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Assessment of Alzheimer’s disease case–control associations using family-based methods

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Abstract

The genetics of Alzheimer’s disease (AD) is heterogeneous and remains only ill-defined. We have recently created a freely available and continuously updated online database (AlzGene; http://www.alzgene.org) for which we collect all published genetic association studies in AD and perform systematic meta-analyses on all polymorphisms with sufficient genotype data. In this study, we tested 27 genes (ACE, BDNF, CH25H, CHRNB2, CST3, CTSD, DAPK1, GALP, hCG2039140, IL1B, LMNA, LOC439999, LOC651924, MAPT, MTHFR, MYH13, PCK1, PGBD1, PRNP, PSEN1, SORCS1, SORL1, TF, TFAM, TNK1, GWA_14q32.13, and GWA_7p15.2), all showing significant association with AD risk in the AlzGene meta-analyses, in a large collection of family-based samples comprised of 4,180 subjects from over 1,300 pedigrees. Overall, we observe significant association with risk for AD and polymorphisms in ACE, CHRNB2, TF, and an as yet uncharacterized locus on chromosome 7p15.2 [rs1859849]. For all four loci, the association was observed with the same alleles as in the AlzGene meta-analyses. The convergence of case–control and family-based findings suggests that these loci currently represent the most promising AD gene candidates. Further fine-mapping and functional analyses are warranted to elucidate the potential biochemical mechanisms and epidemiological relevance of these genes.

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Acknowledgments

The authors wish to thank all families for participating in this study. This work was sponsored by grants from the NIA (to L.B.), NIMH (to R.T.), and the Extendicare Foundation (to L.B.). The AlzGene database project is funded by the Cure Alzheimer’s Fund (to L.B.).

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Authors and Affiliations

  1. Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease (MIND), Department of Neurology, Massachusetts General Hospital, MGH-East (MIND), 114 16th St., Charlestown, MA, 02129, USA

    Brit-Maren M. Schjeide, Kristina Mullin, Jason DiVito, Meghan F. Hogan, Michele Parkinson, Basavaraj Hooli, Rudolph E. Tanzi & Lars Bertram

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

    Matthew B. McQueen & Deborah Blacker

  3. Institute for Behavioral Genetics, University of Colorado, Boulder, CO, USA

    Matthew B. McQueen

  4. Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA

    Christoph Lange

  5. Gerontology Research Unit, Department of Psychiatry, Massachusetts General Hospital, Charlestown, MA, USA

    Deborah Blacker

Authors
  1. Brit-Maren M. Schjeide
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  2. Matthew B. McQueen
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  3. Kristina Mullin
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  4. Jason DiVito
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  5. Meghan F. Hogan
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  6. Michele Parkinson
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  7. Basavaraj Hooli
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  8. Christoph Lange
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  9. Deborah Blacker
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  10. Rudolph E. Tanzi
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  11. Lars Bertram
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Correspondence to Lars Bertram.

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Schjeide, BM.M., McQueen, M.B., Mullin, K. et al. Assessment of Alzheimer’s disease case–control associations using family-based methods. Neurogenetics 10, 19–25 (2009). https://doi.org/10.1007/s10048-008-0151-3

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  • DOI: https://doi.org/10.1007/s10048-008-0151-3

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