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No association between marker D10S1423 and Alzheimer's disease

Molecular Psychiatry volume 8, pages 571–573 (2003)Cite this article

SIR – Recently, three studies reported genetic association of an anonymous microsatellite marker on chromosome 10p12 (D10S1423) and Alzheimer's disease (AD),1,2,3 whereas a fourth study failed to replicate these findings4. At least four linkage studies have implicated regions on chromosome 10 as likely to harbor an AD susceptibility gene5,6,7,8; however, all reported linkage peaks map considerably distal to D10S1423 (>40 cM). In an attempt to clarify these conflicting results, we have tested D10S1423 as well as two adjacent markers (D10S2325 and D10S1426) for association with AD in a large and well characterized sample of multiplex AD families using family-based methodologies. Our results show no evidence of association between any of these markers and disease phenotype, neither in the sample as a whole nor in subsamples stratified by APOE ɛ4-genotype or onset age. These negative findings are consistent with linkage analyses performed on the same sample5 and also with other independent linkage studies,6,7,8 suggesting that the putative chromosome 10 AD gene(s) is located considerably further distal (q-ter).

AD is a genetically complex and heterogeneous disorder in the sense that several genetic as well as nongenetic risk factors are believed to modify disease risk and/or onset age.9 Despite intensive research by a large number of laboratories worldwide, only one genetic risk factor has been established for the most common, late-onset form of the disease: the ɛ4-allele of the gene encoding apolipoprotein E (APOE) on chromosome 19.10 Although several lines of evidence suggest the existence of additional genetic risk factors, none of the association findings between AD and more than three dozen genes has been consistently replicated in independent follow-up analyses.9 The association described for marker D10S1423 is remarkable because three independent studies provided evidence of association between one of its alleles (‘234 bp’) and AD, but there is no evidence for genetic linkage in the corresponding chromosomal region (10p12) in any of the published full genome screens and this marker is not near any known mapped genes.10 Furthermore, the experiment-wide significance levels in at least two of the positive studies were only marginal,1,3 and the association was only evident when controlling for the presence of APOE ɛ4 in the third study.2 Finally, the fourth analysis, with the greatest number of cases, failed to replicate these findings altogether.4 Of note, several research groups using varying samples and various methods of linkage and/or association analysis5,6,7,8,11 have implicated chromosome 10 as harboring a novel AD locus. However, only one of these studies has reported a signal on the short arm of chromosome 10,11 whereas all other reports localize the putative AD gene on chromosome 10 at least 40–90 Mb downstream towards the long arm.

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Acknowledgements

This work was sponsored by grants from the NIMH, NIA (ADRC) and the Alzheimer Association. CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, Contract Number N01-HG-65403. LB was a fellow of the Deutsche Forschungsgemeinschaft (DFG) and the Harvard Center for Neurodegeneration and Repair (HCNR), and AJS is an NIA-NRSA recipient.

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Authors and Affiliations

  1. Department of Neurology, Genetics and Aging Research Unit, Center for Aging, Genetics and Neurodegeneration, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA

    L Bertram, A J Saunders, K Mullin, A Sampson & R E Tanzi

  2. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University Medical Institutions, Baltimore, MD, USA

    S S Basset

  3. Deptartment of Epidemiology, School of Public Health, Univ. of Alabama, Birmingham, AL, USA

    R C P Go

  4. Gerontology Research Unit, Dept. of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA

    T J Moscarillo & D Blacker

  5. Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA

    D Blacker

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  1. L Bertram
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Correspondence to R E Tanzi.

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Bertram, L., Saunders, A., Mullin, K. et al. No association between marker D10S1423 and Alzheimer's disease. Mol Psychiatry 8, 571–573 (2003). https://doi.org/10.1038/sj.mp.4001355

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