Study Report

Basic Info
Reference |
PGC, 201323453885
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Citation |
Cross-Disorder Group of the Psychiatric Genomics Consortium (2013). "Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis." Lancet 381(9875): 1371-1379.
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Study Design |
case-control and family-based |
Study Type |
Re-analysis of GWAS |
Sample Size |
The final dataset consisted of 33 332 cases and 27 888 controls(including pseudocontrols formed from nontransmitted alleles) distributed among the five disorder groups: autism spectrum disorders (4788 trio cases, 4788 trio pseudocontrols, 161 cases, 526 controls), attention defi cit-hyperactivity disorder (1947 trio cases, 1947 trio pseudocontrols, 840 cases, 688 controls), bipolar disorder (6990 cases, 4820 controls), major depressive disorder (9227 cases, 7383 controls), and schizophrenia (9379 cases, 7736 controls). |
Predominant Ethnicity |
Caucasian |
Population |
PGC collections |

Detail Info
Summary |
We analysed genome-wide single-nucleotide polymorphism (SNP) data for the five disorders in 33,332 cases and 27,888 controls of European ancestory. To characterise allelic effects on each disorder, we applied a multinomial logistic regression procedure with model selection to identify the best-fitting model of relations between genotype and phenotype. We examined cross-disorder effects of genome-wide significant loci previously identified for bipolar disorder and schizophrenia, and used polygenic risk-score analysis to examine such effects from a broader set of common variants. We undertook pathway analyses to establish the biological associations underlying genetic overlap for the five disorders. We used enrichment analysis of expression quantitative trait loci (eQTL) data to assess whether SNPs with cross-disorder association were enriched for regulatory SNPs in post-mortem brain-tissue samples. |
Total Sample |
The sample for these analyses consisted of cases, controls, and family-based samples assembled for previous genome-wide PGC mega-analyses of individuallevel data. |
Sample Collection |
The sample for these analyses consisted of cases, controls, and family-based samples assembled for previous genome-wide PGC mega-analyses of individuallevel data. |
Diagnosis Description |
DSM third edition revised or fourth edition |
Technique |
Raw genotype and phenotype data for each study were uploaded to a central server and processed through the same quality control, imputation, and analysis process. We analysed imputed SNP dosages from 1 250 922 autosomal SNPs. |
Analysis Method |
In the primary analysis, we combined effects of each disease analysis by a meta-analytic approach that applied a weighted Z-score; In a second analytical approach, we did a five-degree-offreedom test by summing the chi square values for each individual disease meta-analysis. To characterise the specificity of the allelic effects for our main findings, we examined the association evidence in three ways: we generated forest plots of the disorder beta coefficients with 95% CIs; we calculated a heterogeneity p value for the disorder-specific effects contributing to the overall statistics for meta-analytic association; and we undertook a multinomial logistic regression procedure with model selection for each main SNP for all five disorders to assess the pattern of phenotypic effects. |
Result Description |
SNPs at four loci surpassed the cutoff for genome-wide significance (p<5x10(-8)) in the primary analysis: regions on chromosomes 3p21 and 10q24, and SNPs within two L-type voltage-gated calcium channel subunits, CACNA1C and CACNB2. Model selection analysis supported effects of these loci for several disorders. Loci previously associated with bipolar disorder or schizophrenia had variable diagnostic specificity. Polygenic risk scores showed cross-disorder associations, notably between adult-onset disorders. Pathway analysis supported a role for calcium channel signalling genes for all five disorders. Finally, SNPs with evidence of cross-disorder association were enriched for brain eQTL markers. Our findings show that specific SNPs are associated with a range of psychiatric disorders of childhood onset or adult onset. In particular, variation in calcium-channel activity genes seems to have pleiotropic effects on psychopathology. These results provide evidence relevant to the goal of moving beyond descriptive syndromes in psychiatry, and towards a nosology informed by disease cause. |

SNPs reported by this study (count: 5)
SNP |
Allele Change |
Risk Allele |
Statistical Values |
Author Comments |
Result of Statistical Analysis |
rs11191454 |
A/G |
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Five disorder meta-analysis, P-value=1.39E-08, OR (95% CI)=1.13 (1.08-1.18), Heterogeneity P-value=0.32; for ADHD only, P-value=0.355 |
Significant association was observed in cross-disorder analy......
Significant association was observed in cross-disorder analysis.
More...
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Significant
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rs11191580 |
T/C |
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P-value=1¡¤11E-08 for five disorders combined |
Significant association was observed in cross-disorder analy......
Significant association was observed in cross-disorder analysis.
More...
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Significant
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rs2535629 |
G/A |
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Five disorder meta-analysis, P-value=2.54E-12, OR (95% CI)=1.10 (1.07-1.12), Heterogeneity P-value=0.27; for ADHD only, P-value=0.201 |
Significant association was observed in cross-disorder analy......
Significant association was observed in cross-disorder analysis.
More...
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Significant
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rs2799573 |
T/C |
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Five disorder meta-analysis, P-value=4.29E-08, OR (95% CI)=1.08 (1.05-1.12), Heterogeneity P-value=0.57; for ADHD only, P-value=0.00691 |
Significant association was observed in cross-disorder analy......
Significant association was observed in cross-disorder analysis and ADHD analysis.
More...
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Significant
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rs1024582 |
A/G |
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P-value=0.127 for ADHD |
No significant association was reported in this study.
No significant association was reported in this study.
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Non-significant
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Genes reported by this study (count: 5)
Gene |
Statistical Values/Author Comments |
Result of Statistical Analysis |
NT5C2 |
Significant association was observed in cross-disorder analy......
Significant association was observed in cross-disorder analysis.
More...
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Significant
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AS3MT |
Significant association was observed in cross-disorder analy......
Significant association was observed in cross-disorder analysis.
More...
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Significant
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ITIH3 |
Significant association was observed in cross-disorder analy......
Significant association was observed in cross-disorder analysis.
More...
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Significant
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CACNB2 |
Significant association was observed in cross-disorder analy......
Significant association was observed in cross-disorder analysis and ADHD analysis.
More...
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Significant
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CACNA1C |
No significant association was reported in this study.
No significant association was reported in this study.
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Non-significant
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