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	Lionel, A. C., 201121832240
Citation	Lionel A. C., Crosbie J., Barbosa N., Goodale T., Thiruvahindrapuram B., Rickaby J., Gazzellone M., Carson A. R., Howe J. L., Wang Z., Wei J., Stewart A. F., Roberts R., McPherson R., Fiebig A., Franke A., Schreiber S., Zwaigenbaum L., Fernandez B. A., Roberts W., Arnold P. D., Szatmari P., Marshall C. R., Schachar R. and Scherer S. W. (2011) "Rare copy number variation discovery and cross-disorder comparisons identify risk genes for ADHD." Sci Transl Med, 3(95): 95ra75.
Study Design	case-control
Study Type	Genome-wide CNV analysis
Sample Size	248 cases, 2357 controls
Predominant Ethnicity	MIX
Population	Canada
Gender	participants were 175 boys (71%) and 73 girls (29%)
Age Group	Children/Adolescents : age range: 5-17 years, mean age: 9.5 years

Detail Info

Summary	In this study, they identified de novo and rare copy number variations (CNVs) in 248 unrelated ADHD patients using million-feature genotyping arrays. They found de novo CNVs in 3 of 173 (1.7%) ADHD patients for whom they had DNA from both parents. These CNVs affected brain-expressed genes: DCLK2, SORCS1, SORCS3, and MACROD2. They also detected rare inherited CNVs in 19 of 248 (7.7%) ADHD probands, which they absent in 2357 controls and which either overlapped previously implicated ADHD loci or identified new candidate susceptibility genes. Among these de novo and rare inherited CNVs, there were also examples of genes (ASTN2 , GABRG1, and CNTN5) previously implicated by rare CNVs in other neurodevelopmental conditions including autism spectrum disorder (ASD). To further explore the overlap of risks in ADHD and ASD, they used the same microarrays to test for rare CNVs in an independent, newly collected cohort of 349 unrelated individuals with a primary diagnosis of ASD. Deletions of the neuronal ASTN2 and the ASTN2-intronic TRIM32 genes yielded the strongest association with ADHD and ASD, but numerous other shared candidate genes (such as CHCHD3, MACROD2, and the 16p11.2 region) were also revealed. These results provide support for a role for rare CNVs in ADHD risk and reinforce evidence for the existence of common underlying susceptibility genes for ADHD, ASD, and other neuropsychiatric disorders.
Total Sample	248 unrelated ADHD probands were collected in Canada. In 173 of these families, DNA was genotyped in both parents. 2357 population-based controls (1234 from Ontario and 1123 from Germany) were also analyzed for CNVs using the same array platform and calling strategy as the cases.
Replication Size	349 newly characterized ASD probands
Sample Collection	248 unrelated ADHD probands were collected in Canada. In 173 of these families, DNA was genotyped in both parents. 2357 population-based controls (1234 from Ontario and 1123 from Germany) were also analyzed for CNVs using the same array platform and calling strategy as the cases. Individuals with ASD were recruited from four different Canadian sites: Hospital for Sick Children, Toronto, Ontario; McMaster University, Hamilton, Ontario; Memorial University of Newfoundland, St. John's, Newfoundland; and University of Alberta, Edmonton, Alberta.
Diagnosis Description	Participants were referred for assessment of attention, learning, and behavior problems to the Hospital for Sick Children, Toronto. Participants were included if they met criteria for ADHD based on the results of a semistructured diagnostic interview of the participant's parent(s) and of the proband's teacher, and did not meet any of the exclusion criteria specified by DSM-IV. The ASD probands in this study were 349 unrelated probands (257 boys and 92 girls) who had a clinical diagnosis for ASD by expert clinicians, according to the Autism Diagnostic Interview-Revised (ADI-R) and/or the Autism Diagnostic Observation Schedule (ADOS).
Technique	The Affymetrix SNP 6.0 microarray, which contains 1.8 million markers for CNV interrogation was used for genotyping. De novo CNVs were validated by either qPCR or fluorescence in situ hybridization (FISH) after parentage in all trios with array genotypes was confirmed. DNA sequencing was performed for gene ASTN2 and TRIM32 in all of the ADHD and ASD cases, as well as in ancestry-matched controls.
Analysis Method	CNV calling was performed in a conservative manner using variants detected by two or more of three calling algorithms, which were of sizes greater than 20 kb and spanned at least five array probes. CNV analysis strategy was uniform across cases and controls. Rare variants were defined as those seen exclusively in ADHD patient samples and not in controls (with an overlap criterion of 50% of unique CNV size). de novo CNVs and rare inherited CNVs that overlapped genetic loci previously implicated in ADHD or in other neuro-psychiatric disorders were prioritized.
Result Description	Similar CNV profiles were observed in cases and controls with no significant difference in overall CNV call rate or length. A total of 306 rare CNVs were detected in the ADHD probands. 33 of 34 (97.1%) tested rare stringent calls were validated by qPCR. Using data from probands and both parents (trio data), the de novo CNV rate was determined in ADHD probands to be ~2% (3 of 173). After sequencing all coding exons and splice sites of gene ASTN2 andTRIM32, no significant enrichment of missense variants was observed in the case cohorts compared to the population controls for either gene.

