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.
Similar content being viewed by others
References
Gibson GE, Sheu KF, Blass JP, Baker A, Carlson KC, Harding B, Perrino P (1988) Reduced activities of thiamine dependent enzymes in brains and peripheral tissues of Alzheimer’s patients. Arch Neurol 45:836–840
Gibson GE, Sheu KF, Blass JP (1998) Abnormalities of mitochondrial enzymes in Alzheimer disease. J Neural Transm 105:855–870
Mastrogiacoma F, Lindsay JG, Bettendorff L, Rice J, Kish SJ (1996) Brain protein and alpha-ketoglutarate dehydrogenase complex activity in Alzheimer’s disease. Ann Neurol 39:592–598
Sorbi S, Bird ED, Blass JP (1983) Decreased pyruvate dehydrogenase complex activity in Huntington and Alzheimer brain. Ann Neurol 13:72–78
Yates CM, Butterworth J, Tennant MC, Gordon A (1990) Enzyme activities in relation to pH and lactate in postmortem brain in Alzheimer-type and other dementias. J Neurochem 55:1624–1630
Brown AM, Gordon D, Lee H, Xu Y, Caudy M, Hardy J, Haroutunian V, Blass JP (2004) Association of the dihydrolipoamide dehydrogenase gene with Alzheimer’s disease in an Ashkenazi Jewish population. Am J Med Genet 131B:60–66
Pericak-Vance MA, Grubber J, Bailey LR, Hedges D, West S, Santoro L, Kemmerer B, Hall JL, Saunders AM, Roses AD, Small GW, Scott WK, Conneally PM, Vance JM, Haines JL (2000) Identification of novel genes in late-onset Alzheimer’s disease. Exp Gerontol 35:1343–1352
Liu TC, Kim H, Arizmendi C, Kitano A, Patel MS (1993) Identification of two missense mutations in a dihydrolipoamide dehydrogenase-deficient patient. Proc Natl Acad Sci USA 90:5186–5190
Hong YS, Kerr DS, Craigen WJ, Tan J, Pan Y, Lusk M, Patel MS (1996) Identification of two mutations in a compound heterozygous child with dihydrolipoamide dehydrogenase deficiency. Hum Mol Genet 5:1925–1930
Hong YS, Kerr DS, Liu TC, Lusk M, Powell BR, Patel MS (1997) Deficiency of dihydrolipoamide dehydrogenase due to two mutant alleles (E340K and G101del). Analysis of a family and prenatal testing. Biochim Biophys Acta 1362:160–168
Blacker D, Bertram L, Saunders AJ, Moscarillo TJ, Albert MS, Wiener H, Perry RT, Collins JS, Harrell LE, Go RC, Mahoney A, Beaty T, Fallin MD, Avramopoulos D, Chase GA, Folstein MF, McInnis MG, Bassett SS, Doheny KJ, Pugh EW, Tanzi RE (2003) Results of a high-resolution genome screen of 437 Alzheimer’s disease families. Hum Mol Genet 12:23–32
Kruglyak L, Daly MJ, Reeve-Daly MP, Lander ES (1996) Parametric and nonparametric linkage analysis: a unified multipoint approach. Am J Hum Genet 58:1347–1363
Kong A, Cox NJ (1997) Allele-sharing models: LOD scores and accurate linkage tests. Am J Hum Genet 61:1179–1188
Gordon D, Haynes C, Finch SJ, Brown AM (2006) Increase in linkage information by stratification of pedigree data into gold-standard and standard diagnoses: application to the NIMH Alzheimer Disease Genetics Initiative Dataset. Hum Hered 61:97–103
Morton NE (1956) The detection and estimation of linkage between the genes for elliptocytosis and the Rh blood type. Am J Hum Genet 8:80–96
Blacker D, Albert MS, Bassett SS, Go RC, Harrell LE, Folstein MF (1994) Reliability and validity of NINCDS-ADRDA criteria for Alzheimer’s disease. The National Institute of Mental Health Genetics Initiative. Arch Neurol 51:1198–1204
Blacker D, Haines JL, Rodes L, Terwedow H, Go RC, Harrell LE, Perry RT, Bassett SS, Chase G, Meyers D, Albert MS, Tanzi R (1997) ApoE-4 and age at onset of Alzheimer’s disease: the NIMH genetics initiative. Neurology 48:139–147
McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 34:939–944
Nacmias B, Bagnoli S, Tedde A, Cellini E, Guarnieri BM, Bartoli A, Serio A, Piacentini S, Sorbi S (2006) Cystatin C and apoe polymorphisms in Italian Alzheimer’s disease. Neurosci Lett 392:110–113
American Psychiatric Association (1994) Diagnostic and statistical manual of mental disorders. American Psychiatric Association, Washington
The Dementia Study Group of the Italian Neurological Society (2000) Guidelines for the diagnosis of dementia and Alzheimer’s disease. The Dementia Study Group of the Italian Neurological Society. Neurol Sci 21:187–194
Hosking L, Lumsden S, Lewis K, Yeo A, McCarthy L, Bansal A, Riley J, Purvis I, Xu CF (2004) Detection of genotyping errors by Hardy–Weinberg equilibrium testing. Eur J Hum Genet 12:395–399
Kang SJ, Gordon D, Finch SJ (2004) What SNP genotyping errors are most costly for genetic association studies?. Genet Epidemiol 26:132–141
Leal SM (2005) Detection of genotyping errors and pseudo-SNPs via deviations from Hardy–Weinberg equilibrium. Genet Epidemiol 29:204–214
Cox DG, Kraft P (2006) Quantification of the power of Hardy–Weinberg equilibrium testing to detect genotyping error. Hum Hered 61:10–14
Lewontin RC (1964) The interaction of selection and linkage. I. General considerations; heterotic models. Genetics 49:49–67
Abecasis GR, Cookson WO (2000) GOLD—graphical overview of linkage disequilibrium. Bioinformatics 16:182–183
Smith CAB (1963) Testing for heterogeneity of recombination fraction values in human genetics. Ann Hum Genet 27:175–182
Ott J (1999) Analysis of human genetic linkage. Johns Hopkins, Baltimore
