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

Detail ...

Study Report

Basic Info

Reference	Lesch KP, 200818839057
Citation	Lesch K. P., Timmesfeld N., Renner T. J., Halperin R., Roser C., Nguyen T. T., Craig D. W., Romanos J., Heine M., Meyer J., Freitag C., Warnke A., Romanos M., Schafer H., Walitza S., Reif A., Stephan D. A. and Jacob C. (2008) "Molecular genetics of adult ADHD: converging evidence from genome-wide association and extended pedigree linkage studies." J Neural Transm, 115(11): 1573-85.
Study Design	case-control
Study Type	GWAS (pooled DNA)
Sample Size	343 cases and 304 controls
Predominant Ethnicity	Caucasian
Population	Germany
Gender	156 females and 187 males in case sample; 148 females and 156 males in control sample
Age Group	Adults : aged 18-65, mean age 32.9 years, SD=10.0 in case sample

Detail Info

Summary	A genome-wide association (GWA) study with pooled DNA in adult attention-deficit/hyperactivity disorder (ADHD) employing approximately 500K SNP markers identifies novel risk genes and reveals remarkable overlap with findings from recent GWA scans in substance use disorders. Comparison with results from their previously reported high-resolution linkage scan in extended pedigrees confirms several chromosomal loci, including 16q23.1-24.3 which also reached genome-wide significance in a recent meta-analysis of seven linkage studies (Zhou et al. in Am J Med Genet Part B, 2008). The findings provide additional support for a common effect of genes coding for cell adhesion molecules (e.g., CDH13, ASTN2) and regulators of synaptic plasticity (e.g., CTNNA2, KALRN) despite the complex multifactorial etiologies of adult ADHD and addiction vulnerability.
Total Sample	a total of 343 in- and out patients; a total of 250 control subjects consisting of healthy blood donors were enrolled. This sample was not screened for psychiatric disorder, howerer, all participants were free of medication. Further 54 individuals were additionally recruited and screened for absence of psychiatric disorders.
Sample Collection	Patients are of German origin; 250 control subjects originate from the Wurzburg, and further 54 individuals have no race information.
Diagnosis Description	Patients were recruited and examined with the Structured Clinical Interview of DSM-IV axis-I disorders as previously reported (Jacob et al. 2007). Briefly, inclusion criteria were adult ADHD according to the diagnostic criteria of DSM-IV, onset before the age of 7 years via retrospective diagnosis, life-long persistence, and current diagnosis. Age at recruitment was between 18 and 65 years. Patients with substance use disorder underwent detoxification in an in-patient setting. Exclusion criteria were the symptoms occur exclusively during the course of a pervasive developmental disorder, schizophrenia, or other psychotic disorders or symptoms which are better accounted for by another mental disorder (criterion E of DSM-IV). Further exclusion criteria were IQ level below 80 (MWT-B 13 points), bipolar affective disorder, and history of epilepsy. Diagnosis of childhood manifestation of ADHD was retrospectively assessed with the DSM-IV symptom list for ADHD (17 items) that was used as a structured clinical interview.
Technique	Genomic DNA was extracted from blood samples using standard protocols. Genotyping was performed at the Neurogenomics Division, Translational Genomics Research Institute, Phoenix. DNA quality was assessed and quantified by PicoGreen and pools from DNA of 343 ADHD patients and 304 controls were constructed in triplicate as previously described (Pearson et al. 2007). Briefly, three aliquots from each pool were assayed using the Affymetrix GeneChip Human Mapping 500K Array set (Affymetrix, Santa Clara, CA, USA) for a total of nine technical replicates per ADHD case/control subpool following the manufacturer¡¯s protocol for individual genotyping. Scanning was performed by a GeneChip Scanner 3000.
Analysis Method	Pooling-based 500K SNP genome-wide association study: They first repeatedly ranked 504,219 included SNPs by different approaches after one arbitrarily chosen microarray had been left out from both the case and control sample. Tests based on ANOVA, rank sums, and silhouette score offered the smallest deviation as compared to ranking of the top 1,000 SNPs of all microarrays included. The final SNP-wise ranks were evaluated by ranking the mean of the ranks based on the statistics of ANOVA, rank sums, and silhouette score. Additional association analysis of 50K SNP data from extended ADHD families: the quality control and statistical linkage analysis of this data were described previously (Romanos et al. 2008). They additionally performed a family-based association analysis for 26,196 autosomal SNPs that passed the first control step by using the program FBAT. The tests were performed under an additive genetic model and two-sided at the Bonferroni-corrected significance level of 0.05/26,196 SNPs. Comparison of 50K SNP linkage/association and 500K SNP genome-wide association studies: in addition to the SNP-wise ranks from the GWA data, they included four MOD score results (MODglobal and MODsingle for broad/ narrow ADHD definiton in all families) reported earlier by Romanos et al. (2008) and ranks of the FBAT nominal P-values from the 50K SNP data for comparison analysis. Prioritization of top-ranked SNPs and SNP-regions using functional criteria: adult ADHD-associated SNPs were further prioritized by the following procedure: They first concentrated on the top 1,000 single SNPs and considered the 30 highest ranking of those located in regions of genes (including 100 kb of the flanking sequences) for further analysis. Moreover, the ten highest ranking of the top 100 SNP-regions which comprised clusters of[3 SNPs and were located in regions of genes (SD=100 kb of flanking sequences) were evaluated. In addition, results from the comparison analysis outlined above as well as findings from previous studies on complex traits and neuropsychiatric diseases, especially substance use disorders were also considered.
Result Description	They identifiesd novel risk genes and revealed remarkable overlap with findings from recent GWA scans in substance use disorders. Comparison with results from our previously reported high-resolution linkage scan in extended pedigrees confirms several chromosomal loci, including 16q23.1-24.3 which also reached genome-wide significance in a recent meta-analysis of seven linkage studies (Zhou et al. in Am J Med Genet Part B, 2008). The findings provide additional support for a common effect of genes coding for cell adhesion molecules (e.g., CDH13, ASTN2) and regulators of synaptic plasticity (e.g., CTNNA2, KALRN) despite the complex multifactorial etiologies of adult ADHD and addiction vulnerability.

