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Discovery and replication of dopamine-related gene effects on caudate volume in young and elderly populations (N=1198) using genome-wide search.

Stein JL, Hibar DP, Madsen SK, Khamis M, McMahon KL, de Zubicaray GI, Hansell NK, Montgomery GW, Martin NG, Wright MJ, Saykin AJ, Jack CR, Weiner MW, Toga AW, Thompson PM, Alzheimer’s Disease Neuroimaging Initiative Investigato - Mol. Psychiatry (2011)

Bottom Line: 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).The peak of association was found in and around two genes, WDR41 and PDE8B, involved in dopamine signaling and development.Searching across both samples offers a rigorous way to screen for genes consistently influencing brain structure at different stages of life.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Laboratory of Neuro Imaging, UCLA School of Medicine, Los Angeles, CA, USA.

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.

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Related in: MedlinePlus

Detailed view of the associated locus. Markers are represented as circles (SNPs with no known function) or downward-pointing triangles (coding non-synonymous mutations). Markers are placed at their position on chromosome 5 (x-axis) and graphed based on the −log10(P-values) of their association to the phenotype (y-axis). The level of linkage disequilibrium to the most associated SNP (rs163030) is represented in color using the CEU panel from HapMap Phase II. The location of genes is shown below the plots. Images were created using LocusZoom (http://csg.sph.umich.edu/locuszoom/).
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Figure 2: Detailed view of the associated locus. Markers are represented as circles (SNPs with no known function) or downward-pointing triangles (coding non-synonymous mutations). Markers are placed at their position on chromosome 5 (x-axis) and graphed based on the −log10(P-values) of their association to the phenotype (y-axis). The level of linkage disequilibrium to the most associated SNP (rs163030) is represented in color using the CEU panel from HapMap Phase II. The location of genes is shown below the plots. Images were created using LocusZoom (http://csg.sph.umich.edu/locuszoom/).

Mentions: A large peak of replicated association is found in and around two genes: WDR41 and PDE8B (Figure 2). Association is strongest for the right caudate, but it is also found at a slightly weaker significance level for the left caudate.


Discovery and replication of dopamine-related gene effects on caudate volume in young and elderly populations (N=1198) using genome-wide search.

Stein JL, Hibar DP, Madsen SK, Khamis M, McMahon KL, de Zubicaray GI, Hansell NK, Montgomery GW, Martin NG, Wright MJ, Saykin AJ, Jack CR, Weiner MW, Toga AW, Thompson PM, Alzheimer’s Disease Neuroimaging Initiative Investigato - Mol. Psychiatry (2011)

Detailed view of the associated locus. Markers are represented as circles (SNPs with no known function) or downward-pointing triangles (coding non-synonymous mutations). Markers are placed at their position on chromosome 5 (x-axis) and graphed based on the −log10(P-values) of their association to the phenotype (y-axis). The level of linkage disequilibrium to the most associated SNP (rs163030) is represented in color using the CEU panel from HapMap Phase II. The location of genes is shown below the plots. Images were created using LocusZoom (http://csg.sph.umich.edu/locuszoom/).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3140560&req=5

Figure 2: Detailed view of the associated locus. Markers are represented as circles (SNPs with no known function) or downward-pointing triangles (coding non-synonymous mutations). Markers are placed at their position on chromosome 5 (x-axis) and graphed based on the −log10(P-values) of their association to the phenotype (y-axis). The level of linkage disequilibrium to the most associated SNP (rs163030) is represented in color using the CEU panel from HapMap Phase II. The location of genes is shown below the plots. Images were created using LocusZoom (http://csg.sph.umich.edu/locuszoom/).
Mentions: A large peak of replicated association is found in and around two genes: WDR41 and PDE8B (Figure 2). Association is strongest for the right caudate, but it is also found at a slightly weaker significance level for the left caudate.

Bottom Line: 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).The peak of association was found in and around two genes, WDR41 and PDE8B, involved in dopamine signaling and development.Searching across both samples offers a rigorous way to screen for genes consistently influencing brain structure at different stages of life.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Laboratory of Neuro Imaging, UCLA School of Medicine, Los Angeles, CA, USA.

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.

Show MeSH
Related in: MedlinePlus