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	Williams N. M., 201222420048
Citation	Williams N. M., Franke B., Mick E., Anney R. J., Freitag C. M., Gill M., Thapar A., O'Donovan M. C., Owen M. J., Holmans P., Kent L., Middleton F., Zhang-James Y., Liu L., Meyer J., Nguyen T. T., Romanos J., Romanos M., Seitz C., Renner T. J., Walitza S., Warnke A., Palmason H., Buitelaar J., Rommelse N., Vasquez A. A., Hawi Z., Langley K., Sergeant J., Steinhausen H. C., Roeyers H., Biederman J., Zaharieva I., Hakonarson H., Elia J., Lionel A. C., Crosbie J., Marshall C. R., Schachar R., Scherer S. W., Todorov A., Smalley S. L., Loo S., Nelson S., Shtir C., Asherson P., Reif A., Lesch K. P. and Faraone S. V. (2012) "Genome-wide analysis of copy number variants in attention deficit hyperactivity disorder: the role of rare variants and duplications at 15q13.3." Am J Psychiatry, 169(2): 195-204.
Study Design	case-control
Study Type	Genome-wide CNV analysis
Sample Size	896 cases, 2455 controls
Predominant Ethnicity	Caucasian
Population	European
Gender	84% male
Age Group	Children/Adolescents : mean age: 10.4 years

Detail Info

Summary	The authors performed a genome-wide analysis of large, rare CNVs (<1% population frequency) in children with ADHD (N=896) and comparison subjects (N=2,455) from the IMAGE II Consortium. The authors observed 1,562 individually rare CNVs >100kb in size, which segregated into 912 independent loci. Overall, the rate of rare CNVs >100kb was 1.15 times higher in ADHD case subjects relative to comparison subjects, with duplications spanning known genes showing a 1.2-fold enrichment. In accordance with a previous study, rare CNVs >500 kb showed the greatest enrichment (1.28-fold). CNVs identified in ADHD case subjects were significantly enriched for loci implicated in autism and in schizophrenia. Duplications spanning the CHRNA7 gene at chromosome 15q13.3 were associated with ADHD in single-locus analysis. This finding was consistently replicated in an additional 2,242 ADHD case subjects and 8,552 comparison subjects from four independent cohorts from the United Kingdom, the United States, and Canada. Presence of the duplication at 15q13.3 appeared to be associated with comorbid conduct disorder. These findings support the enrichment of large, rare CNVs in ADHD and implicate duplications at 15q13.3 as a novel risk factor for ADHD. With a frequency of 0.6% in the populations investigated and a relatively large effect size (OR=2.22, 95% CI=1.5-3.6), this locus could be an important contributor to ADHD etiology.
Total Sample	A total of 732 ADHD cases passed quality control. Most had combined-type ADHD (81%), and the remainder had primarily inattentive (14%) or primarily hyperactive-impulsive ADHD (5%). In the subsample for which information on comorbid disorders was available, 18% had comorbid conduct disorder and 47% had comorbid oppositional defiant disorder.
Replication Size	2242 ADHD cases, 8552 controls
Sample Collection	The 896 case subjects investigated in this study consisted of 1) samples collected by a subset of the International Multicenter ADHD Genetics (IMAGE) Project sites but not included in the IMAGE GWAS and 2) samples collected at additional sites in the United Kingdom, Ireland, Germany, Switzerland, the Netherlands, and the United States and were assessed in a manner similar to that of the IMAGE samples. The comparison samples (2,455 population subjects of European ancestry) were collected for a GWAS of schizophrenia and have been described elsewhere. Briefly, the comparison subjects were drawn from a nationally representative U.S. survey panel ascertained via random digit dialing. Replication samples included those from the recently published CNV study from Cardiff, U.K., excluding the 23 ADHD cases that overlap with the IMAGE II discovery sample (296 DSM-IV ADHD case subjects with IQ>70 and 1,047 comparison subjects genotyped on Illumina Human660W-Quad BeadChip [for the case subjects] or HumanHap550 BeadChip [for the comparison subjects]); from the PUWMa (Pfizer-funded study from UCLA, Washington University, and Massachusetts General Hospital) sample of 692 DSM-IV ADHD case subjects and 1,101 comparison subjects genotyped on the Illumina 1M BeadChip; from a Canadian study that included 247 DSM-IV ADHD case subjects and 2,357 comparison subjects genotyped on the Affymetrix 6.0 array; and from an unpublished sample that included 1,013 DSM-IV ADHD case subjects and 4,105 comparison children genotyped on the Illumina Infinium HumanHap550K BeadChip at Children's Hospital of Philadelphia. In the latter study, ADHD case subjects of Northern European descent (ages 6-18) were recruited from pediatric and behavioral health clinics in the Philadelphia area.
Diagnosis Description	At the collection sites, patients had been identified mainly through outpatient clinics, met DSM-IV criteria for ADHD, had been referred for assessment of hyperactive, disruptive, or disorganized behavior, and had been clinically diagnosed as having ADHD (or hyperkinetic disorder, the most closely equivalent category in the ICD-10 nomenclature used by some of the clinics) using semistructured interviews with parents. All sites excluded subjects with an IQ below 70. Comparison subjects were screened for psychosis and bipolar disorder but not for ADHD. A blood sample was collected via phlebotomy services.
Technique	A total of 41 subjects were included in the validation study using quantitative real-time polymerase chain reaction analysis, including eight ADHD 15q13.3 duplication carriers (ADHD carriers) and their family members, eight randomly selected ADHD subjects without duplications (ADHD noncarriers), six comparisonsubjects with the duplication (control carriers), and four random comparison subjects (non-ADHD).
Analysis Method	The genome-wide burden of rare CNVs was assessed according to either the number of rare CNVs per sample or the average rare CNV size per sample. Gene-centric burden analysis was performed by limiting the analysis to rare CNVs that overlapped with the list of genes present in NCBI Build 36.1 (hg18). The significance of the burden comparisons was assessed via permutation (10,000 permutations, one-sided test) using PLINK. Analyses were performed for all large, rare CNVs as well as by stratification according to CNV type and size. Differences in the rates at which CNVs were called in males or females were assessed separately in case and comparison subjects using PLINK, with significance assessed via permutation. Locus-specific tests of association were made using PLINK, again with the significance being assessed via permutation.We also tested the overall significance of case-control comparisons for the total burden of CNVs at loci previously implicated in schizophrenia or autism were also tested using logistic regression analysis. From each replication cohort, All duplications in the case and comparison subjects that spanned the 15q13.3 consensus region by at least 60% were selected. Tests of association were then performed for each replication sample by Fisher's exact test and for meta-analysis by logistic regression with sample site included as an independent variable. The Breslow-Day test was used to test for heterogeneity between replication samples.
Result Description	The authors observed 1,562 individually rare CNVs >100kb in size, which segregated into 912 independent loci. Overall, the rate of rare CNVs >100kb was 1.15 times higher in ADHD case subjects relative to comparison subjects, with duplications spanning known genes showing a 1.2-fold enrichment. In accordance with a previous study, rare CNVs >500 kb showed the greatest enrichment (1.28-fold). CNVs identified in ADHD case subjects were significantly enriched for loci implicated in autism and in schizophrenia. Duplications spanning the CHRNA7 gene at chromosome 15q13.3 were associated with ADHD in single-locus analysis. This finding was consistently replicated in an additional 2,242 ADHD case subjects and 8,552 comparison subjects from four independent cohorts from the United Kingdom, the United States, and Canada. Presence of the duplication at 15q13.3 appeared to be associated with comorbid conduct disorder.

Regions reported by this study (count: 1)