ADHDgene Database

Hot Results

Quick Search

Keyword:
Type:

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

Detail ...

Study Report

Basic Info

Reference	Stergiakouli E., 201222420046
Citation	Stergiakouli E., Hamshere M., Holmans P., Langley K., Zaharieva I., Hawi Z., Kent L., Gill M., Williams N., Owen M. J., O'Donovan M. and Thapar A. (2012) "Investigating the contribution of common genetic variants to the risk and pathogenesis of ADHD." Am J Psychiatry, 169(2): 186-94.
Study Design	case-control
Study Type	GWAS and Genome-wide CNV analysis
Sample Size	799 cases, 6000 controls
Predominant Ethnicity	Caucasian
Population	England, Scotland, Ireland
Gender	699 boys (87.4%) and 100 girls (12.6%)
Age Group	Children/Adolescents : age range: 4-18 years old; mean age: 10 years 3 months [SD=3 years]

Detail Info

Summary	The authors undertook a GWAS of ADHD and examined whether associated SNPs, including those below conventional levels of significance, influenced the same biological pathways affected by CNVs. The authors analyzed genome-wide SNP frequencies in 727 children with ADHD and 5,081 comparison subjects. The gene sets that were enriched in a pathway analysis of the GWAS data (the top 5% of SNPs) were tested for an excess of genes spanned by large, rare CNVs in the children with ADHD. No SNP achieved genome-wide significance levels. As previously reported in a subsample of the present study, large, rare CNVs were significantly more common in case subjects than comparison subjects. Thirteen biological pathways enriched for SNP association significantly overlapped with those enriched for rare CNVs. These included cholesterol-related and CNS development pathways. At the level of individual genes, CHRNA7, which encodes a nicotinic receptor subunit previously implicated in neuropsychiatric disorders, was affected by six large duplications in case subjects (none in comparison subjects), and SNPs in the gene had a gene-wide p value of 0.0002 for association in the GWAS. Both common and rare genetic variants appear to be relevant to ADHD and index-shared biological pathways.
Total Sample	The ADHD patient sample consisted of 799 Caucasian children from Cardiff, Wales (N=559); St. Andrews, Scotland (N=44); and Dublin, Ireland (N=196). Genotype control data were obtained from the Wellcome Trust Case Control Consortium-Phase 2. They comprised 3,000 individuals born in the United Kingdom during 1 week in 1958 (the 1958 British Birth Cohort) and 3,000 individuals from the U.K. Blood Services collection. The ADHD sample for CNV analysis is an extension of 366 cases previously examined for large, rare CNVs (Williams NM. et al., 2010).
Sample Collection	The ADHD patient sample consisted of 799 Caucasian children from Cardiff, Wales (N=559); St. Andrews, Scotland (N=44); and Dublin, Ireland (N=196). All children were recruited from community clinics and met DSM-IV or ICD-10 criteria for ADHD or hyperkinetic disorder. Genotype control data were obtained from the Wellcome Trust Case Control Consortium-Phase 2. They comprised 3,000 individuals born in the United Kingdom during 1 week in 1958 (the 1958 British Birth Cohort) and 3,000 individuals from the U.K. Blood Services collection.
Diagnosis Description	Trained interviewers used the Child and Adolescent Psychiatric Assessment-Parent Version, a semistructured research diagnostic interview, to assess psychiatric diagnoses. Pervasiveness of ADHD symptoms (in school) was assessed using the Child Attention-Deficit Hyperactivity Disorder Teacher Telephone Interview or the Conners Teacher Questionnaire. IQ was assessed using the WISC-IV. To be comparable with other GWAS, children with a major medical or neurological condition (including epilepsy), autism, bipolar disorder, or intellectual disability (IQ<70) were excluded. The comparison subjects were not screened for psychiatric disorders. However, the potential loss of power that is attained by using unscreened comparison subjects is more than offset by the large numbers of comparison samples available.
Technique	DNA samples for ADHD case subjects were genotyped on the Illumina (San Diego) Human660W-Quad BeadChip according to the manufacturer's instructions. Comparison subjects were genotyped by Wellcome Trust Case Control Consortium-Phase2 using the Illumina Human 1.2M BeadChip. BeadStudio (version 2.0) was used to call genotypes and inspect cluster plots. Analysis was based on 518,511 SNPs that were present on both chips. CNVs were defined by PennCNV with loci spanning at least 15 consecutive informative SNPs, with those having copy number calls<2 and >2 being classed as deletions and duplications, respectively. Large (classified as those >500 kb) and rare (<1% frequency) CNVs were used in this analysis.
Analysis Method	Sample and SNP quality control assessments were performed using PLINK, version 1.07. After all the quality control, 502,702 SNPs were tested for association in 727 case subjects and 5,081 comparison subjects. SNPs were tested for association with ADHD using logistic regression in PLINK assuming an additive model. The EIGENSTRAT software package was used to calculate principle components by inferring continuous variation in allele frequencies reflecting ancestral differences in individuals. Two methods were used to test for enrichment of association signal in the combined set of SNPs. The first of these was the Simes test. The other was Fisher's method. Pathway analysis of Cardiff GWAS data was carried out using ALIGATOR. Gene sets with nominally significant (p<0.05) enrichment in the pathway analysis of the GWAS data were tested for an excess of genes affected by large, rare CNVs in case subjects by fitting a logistic model, which overcomes biases relating to gene and CNV size, to the combined set of CNVs.
Result Description	No SNP achieved genome-wide significance levels. As previously reported in a subsample of the present study, large, rare CNVs were significantly more common in case subjects than comparison subjects. Thirteen biological pathways enriched for SNP association significantly overlapped with those enriched for rare CNVs. These included cholesterol-related and CNS development pathways. At the level of individual genes, CHRNA7, which encodes a nicotinic receptor subunit previously implicated in neuropsychiatric disorders, was affected by six large duplications in case subjects (none in comparison subjects), and SNPs in the gene had a gene-wide p value of 0.0002 for association in the GWAS.