CNVs reported by this study (count: 23)

Name	Symbol in Literature	Type	Inheritance	Author Comments
CNV_Lionel[2011]_8	Sample:19896.3_1023kb	Gain	M	Rare CNVs at loci previously implicated in ADHD. Rare CNVs at loci previously implicated in ADHD.
CNV_Lionel[2011]_7	Sample:63900.3_159kb	Gain	M	Rare CNVs at loci previously implicated in ADHD. Rare CNVs at loci previously implicated in ADHD.
CNV_Lionel[2011]_10	Sample:19752.3_3666kb	Gain	M	Rare CNVs at loci previously implicated in ADHD. Previous re...... Rare CNVs at loci previously implicated in ADHD. Previous reported for ADHD,ASD,SZ. More...
CNV_Lionel[2011]_9	Sample:19929.3_147kb	Gain	U	Rare CNVs at loci previously implicated in ADHD. Rare CNVs at loci previously implicated in ADHD.
CNV_Lionel[2011]_4	Sample:113400.3_109kb	Loss	D	Loci implicated by de novo CNVs in ADHD probands. Previous r...... Loci implicated by de novo CNVs in ADHD probands. Previous reported for ASD. More...
CNV_Lionel[2011]_3	Sample:30600.3_318kb	Gain	D	Loci implicated by de novo CNVs in ADHD probands. Loci implicated by de novo CNVs in ADHD probands.
CNV_Lionel[2011]_6	Sample:27060.3_131kb	Gain	M	Rare CNVs at loci previously implicated in ADHD. Rare CNVs at loci previously implicated in ADHD.
CNV_Lionel[2011]_5	Sample:27027.3_482kb	Gain	P	Rare CNVs at loci previously implicated in ADHD. Rare CNVs at loci previously implicated in ADHD.
CNV_Lionel[2011]_16	Sample:19761.3_177kb	Loss	P	Overlapping rare CNVs in unrelated ADHD probands. Previous r...... Overlapping rare CNVs in unrelated ADHD probands. Previous reported for ASD,BPD,SZ. More...
CNV_Lionel[2011]_15	Sample:19698.4_92kb	Loss	M	Overlapping rare CNVs in unrelated ADHD probands. Previous r...... Overlapping rare CNVs in unrelated ADHD probands. Previous reported for ASD. More...
CNV_Lionel[2011]_18	Sample:108300.3_542kb	Loss	M	Overlapping rare CNVs in unrelated ADHD probands. Previous r...... Overlapping rare CNVs in unrelated ADHD probands. Previous reported for ASD. More...
CNV_Lionel[2011]_17	Sample:19812.3_148kb	Loss	U	Overlapping rare CNVs in unrelated ADHD probands. Previous r...... Overlapping rare CNVs in unrelated ADHD probands. Previous reported for ASD,BPD,SZ. More...
CNV_Lionel[2011]_12	Sample:22512.3_165kb	Loss	P	Overlapping rare CNVs in unrelated ADHD probands. Previous r...... Overlapping rare CNVs in unrelated ADHD probands. Previous reported for ADHD. More...
CNV_Lionel[2011]_11	Sample:19839.3_789kb	Gain	P	Rare CNVs at loci previously implicated in ADHD. Previous re...... Rare CNVs at loci previously implicated in ADHD. Previous reported for ADHD,ASD,SZ. More...
CNV_Lionel[2011]_14	Sample:57300.3_262kb	Gain	M	Overlapping rare CNVs in unrelated ADHD probands. Previous r...... Overlapping rare CNVs in unrelated ADHD probands. Previous reported for ASD. More...
CNV_Lionel[2011]_13	Sample:19365.3_22kb	Loss	U	Overlapping rare CNVs in unrelated ADHD probands. Previous r...... Overlapping rare CNVs in unrelated ADHD probands. Previous reported for ADHD. More...
CNV_Lionel[2011]_22	Sample:89700.3_211kb	Gain	P	Rare CNVs at loci implicated in other neurodevelopmental dis...... Rare CNVs at loci implicated in other neurodevelopmental disorders. Precious reported for ASD. More...
CNV_Lionel[2011]_21	Sample:125700.3_49kb	Loss	P	Rare CNVs at loci implicated in other neurodevelopmental dis...... Rare CNVs at loci implicated in other neurodevelopmental disorders. Precious reported for ADHD,ASD,SZ. More...
CNV_Lionel[2011]_20	Sample:27048.3_64kb	Loss	M	Rare CNVs at loci implicated in other neurodevelopmental dis...... Rare CNVs at loci implicated in other neurodevelopmental disorders. Precious reported for ASD. More...
CNV_Lionel[2011]_1	Sample:27696.3_33kb	Loss	D	Loci implicated by de novo CNVs in ADHD probands. Previous r...... Loci implicated by de novo CNVs in ADHD probands. Previous reported for Epilepsy. More...
CNV_Lionel[2011]_19	Sample:87600.3_97kb	Loss	M	Rare CNVs at loci implicated in other neurodevelopmental dis...... Rare CNVs at loci implicated in other neurodevelopmental disorders. Precious reported for Mild intellectual disability. More...
CNV_Lionel[2011]_2	Sample:30600.3_242kb	Gain	D	Loci implicated by de novo CNVs in ADHD probands. Previous r...... Loci implicated by de novo CNVs in ADHD probands. Previous reported for BPD. More...
CNV_Lionel[2011]_23	Sample:27075.3_388kb	Loss	M	Rare CNVs at loci implicated in other neurodevelopmental dis...... Rare CNVs at loci implicated in other neurodevelopmental disorders. Precious reported for ASD,intellectual disability. More...

