Discovery and replication of dopamine-related gene effects on caudate volume in young and elderly populations (N1198) using genome-wide search

J. L. Stein, D. P. Hibar, S. K. Madsen, M. Khamis, K. L. McMahon, G. I. De Zubicaray, N. K. Hansell, G. W. Montgomery, N. G. Martin, M. J. Wright, A. J. Saykin, C. R. Jack, M. W. Weiner, A. W. Toga, P. M. Thompson

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

The caudate is a subcortical brain structure implicated in many common neurological and psychiatric disorders. To identify specific genes associated with variations in caudate volume, structural magnetic resonance imaging and genome-wide genotypes were acquired from two large cohorts, the Alzheimer's Disease NeuroImaging Initiative (ADNI; N=734) and the Brisbane Adolescent/Young Adult Longitudinal Twin Study (BLTS; N=464). In a preliminary analysis of heritability, around 90% of the variation in caudate volume was due to genetic factors. We then conducted genome-wide association to find common variants that contribute to this relatively high heritability. Replicated genetic association was found for the right caudate volume at single-nucleotide polymorphism rs163030 in the ADNI discovery sample (P=2.36 × 10 -6) and in the BLTS replication sample (P=0.012). This genetic variation accounted for 2.79 and 1.61% of the trait variance, respectively. The peak of association was found in and around two genes, WDR41 and PDE8B, involved in dopamine signaling and development. In addition, a previously identified mutation in PDE8B causes a rare autosomal-dominant type of striatal degeneration. Searching across both samples offers a rigorous way to screen for genes consistently influencing brain structure at different stages of life. Variants identified here may be relevant to common disorders affecting the caudate.

Original languageEnglish (US)
Pages (from-to)927-937
Number of pages11
JournalMolecular Psychiatry
Volume16
Issue number9
DOIs
StatePublished - Sep 1 2011

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Keywords

  • Caudate
  • dopamine
  • genome-wide association
  • heritability
  • PDE8B
  • WDR41

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

Stein, J. L., Hibar, D. P., Madsen, S. K., Khamis, M., McMahon, K. L., De Zubicaray, G. I., Hansell, N. K., Montgomery, G. W., Martin, N. G., Wright, M. J., Saykin, A. J., Jack, C. R., Weiner, M. W., Toga, A. W., & Thompson, P. M. (2011). Discovery and replication of dopamine-related gene effects on caudate volume in young and elderly populations (N1198) using genome-wide search. Molecular Psychiatry, 16(9), 927-937. https://doi.org/10.1038/mp.2011.32