ADHDgene Database

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Large-scale studies

Data Summary

Published Variant
- SNP: 1391
- CNV: 398
- Others: 173
Published Gene: 359
Published Region: 128
Pathway by PBA: 8
Study: 361

Study Report

Basic Info

Reference	PGC, 201323453885
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.
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		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...	Significant
rs11191580	T/C		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...	Significant
rs2535629	G/A		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...	Significant
rs2799573	T/C		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...	Significant
rs1024582	A/G		P-value=0.127 for ADHD	No significant association was reported in this study. No significant association was reported in this study.	Non-significant

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...	Significant
AS3MT	Significant association was observed in cross-disorder analy...... Significant association was observed in cross-disorder analysis. More...	Significant
ITIH3	Significant association was observed in cross-disorder analy...... Significant association was observed in cross-disorder analysis. More...	Significant
CACNB2	Significant association was observed in cross-disorder analy...... Significant association was observed in cross-disorder analysis and ADHD analysis. More...	Significant
CACNA1C	No significant association was reported in this study. No significant association was reported in this study.	Non-significant