Genome-Wide Association and Linkage Study in the Amish Detects a Novel Candidate Late-Onset Alzheimer Disease Gene

Anna C. Cummings, Lan Jiang, Digna R. Velez Edwards, Jacob L McCauley, Renee Laux, Lynne L. Mcfarland, Denise Fuzzell, Clare Knebusch, Laura Caywood, Lori Reinhart-Mercer, Laura Nations, John Gilbert, Ioanna Konidari, Michael Tramontana, Michael Cuccaro, William K Scott, Margaret A Pericak-Vance, Jonathan L. Haines

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Summary: 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.

Original languageEnglish
Pages (from-to)342-351
Number of pages10
JournalAnnals of Human Genetics
Volume76
Issue number5
DOIs
StatePublished - Sep 1 2012

Fingerprint

Amish
Genome-Wide Association Study
Alzheimer Disease
Single Nucleotide Polymorphism
Genome
Genes
alpha Catenin
Catenins
Population
Brain

Keywords

  • Alzheimer
  • Amish
  • Founder population
  • GWAS
  • Linkage

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Genome-Wide Association and Linkage Study in the Amish Detects a Novel Candidate Late-Onset Alzheimer Disease Gene. / Cummings, Anna C.; Jiang, Lan; Velez Edwards, Digna R.; McCauley, Jacob L; Laux, Renee; Mcfarland, Lynne L.; Fuzzell, Denise; Knebusch, Clare; Caywood, Laura; Reinhart-Mercer, Lori; Nations, Laura; Gilbert, John; Konidari, Ioanna; Tramontana, Michael; Cuccaro, Michael; Scott, William K; Pericak-Vance, Margaret A; Haines, Jonathan L.

In: Annals of Human Genetics, Vol. 76, No. 5, 01.09.2012, p. 342-351.

Research output: Contribution to journalArticle

Cummings, AC, Jiang, L, Velez Edwards, DR, McCauley, JL, Laux, R, Mcfarland, LL, Fuzzell, D, Knebusch, C, Caywood, L, Reinhart-Mercer, L, Nations, L, Gilbert, J, Konidari, I, Tramontana, M, Cuccaro, M, Scott, WK, Pericak-Vance, MA & Haines, JL 2012, 'Genome-Wide Association and Linkage Study in the Amish Detects a Novel Candidate Late-Onset Alzheimer Disease Gene', Annals of Human Genetics, vol. 76, no. 5, pp. 342-351. https://doi.org/10.1111/j.1469-1809.2012.00721.x
Cummings, Anna C. ; Jiang, Lan ; Velez Edwards, Digna R. ; McCauley, Jacob L ; Laux, Renee ; Mcfarland, Lynne L. ; Fuzzell, Denise ; Knebusch, Clare ; Caywood, Laura ; Reinhart-Mercer, Lori ; Nations, Laura ; Gilbert, John ; Konidari, Ioanna ; Tramontana, Michael ; Cuccaro, Michael ; Scott, William K ; Pericak-Vance, Margaret A ; Haines, Jonathan L. / Genome-Wide Association and Linkage Study in the Amish Detects a Novel Candidate Late-Onset Alzheimer Disease Gene. In: Annals of Human Genetics. 2012 ; Vol. 76, No. 5. pp. 342-351.
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