Neurochemical Research

, Volume 32, Issue 4–5, pp 857–869 | Cite as

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

  • Abraham M. Brown
  • Derek GordonEmail author
  • Hsinhwa Lee
  • Fabienne Wavrant-De Vrièze
  • Elena Cellini
  • Silvia Bagnoli
  • Benedetta Nacmias
  • Sandro Sorbi
  • John Hardy
  • John P. Blass
Original Paper


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.


Energy metabolism Mitochondria Gene Alzheimer’s disease Polymorphism M-test Heterogeneity Diagnostic error Diagnosis Misclassification 



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: HAPMAP: GOLD: PAWE-3D:


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Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Abraham M. Brown
    • 1
    • 2
  • Derek Gordon
    • 3
    Email author
  • Hsinhwa Lee
    • 1
  • Fabienne Wavrant-De Vrièze
    • 4
  • Elena Cellini
    • 5
  • Silvia Bagnoli
    • 5
  • Benedetta Nacmias
    • 5
  • Sandro Sorbi
    • 5
  • John Hardy
    • 4
  • John P. Blass
    • 1
    • 6
    • 7
  1. 1.Burke Medical Research Institute, 785 Mamaroneck AvenueWhite PlainsUSA
  2. 2.Department of BiochemistryWeill Medical College of Cornell UniversityNew YorkUSA
  3. 3.Department of GeneticsRutgers UniversityPiscatawayUSA
  4. 4.Laboratory of NeurogeneticsNational Institute of Neurological Diseases and StrokeBethesdaUSA
  5. 5.Department of Neurological and Psychiatric Sciences, Viale Morgagni 85FlorenceItaly
  6. 6.Department of Neurology and NeuroscienceWeill Medical College of Cornell UniversityNew YorkUSA
  7. 7.Department of MedicineWeill Medical College of Cornell UniversityNew YorkUSA

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