SNPs reported by this study (count: 30)

SNP	Statistical Values	Author Comments	Result of Statistical Analysis
rs10514604	ANOVA P-value=8.06E-07, Mean of ranks=69	one of the top 30 single SNPs located in gene regions (inclu...... one of the top 30 single SNPs located in gene regions (including 100kb of flanking sequences) ranked according to the mean rank calculated across three statistics; annotated by GWAS Catalog More...	Trend
rs10786284	ANOVA P-value=1.96E-06, Mean of ranks=61	one of the top 30 single SNPs located in gene regions (inclu...... one of the top 30 single SNPs located in gene regions (including 100kb of flanking sequences) ranked according to the mean rank calculated across three statistics; annotated by GWAS Catalog More...	Trend
rs10983238	ANOVA P-value=1.37E-07, Mean of ranks=15	one of the top 30 single SNPs located in gene regions (inclu...... one of the top 30 single SNPs located in gene regions (including 100kb of flanking sequences) ranked according to the mean rank calculated across three statistics; annotated by GWAS Catalog More...	Trend
rs11243897	ANOVA P-value=5.63E-08, Mean of ranks=1	one of the top 30 single SNPs located in gene regions (inclu...... one of the top 30 single SNPs located in gene regions (including 100kb of flanking sequences) ranked according to the mean rank calculated across three statistics; annotated by GWAS Catalog More...	Trend
rs11594082	ANOVA P-value=1.00E-05, Mean of ranks=52	one of the top 30 single SNPs located in gene regions (inclu...... one of the top 30 single SNPs located in gene regions (including 100kb of flanking sequences) ranked according to the mean rank calculated across three statistics More...	Non-significant
rs11646411	ANOVA P-value=7.40E-06, Mean of ranks=79	one of the top 30 single SNPs located in gene regions (inclu...... one of the top 30 single SNPs located in gene regions (including 100kb of flanking sequences) ranked according to the mean rank calculated across three statistics; annotated by GWAS Catalog More...	Trend
rs12453316	ANOVA P-value=1.72E-05, Mean of ranks=62	one of the top 30 single SNPs located in gene regions (inclu...... one of the top 30 single SNPs located in gene regions (including 100kb of flanking sequences) ranked according to the mean rank calculated across three statistics More...	Non-significant
rs13395022	ANOVA P-value=9.68E-06, Mean of ranks=57	one of the top 30 single SNPs located in gene regions (inclu...... one of the top 30 single SNPs located in gene regions (including 100kb of flanking sequences) ranked according to the mean rank calculated across three statistics More...	Non-significant
rs1555322	ANOVA P-value=3.60E-06, Mean of ranks=49	one of the top 30 single SNPs located in gene regions (inclu...... one of the top 30 single SNPs located in gene regions (including 100kb of flanking sequences) ranked according to the mean rank calculated across three statistics; annotated by GWAS Catalog More...	Trend
rs16928529	ANOVA P-value=3.90E-06, Mean of ranks=12	one of the top 30 single SNPs located in gene regions (inclu...... one of the top 30 single SNPs located in gene regions (including 100kb of flanking sequences) ranked according to the mean rank calculated across three statistics; annotated by GWAS Catalog More...	Trend
rs2199161	ANOVA P-value=1.62E-06, Mean of ranks=11	one of the top 30 single SNPs located in gene regions (inclu...... one of the top 30 single SNPs located in gene regions (including 100kb of flanking sequences) ranked according to the mean rank calculated across three statistics; annotated by GWAS Catalog More...	Trend
rs220470	ANOVA P-value=1.34E-07, Mean of ranks=28	one of the top 30 single SNPs located in gene regions (inclu...... one of the top 30 single SNPs located in gene regions (including 100kb of flanking sequences) ranked according to the mean rank calculated across three statistics; annotated by GWAS Catalog More...	Trend
rs2237349	ANOVA P-value=4.63E-06, Mean of ranks=64	one of the top 30 single SNPs located in gene regions (inclu...... one of the top 30 single SNPs located in gene regions (including 100kb of flanking sequences) ranked according to the mean rank calculated across three statistics; annotated by GWAS Catalog More...	Trend
rs2241685	ANOVA P-value=8.11E-06, Mean of ranks=54	one of the top 30 single SNPs located in gene regions (inclu...... one of the top 30 single SNPs located in gene regions (including 100kb of flanking sequences) ranked according to the mean rank calculated across three statistics; annotated by GWAS Catalog More...	Trend
rs2242073	ANOVA P-value=8.27E-06, Mean of ranks=40	one of the top 30 single SNPs located in gene regions (inclu...... one of the top 30 single SNPs located in gene regions (including 100kb of flanking sequences) ranked according to the mean rank calculated across three statistics; annotated by GWAS Catalog More...	Trend
