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Basic Info
| Reference | Williams NM, 201020888040 |
|---|---|
| Citation | Williams N. M., Zaharieva I., Martin A., Langley K., Mantripragada K., Fossdal R., Stefansson H., Stefansson K., Magnusson P., Gudmundsson O. O., Gustafsson O., Holmans P., Owen M. J., O'Donovan M. and Thapar A. (2010) "Rare chromosomal deletions and duplications in attention-deficit hyperactivity disorder: a genome-wide analysis." Lancet, 376(9750): 1401-8. |
| Study Design | case-control |
| Study Type | Genome-wide CNV analysis |
| Sample Size | 410 children with ADHD and 1156 unrelated ethnically matched controls from the 1958 British Birth Cohort |
| Predominant Ethnicity | Caucasian |
| Population | United Kingdom |
| Gender | 316 boys, 50 girls in case group |
| Age Group | Children/Adolescents : aged 5-17 years, mean age 10.5 years (SD=2.72) |
Detail Info
| Summary | This study aimed to establish whether burden of CNVs was increased in ADHD, and to investigate whether identified CNVs were enriched for loci previously identified in autism and schizophrenia. They undertook a genome-wide analysis of CNVs in 410 children with ADHD and 1156 unrelated ethnically matched controls from the 1958 British Birth Cohort. Children of white United Kingdom origin, aged 5-17 years, who met diagnostic criteria for ADHD or hyperkinetic disorder, but not schizophrenia and autism, were recruited from community child psychiatry and paediatric outpatient clinics. Single nucleotide polymorphisms (SNPs) were genotyped in the ADHD and control groups with two arrays; CNV analysis was limited to SNPs common to both arrays and included only samples with high-quality data. CNVs in the ADHD group were validated with comparative genomic hybridisation. They assessed the genome-wide burden of large (>500 kb), rare (<1% population frequency) CNVs according to the average number of CNVs per sample, with significance assessed via permutation. Locus-specific tests of association were undertaken for test regions defined for all identified CNVs and for 20 loci implicated in autism or schizophrenia. Findings were replicated in 825 Icelandic patients with ADHD and 35,243 Icelandic controls. Data for full analyses were available for 366 children with ADHD and 1047 controls. 57 large, rare CNVs were identified in children with ADHD and 78 in controls, showing a significantly increased rate of CNVs in ADHD (0.156 vs 0.075; p=8.9E-5). This increased rate of CNVs was particularly high in those with intellectual disability (0.424; p=2.0E-6), although there was also a significant excess in cases with no such disability (0.125, p=0.0077). An excess of chromosome 16p13.11 duplications was noted in the ADHD group (p=0.0008 after correction for multiple testing), a finding that was replicated in the Icelandic sample (p=0.031). CNVs identified in our ADHD cohort were significantly enriched for loci previously reported in both autism (p=0.0095) and schizophrenia (p=0.010). These findings provide genetic evidence of an increased rate of large CNVs in individuals with ADHD and suggest that ADHD is not purely a social construct. |
|---|---|
| Total Sample | Of the 410 children recruited to the study, 375 were single cases, and 35 were known to have an affected sibling (only one case from each pair was included). Control genotype data were available for 1156 individuals (594 men, 562 women) born in the United Kingdom during one week in 1958 (the 1958 British Birth Cohort). The replication group from deCODE Genetics includes 825 Icelandic patients with ADHD (477 combined type, 250 inattentive type, 58 hyperactive-impulsive type, 40 unspecified). These participants were compared with 35,243 Icelandic controls, also from deCODE Genetics. CNV analysis in this sample has been previously described. Finally, 366 children with ADHD and 1047 controls with high-quality SNP array data were included in the final analysis. Children with ADHD had a mean IQ of 86 (range 43-123; SD=13.89). 33 participants with intellectual disability (IQ<70, n=33, mean IQ=60) were identified. |
| Replication Size | 825 Icelandic patients with ADHD and 35,243 Icelandic controls |
| Sample Collection | This study was approved by Wales and northwest United Kingdom multicentre research ethics committees. 410 children thought to have ADHD were consecutively recruited from 90 community child psychiatry and paediatric outpatient clinics across the United Kingdom between 2001 and 2009. All were of white United Kingdom origin (including parents and grandparents). Control genotype data were available for 1156 individuals (594 men, 562 women) born in the United Kingdom during one week in 1958 (the 1958 British Birth Cohort). Psychiatric data were not available for the control cohort. Replication was sought in an independent dataset of 825 Icelandic patients with ADHD (238 female and 587 male participants) from deCODE Genetics. |
