title: Genome-wide association and linkage study in the Amish detects a novel candidate late-onset Alzheimer disease gene.
abstract: To identify novel late-onset Alzheimer disease (LOAD) risk genes, we have analysed Amish populations of Ohio and Indiana. We performed genome-wide SNP linkage and association studies on 798 individuals (109 with LOAD). We tested association using the Modified Quasi-Likelihood Score test and also performed two-point and multipoint linkage analyses. We found that LOAD was significantly associated with APOE (P= 9.0 × 10-6) in all our ascertainment regions except for the Adams County, Indiana, community (P= 0.55). Genome-wide, the most strongly associated SNP was rs12361953 (P= 7.92 × 10-7). A very strong, genome-wide significant multipoint peak [recessive heterogeneity multipoint LOD (HLOD) = 6.14, dominant HLOD = 6.05] was detected on 2p12. Three additional loci with multipoint HLOD scores >3 were detected on 3q26, 9q31 and 18p11. Converging linkage and association results, the most significantly associated SNP under the 2p12 peak was at rs2974151 (P= 1.29 × 10-4). This SNP is located in CTNNA2, which encodes catenin alpha 2, a neuronal-specific catenin known to have function in the developing brain. These results identify CTNNA2 as a novel candidate LOAD gene, and implicate three other regions of the genome as novel LOAD loci. These results underscore the utility of using family-based linkage and association analyses in isolated populations to identify novel loci for traits with complex genetic architecture.
authors.affiliation: Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Cummings
authors.forename: Lan
authors.initials: L
authors.lastname: Jiang
authors.forename: Digna R
authors.initials: DR
authors.lastname: Velez Edwards
authors.forename: Jacob L
authors.initials: JL
authors.lastname: McCauley
authors.forename: Renee
authors.initials: R
authors.lastname: Laux
authors.forename: Lynne L
authors.initials: LL
authors.lastname: McFarland
authors.forename: Denise
authors.initials: D
authors.lastname: Fuzzell
authors.forename: Clare
authors.initials: C
authors.lastname: Knebusch
authors.forename: Laura
authors.initials: L
authors.lastname: Caywood
authors.forename: Lori
authors.initials: L
authors.lastname: Reinhart-Mercer
authors.forename: Laura
authors.initials: L
authors.lastname: Nations
authors.forename: John R
authors.initials: JR
authors.lastname: Gilbert
authors.forename: Ioanna
authors.initials: I
authors.lastname: Konidari
authors.forename: Michael
authors.initials: M
authors.lastname: Tramontana
authors.forename: Michael L
authors.initials: ML
authors.lastname: Cuccaro
authors.forename: William K
authors.initials: WK
authors.lastname: Scott
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Pericak-Vance
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Haines
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics*; D061365:Amish / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics; D005260:Female; D008040:Genetic Linkage; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D051178:alpha Catenin / Q000235:genetics*
chemical_list: D001057:Apolipoproteins E; C079671:CTNNA2 protein, human; D051178:alpha Catenin