title: Targeted sequencing of ABCA7 identifies splicing, stop-gain and intronic risk variants for Alzheimer disease.
abstract: Several variants in the gene ABCA7 have been identified as potential causal variants for late-onset Alzheimer's disease (LOAD). In order to replicate these findings, and search for novel causal variants, we performed targeted sequencing of this gene in cohorts of non-Hispanic White (NHW) and African-American (AA) LOAD cases and controls. We sequenced the gene ABCA7 in 291 NHW LOAD cases and 103 controls. Variants were prioritized for rare, damaging variants and previously reported variants associated with LOAD, and were follow-up genotyped in 4076 NHW and 1157 AA cases and controls. We confirm three previously associated ABCA7 risk variants and extend two of these associations to other populations, an intronic variant in NHW (P=3.0×10-3) (originally reported in a Belgian population), and a splice variant originally associated in the Icelandic population, which was significantly associated in the NHW cohort (P=1.2×10-6) and nominally associated in the AA cohort (P=0.017). We also identify a 3'-UTR splice variant that segregates in four siblings of one family and is nominally associated with LOAD (P=0.040). Multiple variants in ABCA7 contribute to LOAD risk.
authors.affiliation: John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: B W
authors.initials: BW
authors.lastname: Kunkle
authors.affiliation: John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA; Miami Veterans' Affairs Medical Center, Miami, FL, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Carney
authors.affiliation: John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Kohli
authors.affiliation: John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA; Department of Biostatistics & Epidemiology, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: A C
authors.initials: AC
authors.lastname: Naj
authors.affiliation: John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: K L
authors.initials: KL
authors.lastname: Hamilton-Nelson
authors.affiliation: John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: P L
authors.initials: PL
authors.lastname: Whitehead
authors.affiliation: John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Biology, North Carolina A & T University, Greensboro, NC, USA.
authors.forename: R
authors.initials: R
authors.lastname: Lang
authors.affiliation: John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: M L
authors.initials: ML
authors.lastname: Cuccaro
authors.affiliation: John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Vance
authors.affiliation: Department of Biology, North Carolina A & T University, Greensboro, NC, USA.
authors.forename: G S
authors.initials: GS
authors.lastname: Byrd
authors.affiliation: John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: G W
authors.initials: GW
authors.lastname: Beecham
authors.affiliation: John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Gilbert
authors.affiliation: John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: E R
authors.initials: ER
authors.lastname: Martin
authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Haines
authors.affiliation: John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA. Electronic address: m.pericakvance@miami.edu.
authors.forename: M A
authors.initials: MA
authors.lastname: Pericak-Vance
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D001741:Black or African American / Q000235:genetics; D000544:Alzheimer Disease / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007438:Introns; D008297:Male; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D044465:White People / Q000235:genetics
chemical_list: C411895:ABCA7 protein, human; D018528:ATP-Binding Cassette Transporters
keywords: ABCA7; Alzheimer; Genetics; Intronic; Sequencing; Splicing