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. Jack, Michael W. Weiner, Arthur W. Toga, Paul M. Thompson

Research output: Contribution to journalArticle

20 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)102-115
Number of pages14
JournalBrain Imaging and Behavior
Volume7
Issue number2
DOIs
StatePublished - 2013

Keywords

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

ASJC Scopus subject areas

  • Clinical Neurology
  • Psychiatry and Mental health
  • Neurology
  • Cognitive Neuroscience
  • Cellular and Molecular Neuroscience
  • Behavioral Neuroscience
  • Radiology Nuclear Medicine and imaging

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    Hibar, D. P., Stein, J. L., Ryles, A. B., Kohannim, O., Jahanshad, N., Medland, S. E., Hansell, N. K., McMahon, K. L., de Zubicaray, G. I., Montgomery, G. W., Martin, N. G., Wright, M. J., Saykin, A. J., Jack, C. R., Weiner, M. W., Toga, A. W., & Thompson, P. M. (2013). Genome-wide association identifies genetic variants associated with lentiform nucleus volume in N = 1345 young and elderly subjects. Brain Imaging and Behavior, 7(2), 102-115. https://doi.org/10.1007/s11682-012-9199-7