| Diagnosis Description | All 410 children with ADHD met Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV or International Classification of Diseases (ICD)-10 criteria for ADHD or hyperkinetic disorder. Children with schizophrenia, Tourette's syndrome, autistic spectrum disorder, or a neurological disorder including epilepsy were excluded. Diagnoses were confirmed with the Child and Adolescent Psychiatric Assessment, a research diagnostic interview. Interviews were undertaken by trained psychologists who were supervised weekly by a child psychiatrist. Inter-rater reliability for a diagnosis of ADHD was perfect (k=1.0). Symptoms and impairment at school are a diagnostic requirement of the disorder, and the presence of these criteria was confirmed by interviewing the children's teachers using the Child ADHD Teacher Telephone Interview. All children were screened with the autism screening questionnaire and individuals with suspected autistic spectrum disorder were excluded. Assessments of intellectual ability were undertaken for the ADHD group with the Wechsler Intelligence Scale for Children-IV, and complete test scores were available for 396 children. In accordance with DSM-IV and ICD-10, individuals with IQ test scores lower than 70 were regarded as having intellectual disability. All participants in the replication group met DSM-IV criteria for ADHD, and those with schizophrenia and autism were excluded from the sample. Participants were recruited from outpatient paediatric, child, and adult psychiatry clinics in Iceland, and diagnoses had been made on the basis of standardised diagnostic assessments and had been reviewed by experienced clinicians. |
| Technique | Single nucleotide polymorphisms (SNPs) were genotyped in the ADHD group with the Illumina (San Diego, CA, USA) Human660W-Quad BeadChip and in the control group with the HumanHap550 BeadChip. BeadStudio (version 2.0) was used to call genotypes, normalise the signal intensity data, and establish the log R ratio and B allele frequency at every SNP according to the standard Illumina protocols. Several analytic and validation measures were undertook to ensure that the results were not affected by variation in the performance of the two SNP arrays, including cross-platform analysis of CNV calls in 45 samples for which data were available for both BeadChips. CNV analysis was limited to 561,113 autosomal SNPs common to both SNP arrays. CNVs were defined by PennCNV (2009Aug27version). For more information about laboratory procedures in this study, please refer to the original publication. |
| Analysis Method | All analyses included rare CNVs larger than 500 kb. The genome-wide burden of CNVs was first assessed according to the average number of CNVs per sample. Significance of the burden comparisons was assessed via permutation (100 000 permutations, one-sided test) using PLINK (version 1.06) with analyses undertaken for all rare, large CNVs as well as stratified according to CNV type (deletion or duplication). Locus-specific tests of association were also made. These analyses are based on rates of CNVs per patient, but results for the percentage of individuals carrying large, rare CNVs were also provided. They also assessed whether the CNVs identified in this ADHD cohort were significantly enriched for loci previously implicated in autism and schizophrenia. Finally, they undertook locus-specific tests of association using PLINK again with significance assessed via permutation (1,000,000 permutations, one-sided). In view of the very small cell sizes, approximate odds ratios were calculated for locus-specific tests after the addition of 0.5 before computing the log odds-ratio estimate. |
| Result Description | After exclusion of common (minor allele frequency >0.01) CNVs, all association analyses included the remaining 135 rare CNVs larger than 500 kb (57 in patients and 78 in controls). A highly significant excess of large, rare CNVs was identified in children with ADHD compared with control participants, with the average number of CNVs per child with ADHD being 2.09 times higher than that in controls (p=8.9E-5). 50 (14%) affected children were shown to carry a CNV larger than 500 kb, compared with 75 (7%) controls. In each of the ADHD and control samples, the rates of CNVs did not differ between male and female participants. The enrichment of large, rare CNVs was greatest in the children with ADHD and intellectual disability. Irrespective of the presence or absence of intellectual disability, children with ADHD had a significant excess of both deletions and duplications. Of 15 large, rare CNVs (12 ADHD probands without intellectual disability), four were de novo, six were inherited from the mother, and five from the father. In an analysis restricted to children with ADHD without intellectual disability, eight of 40 CNVs larger than 500 kb identified in the ADHD group overlapped with a locus previously implicated in autism, compared with only one of 78 in controls. No specific single