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 R. Gilbert, Ioanna Konidari, Michael Tramontana, Michael L. Cuccaro, William K. Scott, Margaret A. Pericak-Vance, Jonathan L. Haines

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


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 (US)
Pages (from-to)342-351
Number of pages10
JournalAnnals of Human Genetics
Issue number5
StatePublished - Sep 2012


  • Alzheimer
  • Amish
  • Founder population
  • GWAS
  • Linkage

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics


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