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Identification of functional variants from whole-exome sequencing, combined with neuroimaging genetics

Molecular Psychiatry volume 18, page 739 (2013)Cite this article

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The image illustrates the schematic view for discovery of functional variants from whole-exome sequencing. We report on a novel strategy combining whole-exome sequencing and neuroimaging genetics to identify functional variants associated with the rate of hippocampal volume loss in mild cognitive impairment. Whole-exome sequencing was performed on a modest sample using an extreme trait design by selecting individuals at the extremes of the distribution of 2-year longitudinal change in hippocampal volume. To further investigate and extend the exome findings in a larger sample, we conducted quantitative trait analysis, including whole-brain search, combined with genotype imputation. Finally, meta-analysis was performed to validate the exome findings across five independent cross-sectional cohorts. Combining next-generation sequencing and quantitative imaging phenotypes holds promise for the discovery of variants involved in neurodegeneration and other brain disorders. For more information on this topic, please refer to the article by Nho et al. on pages 781–787.

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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 Neurosciences, 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. Departments 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. Department of 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. Institute of Psychiatry, King’s College London, London, UK

    S J Furney, S Lovestone & A Simmons

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

    S J Furney, S Lovestone & A Simmons

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

    S J Furney, S Lovestone & A Simmons

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

    P Mecocci

  18. Toulouse Gerontopole University Hospital, Universite Paul Sabatier, INSERM U 558, 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, University of Eastern Finland, Kuopio University Hospital, 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

Authors
  1. K Nho
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  2. J J Corneveaux
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  3. S Kim
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  4. H Lin
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  5. S L Risacher
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  6. L Shen
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  7. S Swaminathan
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  8. V K Ramanan
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  9. Y Liu
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  10. T Foroud
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  11. M H Inlow
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  12. A L Siniard
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  13. R A Reiman
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  14. P S Aisen
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  15. R C Petersen
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  16. R C Green
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  17. C R Jack
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  18. M W Weiner
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  19. C T Baldwin
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  20. K Lunetta
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  21. L A Farrer
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  22. S J Furney
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  23. S Lovestone
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  24. A Simmons
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  25. P Mecocci
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  26. B Vellas
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  27. M Tsolaki
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  28. I Kloszewska
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  29. H Soininen
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  30. B C McDonald
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  31. M R Farlow
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  32. B Ghetti
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  33. M J Huentelman
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  34. A J Saykin
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Consortia

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

for the AddNeuroMed Consortium

for the Indiana Memory and Aging Study

for the Alzheimer's Disease Neuroimaging Initiative (ADNI)

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Nho, K., Corneveaux, J., Kim, S. et al. Identification of functional variants from whole-exome sequencing, combined with neuroimaging genetics. Mol Psychiatry 18, 739 (2013). https://doi.org/10.1038/mp.2013.81

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