Schaid DJ (1999) Case-parents design for gene-environment interaction. Genet Epidemiol 16:261–273
Single RM, Meyer D, Hollenbach JA, Nelson MP, Noble JA, Erlich HA, Thomson G (2002) Haplotype frequency estimation in patient populations: the effect of departures from Hardy–Weinberg proportions and collapsing over a locus in the HLA region. Genet Epidemiol 22:186–195
Agresti A (2002) Categorical data analysis. In: Wiley series in probability and statistics. Wiley, Hoboken, 710 pp
Fisher RA (1960) The design of experiments. Oliver and Boyd, Edinburgh
Freeman GH, Halton JH (1951) Note on an exact treatment of contingency, goodness of fit and other problems of significance. Biometrika 38:141–149
Fisher RA (1970) Statistical methods for research workers. Hafner/MacMillan, New York
Westfall PH, Young SS (1993) Resampling-based multiple testing. Wiley, New York
Hill WG, Weir BS (1994) Maximum-likelihood estimation of gene location by linkage disequilibrium. Am J Hum Genet 54:705–714
Purcell S, Cherny SS, Sham PC (2003) Genetic power calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics 19:149–150
Gordon D, Finch SJ, Nothnagel M, Ott J (2002) Power and sample size calculations for case–control genetic association tests when errors are present: application to single nucleotide polymorphisms. Hum Hered 54:22–33
Gordon D, Haynes C, Blumenfeld J, Finch SJ (2005) PAWE-3D: visualizing power for association with error in case–control genetic studies of complex traits. Bioinformatics 21:3935–3937
Gordon D, Simonic I, Ott J (2000) Significant evidence for linkage disequilibrium over a 5-cM region among Afrikaners. Genomics 66:87–92
Pandit B, Ahn GS, Hazard SE, Gordon D, Patel SB (2006) A detailed HapMap of the Sitosterolemia locus spanning 69 kb; differences between Caucasians and African-Americans. BMC Med Genet 7:13
Schaid DJ, Sommer SS (1993) Genotype relative risks: methods for design and analysis of candidate-gene association studies. Am J Hum Genet 53:1114–1126
Zondervan KT, Cardon LR (2004) The complex interplay among factors that influence allelic association. Nat Rev Genet 5:89–100
Pfeiffer RM, Gail MH (2003) Sample size calculations for population- and family-based case–control association studies on marker genotypes. Genet Epidemiol 25:136–148
Tu IP, Whittemore AS (1999) Power of association and linkage tests when the disease alleles are unobserved. Am J Hum Genet 64:641–649
Abel L, Muller-Myhsok B (1998) Maximum-likelihood expression of the transmission/disequilibrium test and power considerations. Am J Hum Genet 63:664–667
De La Vega FM, Gordon D, Su X, Scafe C, Isaac H, Gilbert DA, Spier EG (2005) Power and sample size calculations for genetic case/control studies using gene-centric SNP maps: application to human chromosomes 6, 21, and 22 in three populations. Hum Hered 60:43–60
Ji F, Yang Y, Haynes C, Finch SJ, Gordon D (2005) Computing asymptotic power and sample size for case–control genetic association studies in the presence of phenotype and/or genotype misclassification errors. Stat Appl Genet Mol Biol 4:Article 37
Gordon D, Finch SJ (2005) Factors affecting statistical power in the detection of genetic association. J Clin Invest 115:1408–1418
Sasieni PD (1997) From genotypes to genes: doubling the sample size. Biometrics 53:1253–1261
Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261:921–923
Consortium IH (2005) A haplotype map of the human genome. Nature 437:1299–1320
Mayeux R, Saunders AM, Shea S, Mirra S, Evans D, Roses AD, Hyman BT, Crain B, Tang MX, Phelps CH (1998) Utility of the apolipoprotein E genotype in the diagnosis of Alzheimer’s disease. Alzheimer’s Disease Centers Consortium on Apolipoprotein E and Alzheimer’s Disease. N Engl J Med 338:506–511
Daly MJ, Rioux JD, Schaffner SF, Hudson TJ, Lander ES (2001) High-resolution haplotype structure in the human genome. Nat Genet 29:229–232
The International HapMap Consortium (2003) The International HapMap Project. Nature 426:789–796
Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD (1993) Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci USA 90:1977–1981
Wise LH, Lanchbury JS, Lewis CM (1999) Meta-analysis of genome searches. Ann Hum Genet 63:263–272
Wise LH, Lewis CM (1999) A method for meta-analysis of genome searches: application to simulated data. Genet Epidemiol 17(Suppl 1):S767–S771
Pritchard JK (2001) Are rare variants responsible for susceptibility to complex diseases?. Am J Hum Genet 69:124–137
International HapMap Consortium (2005) A haplotype map of the human genome. Nature 437:1299–1320
Thorisson GA, Smith AV, Krishnan L, Stein LD (2005) The International HapMap Project Web site. Genome Res 15:1592–1593
Pritchard JK, Przeworski M (2001) Linkage disequilibrium in humans: models and data. Am J Hum Genet 69:1–14
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/
Author information
Authors and Affiliations
Corresponding author
Additional information
Special issue dedicated to John P. Blass.
A.M. Brown and D. Gordon contributed equally to this work.
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11064-006-9235-3