Brain Imaging and Behavior

, Volume 7, Issue 2, pp 102–115

Genome-wide association identifies genetic variants associated with lentiform nucleus volume in N = 1345 young and elderly subjects

  • Derrek P. Hibar
  • Jason L. Stein
  • April B. Ryles
  • Omid Kohannim
  • Neda Jahanshad
  • Sarah E. Medland
  • Narelle K. Hansell
  • Katie L. McMahon
  • Greig I. de Zubicaray
  • Grant W. Montgomery
  • Nicholas G. Martin
  • Margaret J. Wright
  • Andrew J. Saykin
  • Clifford R. JackJr
  • Michael W. Weiner
  • Arthur W. Toga
  • Paul M. Thompson
  • the Alzheimer’s Disease Neuroimaging Initiative
Original Research

DOI: 10.1007/s11682-012-9199-7

Cite this article as:
Hibar, D.P., Stein, J.L., Ryles, A.B. et al. Brain Imaging and Behavior (2013) 7: 102. doi:10.1007/s11682-012-9199-7

Abstract

Deficits in lentiform nucleus volume and morphometry are implicated in a number of genetically influenced disorders, including Parkinson’s disease, schizophrenia, and ADHD. Here we performed genome-wide searches to discover common genetic variants associated with differences in lentiform nucleus volume in human populations. We assessed structural MRI scans of the brain in two large genotyped samples: the Alzheimer’s Disease Neuroimaging Initiative (ADNI; N = 706) and the Queensland Twin Imaging Study (QTIM; N = 639). Statistics of association from each cohort were combined meta-analytically using a fixed-effects model to boost power and to reduce the prevalence of false positive findings. We identified a number of associations in and around the flavin-containing monooxygenase (FMO) gene cluster. The most highly associated SNP, rs1795240, was located in the FMO3 gene; after meta-analysis, it showed genome-wide significant evidence of association with lentiform nucleus volume (PMA = 4.79 × 10−8). This commonly-carried genetic variant accounted for 2.68 % and 0.84 % of the trait variability in the ADNI and QTIM samples, respectively, even though the QTIM sample was on average 50 years younger. Pathway enrichment analysis revealed significant contributions of this gene to the cytochrome P450 pathway, which is involved in metabolizing numerous therapeutic drugs for pain, seizures, mania, depression, anxiety, and psychosis. The genetic variants we identified provide replicated, genome-wide significant evidence for the FMO gene cluster’s involvement in lentiform nucleus volume differences in human populations.

Keywords

Basal ganglia Genome-wide association study (GWAS) MRI Replication Morphometry Drug metabolism 

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Derrek P. Hibar
    • 1
  • Jason L. Stein
    • 1
  • April B. Ryles
    • 1
  • Omid Kohannim
    • 1
  • Neda Jahanshad
    • 1
  • Sarah E. Medland
    • 2
    • 3
    • 4
  • Narelle K. Hansell
    • 2
  • Katie L. McMahon
    • 5
  • Greig I. de Zubicaray
    • 6
  • Grant W. Montgomery
    • 2
  • Nicholas G. Martin
    • 2
  • Margaret J. Wright
    • 2
  • Andrew J. Saykin
    • 7
  • Clifford R. JackJr
    • 8
  • Michael W. Weiner
    • 9
    • 10
  • Arthur W. Toga
    • 11
  • Paul M. Thompson
    • 1
  • the Alzheimer’s Disease Neuroimaging Initiative
  1. 1.Imaging Genetics Center at the Laboratory of Neuro Imaging, Department of NeurologyUCLA School of MedicineLos AngelesUSA
  2. 2.Genetic Epidemiology LaboratoryQueensland Institute of Medical ResearchBrisbaneAustralia
  3. 3.Neurogenetics LaboratoryQueensland Institute of Medical ResearchBrisbaneAustralia
  4. 4.Broad Institute of Harvard and MITBostonUSA
  5. 5.Centre for Advanced ImagingUniversity of QueenslandBrisbaneAustralia
  6. 6.Functional Magnetic Resonance Imaging Laboratory, School of PsychologyUniversity of QueenslandBrisbaneAustralia
  7. 7.Center for Neuroimaging, Department of Radiology and Imaging ScienceIndiana University School of MedicineIndianapolisUSA
  8. 8.Mayo ClinicRochesterUSA
  9. 9.Departments of Radiology, Medicine, PsychiatryUC San FranciscoSan FranciscoUSA
  10. 10.Department of Veterans Affairs Medical CenterSan FranciscoUSA
  11. 11.Laboratory of Neuro Imaging, Department of NeurologyUCLA School of MedicineLos AngelesUSA

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