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Testing for Linkage and Association Across the Dihydrolipoyl Dehydrogenase Gene Region with Alzheimer’s Disease in Three Sample Populations

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Abstract

Prior case–control studies from our laboratory of a population enriched with individuals of Ashkenazi Jewish descent suggested that association exists between Alzheimer’s disease (AD) and the chromosomal region near the DLD gene, which encodes the mitochondrial dihydrolipoamide dehydrogenase enzyme. In support of this finding, we found that linkage analysis restricted to autopsy-proven patients in the National Institute of Mental Health–National Cell Repository for Alzheimer’s Disease (NIMH–NCRAD) Genetics Initiative pedigree data resulted in point-wise significant evidence for linkage (minimum p-value = 0.024) for a marker position close to the DLD locus. We now report case–control replication studies in two independent Caucasian series from the US and Italy, as well as a linkage analysis from the NIMH–NCRAD Genetics Initiative Database. Pair-wise analysis of the SNPs in the case–control series indicated there was strong linkage disequilibrium across the DLD locus in these populations, as previously reported. These findings suggest that testing for association of complex diseases with DLD locus should have considerable statistical power. Analysis of multi-locus genotypes or haplotypes based upon three SNP loci combined with results from our previous report provided trends toward significant evidence of association of DLD with AD, although neither of the present studies’ association showed significance at the 0.05 level. Combining linkage and association findings for all AD patients (males and females) results in a p-value that is more significant than any of the individual findings’ p-values. Finally, minimum sample size calculations using parameters from the DLD locus suggest that sample sizes on the order of 1,000 total cases and controls are needed to detect association for a wide range of genetic model parameters.

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Acknowledgments

This research was supported by NIH-AG14930 (JPB) and Winifred Masterson Burke Relief Foundation. Supported by the Italian Ministry of Instruction, University and Research grants 2005051707-005 and 2005062887-004. JH and FW-DV were supported by the NIA intramural program. Data and biomaterials were collected in three projects that participated in the NIMH Alzheimer Disease Genetics Initiative. From 1991 to 1998, the Principal Investigators and Co-Investigators were: Massachusetts General Hospital, Boston, MA, U01 MH46281, Marilyn S. Albert, Ph.D., and Deborah Blacker, M.D., Sc.D.; Johns Hopkins University, Baltimore, MD, U01 MH46290, Susan S. Bassett, Ph.D., Gary A. Chase, Ph.D., and Marshal F. Folstein, M.D.; University of Alabama, Birmingham, AL, U01 MH46373, Rodney C.P. Go, Ph.D., and Lindy E. Harrell, M.D. Electronic database information SNPbrowser software: www.allsnps.com/snpbrowser/ HAPMAP: www.hapmap.org GOLD: http://www.sph.umich.edu/csg/abecasis/GOLD/ PAWE-3D: http://linkage.rockefeller.edu/pawe3d/

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Authors and Affiliations

  1. Burke Medical Research Institute, 785 Mamaroneck Avenue, White Plains, NY, 10605, USA

    Abraham M. Brown, Hsinhwa Lee & John P. Blass

  2. Department of Biochemistry, Weill Medical College of Cornell University, New York, NY, 10021, USA

    Abraham M. Brown

  3. Department of Genetics, Rutgers University, Piscataway, NJ, 08854, USA

    Derek Gordon

  4. Laboratory of Neurogenetics, National Institute of Neurological Diseases and Stroke, Bethesda, MD, 20892, USA

    Fabienne Wavrant-De Vrièze & John Hardy

  5. Department of Neurological and Psychiatric Sciences, Viale Morgagni 85, 50134, Florence, Italy

    Elena Cellini, Silvia Bagnoli, Benedetta Nacmias & Sandro Sorbi

  6. Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY, 10021, USA

    John P. Blass

  7. Department of Medicine, Weill Medical College of Cornell University, New York, NY, 10021, USA

    John P. Blass

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  1. Abraham M. Brown
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Correspondence to Derek Gordon.

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Special issue dedicated to John P. Blass.

A.M. Brown and D. Gordon contributed equally to this work.

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Brown, A.M., Gordon, D., Lee, H. et al. Testing for Linkage and Association Across the Dihydrolipoyl Dehydrogenase Gene Region with Alzheimer’s Disease in Three Sample Populations. Neurochem Res 32, 857–869 (2007). https://doi.org/10.1007/s11064-006-9235-3

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