rs2502731	ANOVA P-value=1.58E-06, Mean of ranks=19	one of the top 30 single SNPs located in gene regions (inclu...... one of the top 30 single SNPs located in gene regions (including 100kb of flanking sequences) ranked according to the mean rank calculated across three statistics; annotated by GWAS Catalog More...	Trend
rs2281597	ANOVA P-value=5.41E-07, Mean of ranks=18	one of the top 30 single SNPs located in gene regions (inclu...... one of the top 30 single SNPs located in gene regions (including 100kb of flanking sequences) ranked according to the mean rank calculated across three statistics; annotated by GWAS Catalog More...	Trend
rs2677744	ANOVA P-value=9.69E-07, Mean of ranks=13	one of the top 30 single SNPs located in gene regions (inclu...... one of the top 30 single SNPs located in gene regions (including 100kb of flanking sequences) ranked according to the mean rank calculated across three statistics; annotated by GWAS Catalog More...	Trend
rs2587695	ANOVA P-value=2.73E-07, Mean of ranks=2	one of the top 30 single SNPs located in gene regions (inclu...... one of the top 30 single SNPs located in gene regions (including 100kb of flanking sequences) ranked according to the mean rank calculated across three statistics; annotated by GWAS Catalog More...	Trend
rs3799977	ANOVA P-value=4.90E-06, Mean of ranks=80	one of the top 30 single SNPs located in gene regions (inclu...... one of the top 30 single SNPs located in gene regions (including 100kb of flanking sequences) ranked according to the mean rank calculated across three statistics; annotated by GWAS Catalog More...	Trend
rs2842643	ANOVA P-value=3.28E-06, Mean of ranks=70	one of the top 30 single SNPs located in gene regions (inclu...... one of the top 30 single SNPs located in gene regions (including 100kb of flanking sequences) ranked according to the mean rank calculated across three statistics; annotated by GWAS Catalog More...	Trend
rs412050	ANOVA P-value=5.83E-06, Mean of ranks=23	one of the top 30 single SNPs located in gene regions (inclu...... one of the top 30 single SNPs located in gene regions (including 100kb of flanking sequences) ranked according to the mean rank calculated across three statistics; annotated by GWAS Catalog More...	Trend
rs3893215	ANOVA P-value=2.56E-05, Mean of ranks=73	one of the top 30 single SNPs located in gene regions (inclu...... one of the top 30 single SNPs located in gene regions (including 100kb of flanking sequences) ranked according to the mean rank calculated across three statistics More...	Non-significant
rs4964805	ANOVA P-value=4.74E-06, Mean of ranks=32	one of the top 30 single SNPs located in gene regions (inclu...... one of the top 30 single SNPs located in gene regions (including 100kb of flanking sequences) ranked according to the mean rank calculated across three statistics; annotated by GWAS Catalog More...	Trend
rs469727	ANOVA P-value=7.54E-06, Mean of ranks=55	one of the top 30 single SNPs located in gene regions (inclu...... one of the top 30 single SNPs located in gene regions (including 100kb of flanking sequences) ranked according to the mean rank calculated across three statistics; annotated by GWAS Catalog More...	Trend
rs7164335	ANOVA P-value=1.30E-07, Mean of ranks=50	one of the top 30 single SNPs located in gene regions (inclu...... one of the top 30 single SNPs located in gene regions (including 100kb of flanking sequences) ranked according to the mean rank calculated across three statistics; annotated by GWAS Catalog More...	Trend
rs515910	ANOVA P-value=4.36E-06, Mean of ranks=24	one of the top 30 single SNPs located in gene regions (inclu...... one of the top 30 single SNPs located in gene regions (including 100kb of flanking sequences) ranked according to the mean rank calculated across three statistics; annotated by GWAS Catalog More...	Trend
rs7995215	ANOVA P-value=1.35E-08, Mean of ranks=53	one of the top 30 single SNPs located in gene regions (inclu...... one of the top 30 single SNPs located in gene regions (including 100kb of flanking sequences) ranked according to the mean rank calculated across three statistics; annotated by GWAS Catalog More...	Trend
rs7175404	ANOVA P-value=6.03E-07, Mean of ranks=14	one of the top 30 single SNPs located in gene regions (inclu...... one of the top 30 single SNPs located in gene regions (including 100kb of flanking sequences) ranked according to the mean rank calculated across three statistics; annotated by GWAS Catalog More...	Trend
rs864643	ANOVA P-value=1.30E-08, Mean of ranks=4	one of the top 30 single SNPs located in gene regions (inclu...... one of the top 30 single SNPs located in gene regions (including 100kb of flanking sequences) ranked according to the mean rank calculated across three statistics; annotated by GWAS Catalog More...	Trend

