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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

Manhattan plots show the significance of association of each SNP with caudate volume, from genome-wide association analysis conducted in the ADNI cohort. Each marker is represented as a dot and the −log10(P-value) is displayed on the y-axis. Association was conducted separately for average bilateral (top), left (middle), and right (bottom) caudate volumes. Markers above the blue line represent a P-value < 1×10−5. ChrXY represents the pseudo-autosomal region of the X chromosome, and ChrMT represents mitochondrial SNPs. BLTS Manhattan plots are shown in Supplementary Figure 4.
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Figure 1: Manhattan plots show the significance of association of each SNP with caudate volume, from genome-wide association analysis conducted in the ADNI cohort. Each marker is represented as a dot and the −log10(P-value) is displayed on the y-axis. Association was conducted separately for average bilateral (top), left (middle), and right (bottom) caudate volumes. Markers above the blue line represent a P-value < 1×10−5. ChrXY represents the pseudo-autosomal region of the X chromosome, and ChrMT represents mitochondrial SNPs. BLTS Manhattan plots are shown in Supplementary Figure 4.

Mentions: Given the high heritability of caudate volume, we conducted a genome-wide association analysis to search for common genetic variants that might explain some modest proportion of the substantial genetic influence on caudate volume. We analyzed the 734 ADNI subjects as a discovery sample and the 464 BLTS subjects as a replication sample (1198 subjects, in total). For ADNI, we conducted a standard regression of phenotype on the additive allelic effect at each SNP, after statistically controlling for age and sex. Genome-wide association results for the ADNI sample are shown in Figure 1 and the most significant SNPs are presented in Table 2, at a threshold of P<1×10−5. Subsequent replication of the findings was conducted using the BLTS sample. As noted in the Methods, a mixed effects model was used to regress the phenotype on the additive allelic effect at each SNP, after statistically controlling for age, sex, and for genetic relatedness, through the kinship matrix. Q-Q plots and λ inflation factors (36) show no inflation of statistical significance (Supplementary Figure 4).


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)

Manhattan plots show the significance of association of each SNP with caudate volume, from genome-wide association analysis conducted in the ADNI cohort. Each marker is represented as a dot and the −log10(P-value) is displayed on the y-axis. Association was conducted separately for average bilateral (top), left (middle), and right (bottom) caudate volumes. Markers above the blue line represent a P-value < 1×10−5. ChrXY represents the pseudo-autosomal region of the X chromosome, and ChrMT represents mitochondrial SNPs. BLTS Manhattan plots are shown in Supplementary Figure 4.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 1: Manhattan plots show the significance of association of each SNP with caudate volume, from genome-wide association analysis conducted in the ADNI cohort. Each marker is represented as a dot and the −log10(P-value) is displayed on the y-axis. Association was conducted separately for average bilateral (top), left (middle), and right (bottom) caudate volumes. Markers above the blue line represent a P-value < 1×10−5. ChrXY represents the pseudo-autosomal region of the X chromosome, and ChrMT represents mitochondrial SNPs. BLTS Manhattan plots are shown in Supplementary Figure 4.
Mentions: Given the high heritability of caudate volume, we conducted a genome-wide association analysis to search for common genetic variants that might explain some modest proportion of the substantial genetic influence on caudate volume. We analyzed the 734 ADNI subjects as a discovery sample and the 464 BLTS subjects as a replication sample (1198 subjects, in total). For ADNI, we conducted a standard regression of phenotype on the additive allelic effect at each SNP, after statistically controlling for age and sex. Genome-wide association results for the ADNI sample are shown in Figure 1 and the most significant SNPs are presented in Table 2, at a threshold of P<1×10−5. Subsequent replication of the findings was conducted using the BLTS sample. As noted in the Methods, a mixed effects model was used to regress the phenotype on the additive allelic effect at each SNP, after statistically controlling for age, sex, and for genetic relatedness, through the kinship matrix. Q-Q plots and λ inflation factors (36) show no inflation of statistical significance (Supplementary Figure 4).

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