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

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.

Changes in dihydrolipoamide dehydrogenase expression and activity during postnatal development and aging in the rat brain

“…Studies of adult DLDHdeficient mice have suggested that a partial decrease of DLDH, which is sufficient to diminish activity of its associated enzyme complexes (Johnson, et al, 1997), results in an elevated level of susceptibility to chemical neurotoxicity (Klivenyi, et al, 2004). Moreover, variations in the DLD gene have been linked to Alzheimer's disease (Brown, et al, 2004, Brown, et al, 2007.…”

Mitochondria and Alzheimer's disease

“…In another study, an analysis regarding the subhaplogroups of MtDNA showed that within the H haplogroup the H5 subtype showed the highest and most significant difference between AD patients and controls [49]. Other studies also reported differences in mitochondrial haplogroups in AD and many other studies are in progress on DNA and cells from different groups [50].…”

Metabolic study of Alzheimer’s disease using mutant C. elegans

“…Genetic association of the core metabolic enzyme DLD with late-onset AD [34]; and reduced activity of DLD-containing enzymes suggests glucose hypometabolism as a key factor in AD [36,38,444]. To determine how reduced glucose metabolism affects Aβ or tau toxicity in C.…”

“…Increased risk of late-onset Alzheimer's disease is genetically associated with four single nucleotide variants of dld, though how each variant specifically affects DLD enzyme activity is still unknown [34]. The dld gene encodes a core enzyme of energy metabolism in TCA cycle.…”

“…Increased risk of late-onset AD is genetically linked to the human dld locus [34]. The DLD enzyme is a subunit of three ketoacid dehydrogenase complexes, each of which contributes to energy metabolism, pyruvate dehydrogenase PDH, α-ketoglutarate dehydrogenase complex (KGDH) and branched chain ketoacid dehydrogenase complex (BCKDH) [35,443].…”