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Genetic association of ubiquilin with Alzheimer's disease and related quantitative measures

Molecular Psychiatry volume 11, pages 273–279 (2006)Cite this article

Abstract

The gene coding for ubiquilin 1 (UBQLN1) is located near a linkage peak on chromosome 9q22.2 and it also impacts the function of presenilin proteins involved in early-onset Alzheimer's disease (AD). Recently, genetic variation in UBQLN1 has been shown to affect the risk of AD in two independent family-based samples. The purpose of this study was to confirm the reported association in a large case–control sample and to also examine the association of UBQLN1 SNPs with quantitative measures of AD progression, namely age-at-onset (AAO), disease duration and Mini-Mental State Examination (MMSE) score. We examined the associations of three SNPs in the UBQLN1 gene (intron 6/A>C, intron 8/T>C and intron 9/A>G) in up to 978 LOAD cases and 808 controls. All SNPs were in significant linkage disequilibrium (P<0.0001). While modest significant associations were observed in the single-site regression analysis, 3-site haplotype analysis revealed significant associations (P<0.0001 for overall haplotype analysis). One common haplotype (H4) defined by intron 6/A–intron 8/C–intron 9/G alleles was associated with AD risk and one less common haplotype (H5) defined by intron 6/C–intron 8/C–intron 9/A alleles was associated with protection. The adjusted odds ratios with potentially one and two copies of risk haplotype H4 were 1.5 (95% CI: 0.99–2.26; P=0.054) and 3.66 (95% CI: 1.43–9.39; P=0.007), respectively, and odds ratio for haplotype H5 carriers was 0.31 (95% CI: 0.10–0.95; P=0.0398). In addition to disease risk, the homozygosity of the risk haplotype was also associated with older AAO, longer disease duration and lower MMSE score. In summary, our data from a large case–control cohort indicate that genetic variation in the UBQLN1 gene has a modest effect on risk, AAO and disease duration of AD. Our haplotype data suggest the presence of additional putative functional variants either in the UBQLN1 gene or nearby genes and provide strong justification for additional work in this region on chromosome 9.

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Acknowledgements

This study was supported by National Institute on Aging grants AG 13672 and AG 05133. We thank Ms. Margaret Kenney for providing help in statistical analyses.

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Authors and Affiliations

  1. Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA

    M I Kamboh, R L Minster & E Feingold

  2. Alzheimer's Disease Research Center, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    M I Kamboh & S T DeKosky

  3. Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA

    E Feingold

  4. Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    S T DeKosky

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  1. M I Kamboh
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  2. R L Minster
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Correspondence to M I Kamboh.

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Kamboh, M., Minster, R., Feingold, E. et al. Genetic association of ubiquilin with Alzheimer's disease and related quantitative measures. Mol Psychiatry 11, 273–279 (2006). https://doi.org/10.1038/sj.mp.4001775

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