Genes reported by this study (count: 12)

Gene	Statistical Values/Author Comments	Result of Statistical Analysis
MACROD2	A 109kb de novo exonic deletion was detected in a male ADHD ...... A 109kb de novo exonic deletion was detected in a male ADHD proband (113400.3) overlapping MACROD2 at 20p12.1. More...	Trend
DRD5	Rare inherited CNVs in ADHD probands which absent in control...... Rare inherited CNVs in ADHD probands which absent in controls overlapped with DRD5 which is previously implicated ADHD loci. More...	Trend
PTPRN2	Rare inherited CNVs in ADHD probands which absent in control...... Rare inherited CNVs in ADHD probands which absent in controls overlapped with PTPRN2, which indicate it a new candidate susceptibility gene for ADHD. More...	Trend
ZBBX	Rare inherited CNVs in ADHD probands which absent in control...... Rare inherited CNVs in ADHD probands which absent in controls overlapped with ZBBX, which indicate it a new candidate susceptibility gene for ADHD. More...	Trend
SORCS3	In one male ADHD proband (30600.3) of a second family, a pai...... In one male ADHD proband (30600.3) of a second family, a pair of adjacent de novo CNVs at 10q25.1 duplicated regions of sizes 242 and 318kb, overlapping the genes SORCS3 and SORCS1 respectively. More...	Trend
TRIM32	Tests in a newly collected cohort of 349 unrelated individua...... Tests in a newly collected cohort of 349 unrelated individuals with ASD showed that deletions of TRIM32 yielded the strongest association with ADHD and ASD. More...	Trend
SORCS1	In one male ADHD proband (30600.3) of a second family, a pai...... In one male ADHD proband (30600.3) of a second family, a pair of adjacent de novo CNVs at 10q25.1 duplicated regions of sizes 242 and 318kb, overlapping the genes SORCS3 and SORCS1 respectively. More...	Trend
CPLX2	Rare inherited CNVs in ADHD probands which absent in control...... Rare inherited CNVs in ADHD probands which absent in controls overlapped with CPLX2, which indicate it a new candidate susceptibility gene for ADHD. More...	Trend
ASTN2	Rare inherited CNVs in ADHD probands which absent in control...... Rare inherited CNVs in ADHD probands which absent in controls overlapped with ASTN2, which indicate it a new candidate susceptibility gene for ADHD. De novo and/or rare inherited CNVs associated with this gene were detected for not only ADHD, but also other neurodevelopmental conditions including ASD. Tests in a newly collected cohort of 349 unrelated individuals with ASD showed that deletions of ASTN2 yielded the strongest association with ADHD and ASD. More...	Trend
DCLK2	In one family, a 33kb de novo deletion at 4q31.3 was detecte...... In one family, a 33kb de novo deletion at 4q31.3 was detected in a male proband (27696.3) with ADHD and anxiety traits who also exhibited seizure-like symptoms. The deletion eliminates two exons of the DCLK2 gene. More...	Trend
CNTN5	De novo and/or rare inherited CNVs associated with this gene...... De novo and/or rare inherited CNVs associated with this gene were detected for not only ADHD, but also other neurodevelopmental conditions including ASD. More...	Trend
GABRG1	De novo and/or rare inherited CNVs associated with this gene...... De novo and/or rare inherited CNVs associated with this gene were detected for not only ADHD, but also other neurodevelopmental conditions including ASD. More...	Trend