (R.C.P.), Mayo Clinic, Rochester, MN.
authors.forename: Thuy
authors.initials: T
authors.lastname: Nguyen
authors.affiliation: Form the Department of Neuroscience (M.A., S.J.L., M.C., J.O.W., M.M.C., J.S.R., J.D.B., T.N., K.M., D.W.D., N.E.-T.), Department of Neurology (N.R.G.-R., N.E.-T.), Mayo Clinic, Jacksonville, FL; and Department of Neurology (R.C.P.), Mayo Clinic, Rochester, MN.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Malphrus
authors.affiliation: Form the Department of Neuroscience (M.A., S.J.L., M.C., J.O.W., M.M.C., J.S.R., J.D.B., T.N., K.M., D.W.D., N.E.-T.), Department of Neurology (N.R.G.-R., N.E.-T.), Mayo Clinic, Jacksonville, FL; and Department of Neurology (R.C.P.), Mayo Clinic, Rochester, MN.
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Petersen
authors.affiliation: Form the Department of Neuroscience (M.A., S.J.L., M.C., J.O.W., M.M.C., J.S.R., J.D.B., T.N., K.M., D.W.D., N.E.-T.), Department of Neurology (N.R.G.-R., N.E.-T.), Mayo Clinic, Jacksonville, FL; and Department of Neurology (R.C.P.), Mayo Clinic, Rochester, MN.
authors.forename: Neill R
authors.initials: NR
authors.lastname: Graff-Radford
authors.affiliation: Form the Department of Neuroscience (M.A., S.J.L., M.C., J.O.W., M.M.C., J.S.R., J.D.B., T.N., K.M., D.W.D., N.E.-T.), Department of Neurology (N.R.G.-R., N.E.-T.), Mayo Clinic, Jacksonville, FL; and Department of Neurology (R.C.P.), Mayo Clinic, Rochester, MN.
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.affiliation: Form the Department of Neuroscience (M.A., S.J.L., M.C., J.O.W., M.M.C., J.S.R., J.D.B., T.N., K.M., D.W.D., N.E.-T.), Department of Neurology (N.R.G.-R., N.E.-T.), Mayo Clinic, Jacksonville, FL; and Department of Neurology (R.C.P.), Mayo Clinic, Rochester, MN.
authors.forename: Nilüfer
authors.initials: N
authors.lastname: Ertekin-Taner