SNPs reported by this study (count: 20)

SNP	Allele Change	Risk Allele	Statistical Values	Author Comments	Result of Statistical Analysis
rs6815704	A/G	A	P=0.0000209, OR=1.4, 95% CI=1.20-1.64	One of the top 32 independent SNP in this ADHD GWAS. One of the top 32 independent SNP in this ADHD GWAS.	Trend
rs9842394	T/C	T	P=0.0000268, OR=0.77, 95% CI=0.69-0.87	One of the top 33 independent SNP in this ADHD GWAS. One of the top 33 independent SNP in this ADHD GWAS.	Trend
rs406742	G/A	G	P=0.0000149, OR=1.33, 95% CI=1.17-1.51	One of the top 30 independent SNP in this ADHD GWAS. One of the top 30 independent SNP in this ADHD GWAS.	Trend
rs790531	G/A	G	P=0.000015, OR=1.62, 95% CI=1.30-2.02	One of the top 31 independent SNP in this ADHD GWAS. One of the top 31 independent SNP in this ADHD GWAS.	Trend
rs11686538	G/A	G	P=0.0000127, OR=0.74, 95% CI=0.64-0.84	One of the top 28 independent SNP in this ADHD GWAS. One of the top 28 independent SNP in this ADHD GWAS.	Trend
rs1304358	C/T	C	P=0.0000127, OR=1.3, 95% CI=1.16-1.47	One of the top 29 independent SNP in this ADHD GWAS. One of the top 29 independent SNP in this ADHD GWAS.	Trend
rs4238186	A/G	A	P=0.0000111, OR=1.39, 95% CI=1.20-1.61	One of the top 26 independent SNP in this ADHD GWAS. One of the top 26 independent SNP in this ADHD GWAS.	Trend
rs7746680	A/G	A	P=0.0000114, OR=1.35, 95% CI=1.18-1.54	One of the top 27 independent SNP in this ADHD GWAS. One of the top 27 independent SNP in this ADHD GWAS.	Trend
rs1370072	T/C	T	P=0.0000328, OR=1.29, 95% CI=1.14-1.45	One of the top 38 independent SNP in this ADHD GWAS. One of the top 38 independent SNP in this ADHD GWAS.	Trend
rs874836	A/G	A	P=0.0000332, OR=1.41, 95% CI=1.20-1.67	One of the top 39 independent SNP in this ADHD GWAS. One of the top 39 independent SNP in this ADHD GWAS.	Trend
rs1050567	T/C	T	P=0.0000289, OR=1.44, 95% CI=1.22-1.72	One of the top 36 independent SNP in this ADHD GWAS. One of the top 36 independent SNP in this ADHD GWAS.	Trend
rs9384245	T/C	T	P=0.00003, OR=0.77, 95% CI=0.68-0.87	One of the top 37 independent SNP in this ADHD GWAS. One of the top 37 independent SNP in this ADHD GWAS.	Trend
rs2636788	G/A	G	P=0.0000274, OR=0.7, 95% CI=0.59-0.83	One of the top 34 independent SNP in this ADHD GWAS. One of the top 34 independent SNP in this ADHD GWAS.	Trend
rs1490046	A/G	A	P=0.0000287, OR=1.56, 95% CI=1.27-1.92	One of the top 35 independent SNP in this ADHD GWAS. One of the top 35 independent SNP in this ADHD GWAS.	Trend
rs11175219	T/C	T	P=0.0000106, OR=1.46, 95% CI=1.23-1.73	One of the top 25 independent SNP in this ADHD GWAS. One of the top 25 independent SNP in this ADHD GWAS.	Trend
rs616668	G/T	G	P=0.00000862, OR=1.38, 95% CI=1.20-1.59	One of the top 24 independent SNP in this ADHD GWAS. One of the top 24 independent SNP in this ADHD GWAS.	Trend
rs3779312	T/C	T	P=0.00000838, OR=1.37, 95% CI=1.19-1.57	One of the top 23 independent SNP in this ADHD GWAS. One of the top 23 independent SNP in this ADHD GWAS.	Trend
rs42259	T/C	T	P=0.00000676, OR=1.41, 95% CI=1.22-1.64	One of the top 22 independent SNP in this ADHD GWAS. One of the top 22 independent SNP in this ADHD GWAS.	Trend
rs11079828	T/C	T	P=0.00000654, OR=1.32, 95% CI=1.17-1.49	One of the top 21 independent SNP in this ADHD GWAS. One of the top 21 independent SNP in this ADHD GWAS.	Trend
rs1744062	G/A	G	P=0.00000416, OR=0.75, 95% CI=0.67-0.85	One of the top 20 independent SNP in this ADHD GWAS. One of the top 20 independent SNP in this ADHD GWAS.	Trend