Genes reported by this study (count: 30)

Gene	Statistical Values/Author Comments	Result of Statistical Analysis
CSMD2	Trend associated SNP was mapped in this gene. Trend associated SNP was mapped in this gene.	Trend
ITGAE	Trend associated SNP was mapped in this gene. Trend associated SNP was mapped in this gene.	Trend
CRYGC	Trend associated SNP was mapped in this gene. Trend associated SNP was mapped in this gene.	Trend
SUPT3H	Trend associated SNP was mapped in this gene. Trend associated SNP was mapped in this gene.	Trend
ITGA11	Trend associated SNP was mapped in this gene. Trend associated SNP was mapped in this gene.	Trend
CTNNA2	No significant or Trend associated SNP was mapped in this ge...... No significant or Trend associated SNP was mapped in this gene. More...	Non-significant
KCNC1	No significant or Trend associated SNP was mapped in this ge...... No significant or Trend associated SNP was mapped in this gene. More...	Non-significant
MYT1L	Trend associated SNP was mapped in this gene. Trend associated SNP was mapped in this gene.	Trend
CDH13	Trend associated SNP was mapped in this gene. Trend associated SNP was mapped in this gene.	Trend
CREB5	Trend associated SNP was mapped in this gene. Trend associated SNP was mapped in this gene.	Trend
MOBP	Trend associated SNP was mapped in this gene. Trend associated SNP was mapped in this gene.	Trend
MMP24	Trend associated SNP was mapped in this gene. Trend associated SNP was mapped in this gene.	Trend
CDH23	No significant or Trend associated SNP was mapped in this ge...... No significant or Trend associated SNP was mapped in this gene. More...	Non-significant
TFEB	Trend associated SNP was mapped in this gene. Trend associated SNP was mapped in this gene.	Trend
MAP1B	Trend associated SNP was mapped in this gene. Trend associated SNP was mapped in this gene.	Trend
GPC6	Trend associated SNP was mapped in this gene. Trend associated SNP was mapped in this gene.	Trend
AK8	Trend associated SNP was mapped in this gene. Trend associated SNP was mapped in this gene.	Trend
PPM1F	Trend associated SNP was mapped in this gene. Trend associated SNP was mapped in this gene.	Trend
AK094352	Trend associated SNP was mapped in this gene. Trend associated SNP was mapped in this gene.	Trend
REEP5	Trend associated SNP was mapped in this gene. Trend associated SNP was mapped in this gene.	Trend
PCDP1	Trend associated SNP was mapped in this gene. Trend associated SNP was mapped in this gene.	Trend
ASTN2	Trend associated SNP was mapped in this gene. Trend associated SNP was mapped in this gene.	Trend
TLL2	Trend associated SNP was mapped in this gene. Trend associated SNP was mapped in this gene.	Trend
UNC5B	Trend associated SNP was mapped in this gene. Trend associated SNP was mapped in this gene.	Trend
ATP2C2	Trend associated SNP was mapped in this gene. Trend associated SNP was mapped in this gene.	Trend
WDR96	Trend associated SNP was mapped in this gene. Trend associated SNP was mapped in this gene.	Trend
MAN2A2	Trend associated SNP was mapped in this gene. Trend associated SNP was mapped in this gene.	Trend
NT5DC3	Trend associated SNP was mapped in this gene. Trend associated SNP was mapped in this gene.	Trend
SDK2	No significant or Trend associated SNP was mapped in this ge...... No significant or Trend associated SNP was mapped in this gene. More...	Non-significant
DNM1	Trend associated SNP was mapped in this gene. Trend associated SNP was mapped in this gene.	Trend

