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Whole-exome sequencing and imaging genetics identify functional variants for rate of change in hippocampal volume in mild cognitive impairment

Molecular Psychiatry volume 18, pages 781–787 (2013)Cite this article

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Abstract

Whole-exome sequencing of individuals with mild cognitive impairment, combined with genotype imputation, was used to identify coding variants other than the apolipoprotein E (APOE) ɛ4 allele associated with rate of hippocampal volume loss using an extreme trait design. Matched unrelated APOE ɛ3 homozygous male Caucasian participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were selected at the extremes of the 2-year longitudinal change distribution of hippocampal volume (eight subjects with rapid rates of atrophy and eight with slow/stable rates of atrophy). We identified 57 non-synonymous single nucleotide variants (SNVs) which were found exclusively in at least 4 of 8 subjects in the rapid atrophy group, but not in any of the 8 subjects in the slow atrophy group. Among these SNVs, the variants that accounted for the greatest group difference and were predicted in silico as ‘probably damaging’ missense variants were rs9610775 (CARD10) and rs1136410 (PARP1). To further investigate and extend the exome findings in a larger sample, we conducted quantitative trait analysis including whole-brain search in the remaining ADNI APOE ɛ3/ɛ3 group (N=315). Genetic variation within PARP1 and CARD10 was associated with rate of hippocampal neurodegeneration in APOE ɛ3/ɛ3. Meta-analysis across five independent cross sectional cohorts indicated that rs1136410 is also significantly associated with hippocampal volume in APOE ɛ3/ɛ3 individuals (N=923). Larger sequencing studies and longitudinal follow-up are needed for confirmation. The combination of next-generation sequencing and quantitative imaging phenotypes holds significant promise for discovery of variants involved in neurodegeneration.

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Acknowledgements

Data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) (Supplementary information).

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Author notes

  1. K Nho, J J Corneveaux, S Kim, H Lin, S L Risacher, L Shen, S Swaminathan, V K Ramanan, Y Liu, T Foroud, M H Inlow, A L Siniard, R A Reiman, P S Aisen, R C Petersen, R C Green, C R Jack, M W Weiner, C T Baldwin, K Lunetta, L A Farrer, S J Furney, S Lovestone, A Simmons, P Mecocci, B Vellas, M Tsolaki, I Kloszewska, H Soininen, B C McDonald, M R Farlow, B Ghetti, M J Huentelman and A J Saykin: Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.ucla.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.ucla.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf.

Authors and Affiliations

  1. Department of Radiology and Imaging Sciences, Center for Neuroimaging, Indiana University School of Medicine, Indianapolis, IN, USA

    K Nho, S Kim, S L Risacher, L Shen, S Swaminathan, V K Ramanan, T Foroud, B C McDonald & A J Saykin

  2. Neurogenomics Division, The Translational Genomics Research Institute (TGen), Phoenix, AZ, USA

    J J Corneveaux, A L Siniard, R A Reiman & M J Huentelman

  3. Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA

    S Kim, H Lin, L Shen, Y Liu, T Foroud & A J Saykin

  4. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA

    S Swaminathan, V K Ramanan, Y Liu, T Foroud & A J Saykin

  5. Department of Mathematics, Rose-Hulman Institute of Technology, Terre Haute, IN, USA

    M H Inlow

  6. Department of Neuroscience, University of California, San Diego, San Diego, CA, USA

    P S Aisen

  7. Mayo Clinic, Rochester, MN, USA

    R C Petersen & C R Jack

  8. Division of Genetics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    R C Green

  9. Department of Radiology, Medicine and Psychiatry, University of California, San Francisco, San Francisco, CA, USA

    M W Weiner

  10. Department of Veterans Affairs Medical Center, San Francisco, CA, USA

    M W Weiner

  11. Biomedical Genetics, Boston University School of Medicine, Boston, MA, USA

    C T Baldwin & L A Farrer

  12. Department of Biostatistics, School of Public Health, Boston University, Boston, MA, USA

    K Lunetta

  13. Genetic Epidemiology Center, Boston University School of Medicine, Boston, MA, USA

    L A Farrer

  14. King’s College London, Institute of Psychiatry, London, UK

    S J Furney, S Lovestone & A Simmons

  15. King’s College London, NIHR Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust, Institute of Psychiatry, London, UK

    S J Furney, S Lovestone & A Simmons

  16. King’s College London, NIHR Biomedical Research Unit for Dementia at South London and Maudsley NHS Foundation Trust, Institute of Psychiatry, London, UK

    S J Furney, S Lovestone & A Simmons

  17. Institute of Gerontology and Geriatrics, University of Perugia, Perugia, Italy

    P Mecocci

  18. Department of Geriatric Medicine, Gerontopole de Toulouse, Toulouse University Hospital, Toulouse, France

    B Vellas

  19. Third Department of Neurology, Aristotle University of Thessaloniki, Thessaloniki, Greece

    M Tsolaki

  20. Department of Old Age Psychiatry and Psychotic Disorders, Medical University of Lodz, Lodz, Poland

    I Kloszewska

  21. Department of Neurology, Kuopio University Hospital, University of Eastern Finland, Kuopio, Finland

    H Soininen

  22. Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA

    B C McDonald, M R Farlow & A J Saykin

  23. Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA

    B Ghetti

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for the Multi-Institutional Research on Alzheimer Genetic Epidemiology (MIRAGE) Study

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for the Alzheimer’s Disease Neuroimaging Initiative (ADNI)

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Nho, K., Corneveaux, J., Kim, S. et al. Whole-exome sequencing and imaging genetics identify functional variants for rate of change in hippocampal volume in mild cognitive impairment. Mol Psychiatry 18, 781–787 (2013). https://doi.org/10.1038/mp.2013.24

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  • DOI: https://doi.org/10.1038/mp.2013.24

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