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Implication of Additional Loci

Joseph H. Lee, DrPH; Rong Cheng, PhD; Neill Graff-Radford, MD; Tatiana Foroud, PhD; Richard Mayeux, MD, MSc; for the National Institute on Aging Late-Onset Alzheimer's Disease Family Study Group

Arch Neurol. 2008;65(11):1518-1526.

Objective  To identify putative genetic loci related to the risk of late-onset Alzheimer disease (LOAD).

Design  Linkage analysis and family-based and case-control association analyses from a genomewide scan using approximately 6000 single-nucleotide polymorphic markers at an average intermarker distance of 0.65 cM.

Setting  The National Institute on Aging Genetics Initiative for Late-Onset Alzheimer's Disease (NIA-LOAD) was created to expand the resources for studies to identify additional genes contributing to the risk for LOAD.

Participants  We investigated 1902 individuals from 328 families with LOAD and 236 unrelated control subjects.

Main Outcome Measures  Clinical diagnosis of LOAD.

Results  The strongest overall finding was at chromosome 19q13.32, confirming the effect of the apolipoprotein E gene on LOAD risk in the family-based and case-control analyses. However, single-nucleotide polymorphisms at the following loci were also statistically significant in 1 or more of the analyses performed: 7p22.2, 7p21.3, and 16q21 in the linkage analyses; 17q21.31 and 22q11.21 in the family-based association analysis; and 7q31.1 and 22q12.3 in the case-control analysis. Positive associations at 7q31.1 and 20q13.33 were also significant in the meta-analysis results in a publicly available database.

Conclusions  Several additional loci may harbor genetic variants associated with LOAD. This data set provides a wealth of phenotypic and genotypic information for use as a resource in discovery and confirmatory research.

Author Affiliations: Gertrude H. Sergievsky Center, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University College of Physicians and Surgeons, New York, New York (Drs Lee, Cheng, and Mayeux); Department of Neurology, Mayo Clinic, Jacksonville, Florida (Dr Graff-Radford); and Department of Medical and Molecular Genetics, Indiana University, Indianapolis (Dr Foroud).

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