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Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database

Nature Genetics volume 39, pages 1723 (2007) | Download Citation

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Abstract

The past decade has witnessed hundreds of reports declaring or refuting genetic association with putative Alzheimer disease susceptibility genes. This wealth of information has become increasingly difficult to follow, much less interpret. We have created a publicly available, continuously updated database that comprehensively catalogs all genetic association studies in the field of Alzheimer disease (http://www.alzgene.org). We performed systematic meta-analyses for each polymorphism with available genotype data in at least three case-control samples. In addition to identifying the ε4 allele of APOE and related effects, we pinpointed over a dozen potential Alzheimer disease susceptibility genes (ACE, CHRNB2, CST3, ESR1, GAPDHS, IDE, MTHFR, NCSTN, PRNP, PSEN1, TF, TFAM and TNF) with statistically significant allelic summary odds ratios (ranging from 1.11–1.38 for risk alleles and 0.92–0.67 for protective alleles). Our database provides a powerful tool for deciphering the genetics of Alzheimer disease, and it serves as a potential model for tracking the most viable gene candidates in other genetically complex diseases.

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Acknowledgements

We are grateful to the Alzheimer Research Forum for hosting AlzGene on their website. In particular, we would like to thank J. Kinoshita, C. Knep and P. Noyes for the online adaptation of AlzGene and many helpful discussions. We would also like to thank the members of the Scientific Advisory Board for their comments and suggestions before and during the development of the database (http://www.alzforum.org/res/com/gen/alzgene/credits.asp), C. Lange for helpful discussions regarding the power calculations and B. Hooli for help with computer programing. Funding for this study was provided by an anonymous donor.

Author information

Affiliations

  1. Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease (MIND), Department of Neurology, Massachusetts General Hospital, Charlestown, Massachusetts, 02129, USA.

    • Lars Bertram
    • , Kristina Mullin
    •  & Rudolph E Tanzi
  2. Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, 02115 USA.

    • Matthew B McQueen
    •  & Deborah Blacker
  3. Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado, 80309, USA.

    • Matthew B McQueen
  4. Gerontology Research Unit, Department of Psychiatry, Massachusetts General Hospital, Charlestown, Massachusetts, 02129, USA.

    • Deborah Blacker

Authors

  1. Search for Lars Bertram in:

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Contributions

This study was designed by L.B. (principal investigator), M.B.M., D.B. and R.E.T. Literature searches, data entry and online curation of data were performed by K.M. and L.B. Analysis scripts were developed and written by M.B.M., and analyses were performed by M.B.M. and L.B. The manuscript was written by L.B., with contributions from M.B.M., D.B. and R.E.T.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Lars Bertram.

Supplementary information

PDF files

  1. 1.

    Supplementary Fig. 1

    Overview of literature searches and flow chart for studies in “data freeze” used for all analyses presented in this study.

  2. 2.

    Supplementary Fig. 2

    Forest plots of random effects meta-analyses using allelic contrasts for polymorphisms showing significant summary ORs (“positive” genes; current on 12/1/05).

  3. 3.

    Supplementary Fig. 3

    Begg modified funnel plots of random effects meta-analyses using allelic contrasts for polymorphisms showing significant summary ORs (“positive” genes; current on 12/1/05).

  4. 4.

    Supplementary Table 1

    Number of AD genetic association studies identified in AlzGene vs. two other publicly available databases for ten randomly selected genes (current on March 21st 2006).

  5. 5.

    Supplementary Table 2

    Overview of all 130 polymorphisms with genotype data available in at least three independent case-control samples in AlzGene on 12/1/05 (referred to as “data freeze” in the paper).

  6. 6.

    Supplementary Table 3

    Random effects meta-analyses and HWE sensitivity analyses comparing allele vs. genotype contrasts for polymorphisms showing significant summary ORs in the allelic analyses (“positive” results, displayed in Table 2; current on 12/1/05).

  7. 7.

    Supplementary Table 4

    Population attributable fractions (PAF) of polymorphisms showing significant ORs in allelic contrasts (displayed in Table 2 and Supplementary Table 3).

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    Supplementary Table 5

    Stepwise correction of between-study heterogeneity for datasets not homogeneous in random effects meta-analyses using allelic contrasts on studies of all ethnicities (current on 12/ 1/ 05).

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DOI

https://doi.org/10.1038/ng1934

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