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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	Elia, J., 201222138692
Citation	Elia, J., J. T. Glessner, K. Wang, N. Takahashi, C. J. Shtir, D. Hadley, P. M. Sleiman, H. Zhang, C. E. Kim, R. Robison, G. J. Lyon, J. H. Flory, J. P. Bradfield, M. Imielinski, C. Hou, E. C. Frackelton, R. M. Chiavacci, T. Sakurai, C. Rabin, F. A. Middleton, K. A. Thomas, M. Garris, F. Mentch, C. M. Freitag, H. C. Steinhausen, A. A. Todorov, A. Reif, A. Rothenberger, B. Franke, E. O. Mick, H. Roeyers, J. Buitelaar, K. P. Lesch, T. Banaschewski, R. P. Ebstein, F. Mulas, R. D. Oades, J. Sergeant, E. Sonuga-Barke, T. J. Renner, M. Romanos, J. Romanos, A. Warnke, S. Walitza, J. Meyer, H. Palmason, C. Seitz, S. K. Loo, S. L. Smalley, J. Biederman, L. Kent, P. Asherson, R. J. Anney, J. W. Gaynor, P. Shaw, M. Devoto, P. S. White, S. F. Grant, J. D. Buxbaum, J. L. Rapoport, N. M. Williams, S. F. Nelson, S. V. Faraone and H. Hakonarson (2012). "Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder." Nat Genet 44(1): 78-84.
Study Design	case-control
Study Type	Genome-wide CNV analysis
Sample Size	1,013 cases and 4,105 healthy controls
Predominant Ethnicity	Caucasian
Population	CHOP collection
Age Group	Children/Adolescents and Adults : Age ranges are 6-18, 6-12, 6-17, 5-14 and 19-60 for different ADHD cohorts.

Detail Info

Summary	We performed a whole-genome copy number variation (CNV) study on 1,013 cases with ADHD and 4,105 healthy children of European ancestry using 550,000 SNPs. We evaluated statistically significant findings in multiple independent cohorts, with a total of 2,493 cases with ADHD and 9,222 controls of European ancestry, using matched platforms. CNVs affecting metabotropic glutamate receptor genes were enriched across all cohorts (P = 2.1 x 10(-9)). We saw GRM5 (encoding glutamate receptor, metabotropic 5) deletions in ten cases and one control (P = 1.36 x 10(-6)). We saw GRM7 deletions in six cases, and we saw GRM8 deletions in eight cases and no controls. GRM1 was duplicated in eight cases. We experimentally validated the observed variants using quantitative RT-PCR. A gene network analysis showed that genes interacting with the genes in the GRM family are enriched for CNVs in approximately 10% of the cases (P = 4.38 x 10(-10)) after correction for occurrence in the controls. We identified rare recurrent CNVs affecting glutamatergic neurotransmission genes that were overrepresented in multiple ADHD cohorts.
Total Sample	Our discovery cohort included a total of 1,013 cases of European descent with ADHD recruited and genotyped at The Children¡¯s Hospital of Philadelphia (CHOP) and was comprised of 664 cases without available parental information and 349 cases from trios with complete information. The control group included 4,105 healthy children of European ancestry that were 6-18 years old, 32% of which were female and 68% of which were male. For the replication, we used 624 samples from the IMAGE cohort that met quality control criteria: the PUWMa consortium contributed 864 cases with ADHD and 1,258 parents, and the IMAGE II consortium contributed 787 cases with ADHD and 898 unrelated controls. We used an additional 128 cases from the US National Institute of Mental Health (NIMH) and 90 cases from the University of Utah for the replication.
Replication Size	2,493 cases and 9,222 controls of European ancestry
Sample Collection	The Children's Hospital of Philadelphia (CHOP)
Diagnosis Description	We established a minimum inclusion intelligence quotient threshold of 70 to exclude individuals with intellectual disability. We screened medical records and parental- or self-reported questionnaires for individuals with developmental delays or special educational needs.
Technique	We genotyped the DNA samples on different platforms. To manage differences in CNV detection between the arrays, we used controls genotyped on platforms that matched the platforms used for the cases.
Analysis Method	We used PennCNV to produce CNV calls for the cases and controls. We also ran QuantiSNP to evaluate CNV calls that had a minimum of three SNPs on autosomes. To identify CNVs associated with ADHD, we applied a segment-based approach for consecutive SNPs with more CNVs in cases than in controls. TDT test was used to detect genome-wide significant associations in the genotype GWAS analysis. To ensure CNV reliability, we experimentally validated all CNVRs using quantitative RT-PCR (qRT-PCR). GRM receptor gene interaction networks affected in ADHD was built by using Cytoscape Software.
Result Description	CNVs affecting metabotropic glutamate receptor genes were enriched across all cohorts (P = 2.1 x 10(-9)). We saw GRM5 (encoding glutamate receptor, metabotropic 5) deletions in ten cases and one control (P = 1.36 x 10(-6)). We saw GRM7 deletions in six cases, and we saw GRM8 deletions in eight cases and no controls. GRM1 was duplicated in eight cases. We experimentally validated the observed variants using quantitative RT-PCR. A gene network analysis showed that genes interacting with the genes in the GRM family are enriched for CNVs in approximately 10% of the cases (P = 4.38 x 10(-10)) after correction for occurrence in the controls. We identified rare recurrent CNVs affecting glutamatergic neurotransmission genes that were overrepresented in multiple ADHD cohorts.