Genes reported by this study (count: 17)

Gene	Statistical Values/Author Comments	Result of Statistical Analysis
SLIT1	One of the top 20 independent SNPs with P=0.0000274 locates ...... One of the top 20 independent SNPs with P=0.0000274 locates intronic relative to this gene. More...	Trend
PLCL1	One of the top 20 independent SNPs with P=0.0000127 locates ...... One of the top 20 independent SNPs with P=0.0000127 locates intronic relative to this gene. More...	Trend
PEX5L	One of the top 20 independent SNPs with P=0.0000268 locates ...... One of the top 20 independent SNPs with P=0.0000268 locates intronic relative to this gene. More...	Trend
XPO1	One of the top 20 independent SNPs with P=0.0000289 locates ...... One of the top 20 independent SNPs with P=0.0000289 locates 3'-UTR relative to this gene. More...	Trend
TIAM2	One of the top 20 independent SNPs with P=0.00003 locates in...... One of the top 20 independent SNPs with P=0.00003 locates intronic relative to this gene. More...	Trend
SRGAP1	One of the top 20 independent SNPs with P=0.0000106 locates ...... One of the top 20 independent SNPs with P=0.0000106 locates intronic relative to this gene. More...	Trend
IL20RA	One of the top 20 independent SNPs with P=0.00000416 locates...... One of the top 20 independent SNPs with P=0.00000416 locates within noncoding region relative to this gene. More...	Trend
HOXB1	One of the top 20 independent SNPs with P=0.00000654 locates...... One of the top 20 independent SNPs with P=0.00000654 locates upstream relative to this gene. More...	Trend
ATXN2	One of the top 20 independent SNPs with P=0.00000862 locates...... One of the top 20 independent SNPs with P=0.00000862 locates intronic relative to this gene. More...	Trend
XKR3	One of the top 20 independent SNPs with P=0.0000332 locates ...... One of the top 20 independent SNPs with P=0.0000332 locates intronic relative to this gene. More...	Trend
MAGI2	One of the top 20 independent SNPs with P=0.00000838 locates...... One of the top 20 independent SNPs with P=0.00000838 locates intronic relative to this gene. More...	Trend
GRID2	One of the top 20 independent SNPs with P=0.0000209 locates ...... One of the top 20 independent SNPs with P=0.0000209 locates intronic relative to this gene. More...	Trend
DLEU2	One of the top 20 independent SNPs with P=0.000015 locates w...... One of the top 20 independent SNPs with P=0.000015 locates within noncoding region relative to this gene. More...	Trend
CHRNA7	was affected by six large duplications in case subjects (non...... was affected by six large duplications in case subjects (none in comparison subjects), and SNPs in the gene had a gene-wide p value of 0.0002 for association in the GWAS. More...	Trend
LOC100128765	One of the top 20 independent SNPs with P=0.0000111 locates ...... One of the top 20 independent SNPs with P=0.0000111 locates intergenic relative to this gene. More...	Trend
TRIO	One of the top 20 independent SNPs with P=0.00000676 locates...... One of the top 20 independent SNPs with P=0.00000676 locates intronic relative to this gene. More...	Trend
DOCK10	One of the top 20 independent SNPs with P=0.0000127 locates ...... One of the top 20 independent SNPs with P=0.0000127 locates intronic relative to this gene. More...	Trend