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

Authors

  • Anna C. Cummings,

    1. Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, TN, USA
    Search for more papers by this author
  • Lan Jiang,

    1. Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, TN, USA
    Search for more papers by this author
  • Digna R. Velez Edwards,

    1. Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, TN, USA
    2. Vanderbilt Epidemiology Center, Vanderbilt University Medical Center, Nashville, TN, USA
    Search for more papers by this author
  • Jacob L. McCauley,

    1. Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA
    Search for more papers by this author
  • Renee Laux,

    1. Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, TN, USA
    Search for more papers by this author
  • Lynne L. McFarland,

    1. Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, TN, USA
    Search for more papers by this author
  • Denise Fuzzell,

    1. Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, TN, USA
    Search for more papers by this author
  • Clare Knebusch,

    1. Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, TN, USA
    Search for more papers by this author
  • Laura Caywood,

    1. Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA
    Search for more papers by this author
  • Lori Reinhart-Mercer,

    1. Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA
    Search for more papers by this author
  • Laura Nations,

    1. Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA
    Search for more papers by this author
  • John R. Gilbert,

    1. Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA
    Search for more papers by this author
  • Ioanna Konidari,

    1. Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA
    Search for more papers by this author
  • Michael Tramontana,

    1. School of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
    Search for more papers by this author
  • Michael L. Cuccaro,

    1. Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA
    Search for more papers by this author
  • William K. Scott,

    1. Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA
    Search for more papers by this author
  • Margaret A. Pericak-Vance,

    1. Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA
    Search for more papers by this author
  • Jonathan L. Haines

    Corresponding author
    1. Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, TN, USA
    Search for more papers by this author

Jonathan L. Haines, Center for Human Genetics Research, Vanderbilt University Medical Center, 519 Light Hall, Nashville, TN. Tel: 615–343-5851; Fax: 615–343-8619 37232-0700; E-mail: jonathan@chgr.mc.vanderbilt.edu

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.

Ancillary