CNVs reported by this study (count: 19)

Name	Symbol in Literature	Type	Inheritance	Author Comments
CNV_Elia[2012]_9	chr19:38,427,720-38,444,834	Del	2:2:1(80%)	New CNVRs overrepresented in individuals with ADHD. New CNVRs overrepresented in individuals with ADHD.
CNV_Elia[2012]_8	chr1:56,053,497-56,064,495	Del	1:0:3(25%)	New CNVRs overrepresented in individuals with ADHD. New CNVRs overrepresented in individuals with ADHD.
CNV_Elia[2012]_11	chr2:81,419,297-81,446,082	Dup	1:0:1(50%)	New CNVRs overrepresented in individuals with ADHD. New CNVRs overrepresented in individuals with ADHD.
CNV_Elia[2012]_10	chr3:1,844,168-1,859,889	Del	2:4:0(100%)	New CNVRs overrepresented in individuals with ADHD. New CNVRs overrepresented in individuals with ADHD.
CNV_Elia[2012]_13	chr19:15,992,679-15,997,923	Del		de novo CNVs in the CHOP discovery cohort. de novo CNVs in the CHOP discovery cohort.
CNV_Elia[2012]_12	chr4:113,772,340-113,788,584	Dup	0:0:0(NA)	New CNVRs overrepresented in individuals with ADHD. New CNVRs overrepresented in individuals with ADHD.
CNV_Elia[2012]_15	chr17:71,112,486-71,120,734	Del		de novo CNVs in the CHOP discovery cohort. de novo CNVs in the CHOP discovery cohort.
CNV_Elia[2012]_14	chr22:38,384,374-38,403,731	Del		de novo CNVs in the CHOP discovery cohort. de novo CNVs in the CHOP discovery cohort.
CNV_Elia[2012]_17	chr19:59,423,491-59,428,132	Dup		de novo CNVs in the CHOP discovery cohort. de novo CNVs in the CHOP discovery cohort.
CNV_Elia[2012]_16	chr12:55,902,280-55,923,860	Del		de novo CNVs in the CHOP discovery cohort. de novo CNVs in the CHOP discovery cohort.
CNV_Elia[2012]_19	chr18:65,358,832-65,367,619	Del		de novo CNVs in the CHOP discovery cohort. de novo CNVs in the CHOP discovery cohort.
CNV_Elia[2012]_18	chr16:87,694,595-87,778,383	Del		de novo CNVs in the CHOP discovery cohort. de novo CNVs in the CHOP discovery cohort.
CNV_Elia[2012]_1	chr11:88,269,449-88,351,661	Del	4:1:3(62.5%)	New CNVRs overrepresented in individuals with ADHD. New CNVRs overrepresented in individuals with ADHD.
CNV_Elia[2012]_2	chr7:126,441,593-126,621,501	Del	0:1:0(100%)	New CNVRs overrepresented in individuals with ADHD. New CNVRs overrepresented in individuals with ADHD.
CNV_Elia[2012]_3	chr3:7,183,953-7,197,236	Del	0:2:0(100%)	New CNVRs overrepresented in individuals with ADHD. New CNVRs overrepresented in individuals with ADHD.
CNV_Elia[2012]_4	chr6:146,657,076-146,694,047	Dup	2:0:0(100%)	New CNVRs overrepresented in individuals with ADHD. New CNVRs overrepresented in individuals with ADHD.
CNV_Elia[2012]_5	chr1:72,317,292-72,328,395	Dup	0:3:0(100%)	New CNVRs overrepresented in individuals with ADHD. New CNVRs overrepresented in individuals with ADHD.
CNV_Elia[2012]_6	chr7:153,495,598-153,564,827	Dup	1:2:0(100%)	New CNVRs overrepresented in individuals with ADHD. New CNVRs overrepresented in individuals with ADHD.
CNV_Elia[2012]_7	chr5:65,027,976-65,046,520	Del	2:0:2(50%)	New CNVRs overrepresented in individuals with ADHD. New CNVRs overrepresented in individuals with ADHD.