Regions reported by this study (count: 10)

Region	Statistical Values	Author Comments	Result of Statistical Analysis
6p25.2	14 highest ranking SNPs in this region; mean rank of best SNP is 331	One of the ten highest ranking SNP-regions comprising cluste...... One of the ten highest ranking SNP-regions comprising clusters of>3 SNPs located in genes (up-/down-stream 100 kb of flanking sequences). More...	Trend
7p12.2	10 highest ranking SNPs in this region; mean rank of best SNP is 491	One of the ten highest ranking SNP-regions comprising cluste...... One of the ten highest ranking SNP-regions comprising clusters of>3 SNPs located in genes (up-/down-stream 100 kb of flanking sequences). More...	Trend
3q21.2	15 highest ranking SNPs in this region; mean rank of best SNP is 321	One of the ten highest ranking SNP-regions comprising cluste...... One of the ten highest ranking SNP-regions comprising clusters of>3 SNPs located in genes (up-/down-stream 100 kb of flanking sequences). More...	Trend
5q35.3	15 highest ranking SNPs in this region; mean rank of best SNP is 68	One of the ten highest ranking SNP-regions comprising cluste...... One of the ten highest ranking SNP-regions comprising clusters of>3 SNPs located in genes (up-/down-stream 100 kb of flanking sequences). More...	Trend
11q14.2	11 highest ranking SNPs in this region; mean rank of best SNP is 238	One of the ten highest ranking SNP-regions comprising cluste...... One of the ten highest ranking SNP-regions comprising clusters of>3 SNPs located in genes (up-/down-stream 100 kb of flanking sequences). More...	Trend
11q14.3	8 highest ranking SNPs in this region; mean rank of best SNP is 384	One of the ten highest ranking SNP-regions comprising cluste...... One of the ten highest ranking SNP-regions comprising clusters of>3 SNPs located in genes (up-/down-stream 100 kb of flanking sequences). More...	Trend
7q36.2	7 highest ranking SNPs in this region; mean rank of best SNP is 61	One of the ten highest ranking SNP-regions comprising cluste...... One of the ten highest ranking SNP-regions comprising clusters of>3 SNPs located in genes (up-/down-stream 100 kb of flanking sequences). More...	Trend
10q11.22	11 highest ranking SNPs in this region; mean rank of best SNP is 282	One of the ten highest ranking SNP-regions comprising cluste...... One of the ten highest ranking SNP-regions comprising clusters of>3 SNPs located in genes (up-/down-stream 100 kb of flanking sequences). More...	Trend
11q23.3	13 highest ranking SNPs in this region; mean rank of best SNP is 374	One of the ten highest ranking SNP-regions comprising cluste...... One of the ten highest ranking SNP-regions comprising clusters of>3 SNPs located in genes (up-/down-stream 100 kb of flanking sequences). More...	Trend
12q23.3	20 highest ranking SNPs in this region; mean rank of best SNP is 86	One of the ten highest ranking SNP-regions comprising cluste...... One of the ten highest ranking SNP-regions comprising clusters of>3 SNPs located in genes (up-/down-stream 100 kb of flanking sequences). More...	Trend