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

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), pp. 927-937.

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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.

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25 citations in Web of Science®

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ID Code: 85837
Item Type: Journal Article
Refereed: No
Keywords: Caudate, dopamine, genome-wide association, heritability, PDE8B, WDR41
DOI: 10.1038/mp.2011.32
ISSN: 1476-5578
Divisions: Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 2011 Macmillan Publishers Limited
Deposited On: 04 Sep 2015 01:15
Last Modified: 04 Sep 2015 01:15

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