Genes reported by this study (count: 13)

Gene	Statistical Values/Author Comments	Result of Statistical Analysis
GRM5	This gene was found directly affected by CNVRs overrepresent...... This gene was found directly affected by CNVRs overrepresented in individuals with ADHD. More...	Significant
CNTN4	This gene was found directly affected by CNVRs overrepresent...... This gene was found directly affected by CNVRs overrepresented in individuals with ADHD. More...	Significant
GRM1	This gene was found directly affected by CNVRs overrepresent...... This gene was found directly affected by CNVRs overrepresented in individuals with ADHD. More...	Significant
CTNNA2	This gene was found directly affected by CNVRs overrepresent...... This gene was found directly affected by CNVRs overrepresented in individuals with ADHD. More...	Significant
SLC7A10	This gene was found directly affected by CNVRs overrepresent...... This gene was found directly affected by CNVRs overrepresented in individuals with ADHD. More...	Significant
NEGR1	This gene was found directly affected by CNVRs overrepresent...... This gene was found directly affected by CNVRs overrepresented in individuals with ADHD. More...	Significant
GRM8	This gene was found directly affected by CNVRs overrepresent...... This gene was found directly affected by CNVRs overrepresented in individuals with ADHD. More...	Significant
GRM7	This gene was found directly affected by CNVRs overrepresent...... This gene was found directly affected by CNVRs overrepresented in individuals with ADHD. More...	Significant
USP24	This gene was found directly affected by CNVRs overrepresent...... This gene was found directly affected by CNVRs overrepresented in individuals with ADHD. More...	Significant
SGTB	This gene was found directly affected by CNVRs overrepresent...... This gene was found directly affected by CNVRs overrepresented in individuals with ADHD. More...	Significant
LARP7	This gene was found directly affected by CNVRs overrepresent...... This gene was found directly affected by CNVRs overrepresented in individuals with ADHD. More...	Significant
NLN	This gene was found directly affected by CNVRs overrepresent...... This gene was found directly affected by CNVRs overrepresented in individuals with ADHD. More...	Significant
DPP6	This gene was found directly affected by CNVRs overrepresent...... This gene was found directly affected by CNVRs overrepresented in individuals with ADHD. More...	Significant