autism locus showed a significant excess of CNVs in children with ADHD. Of the CNVs identified in ADHD, nine of 40 overlapped with a locus previously implicated in schizophrenia. Locus-specific tests revealed that this finding was largely due to the 16p13.11 region. Logistic regression analysis showed no significant association between CNV size and overlap with autism or schizophrenia loci. When restricting genome-wide locus-specific tests to participants without intellectual disability, a locus on chromosome 16p13.11 showed a significant excess of rare CNVs larger than 500 kb in children with ADHD. They next sought replication of their finding of an excess of chromosome 16p13.11 duplications in an independent dataset of 825 Icelandic patients with ADHD and 35,243 Icelandic controls. In this second sample, there was a significant excess of chromosome 16p13.11 duplications in the ADHD group compared with controls. Analysis of the Icelandic data also revealed that the CNVs identified in the ADHD sample were significantly enriched for loci previously implicated in schizophrenia, but not autism. |
| Name | Symbol in Literature | Type | Inheritance | Author Comments |
|---|---|---|---|---|
| CNV_Williams[2010]_36 | Sample ID: 37 (case) | Gain | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... | |
| CNV_Williams[2010]_35 | Sample ID: 36 (case) | Loss | De novo | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... |
| CNV_Williams[2010]_34 | Sample ID: 35 (case) | Loss | De novo | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... |
| CNV_Williams[2010]_33 | Sample ID: 34 (case) | Gain | Paternal | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... |
| CNV_Williams[2010]_40 | Sample ID: 41 (case) | Gain | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... | |
| CNV_Williams[2010]_39 | Sample ID: 39 (case) | Gain | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... | |
| CNV_Williams[2010]_38 | Sample ID: 39 (case) | Loss | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... | |
| CNV_Williams[2010]_37 | Sample ID: 37 (case) | Gain | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... | |
| CNV_Williams[2010]_44 | Sample ID: 46 (case) | Gain | Maternal | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... |
| CNV_Williams[2010]_43 | Sample ID: 45 (case) | Gain | Paternal | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... |
| CNV_Williams[2010]_42 | Sample ID: 44 (case) | Gain | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... | |
| CNV_Williams[2010]_41 | Sample ID: 42 (case) | Gain | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... | |
| CNV_Williams[2010]_48 | Sample ID: 50 (case) | Loss | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... | |
| CNV_Williams[2010]_47 | Sample ID: 49 (case) | Gain | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... | |
| CNV_Williams[2010]_46 | Sample ID: 48 (case) | Gain | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... | |
| CNV_Williams[2010]_45 | Sample ID: 47 (case) | Gain | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... | |
| CNV_Williams[2010]_19 | Sample ID: 20 (case) | Gain | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... | |
| CNV_Williams[2010]_20 | Sample ID: 21 (case) | Gain | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... | |
| CNV_Williams[2010]_17 | Sample ID: 18 (case) | Loss | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... | |
| CNV_Williams[2010]_18 | Sample ID: 19 (case) | Gain | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... | |
| CNV_Williams[2010]_23 | Sample ID: 24 (case) | Gain | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... | |
| CNV_Williams[2010]_24 | Sample ID: 25 (case) | Loss | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... | |
| CNV_Williams[2010]_21 | Sample ID: 22 (case) | Gain | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... | |
| CNV_Williams[2010]_22 | Sample ID: 23 (case) | Gain | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... | |
| CNV_Williams[2010]_27 | Sample ID: 28 (case) | Gain | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... | |
| CNV_Williams[2010]_28 | Sample ID: 29 (case) | Loss | Maternal | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... |
| CNV_Williams[2010]_25 | Sample ID: 25 (case) | Gain | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... | |
| CNV_Williams[2010]_26 | Sample ID: 27 (case) | Loss | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... | |
| CNV_Williams[2010]_31 | Sample ID: 32 (case) | Gain | De novo | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... |
| CNV_Williams[2010]_32 | Sample ID: 32 (case) | Loss | De novo | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... |
| CNV_Williams[2010]_29 | Sample ID: 39 (case) | Loss | De novo | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... |
| CNV_Williams[2010]_30 | Sample ID: 31 (case) | Gain | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... | |
| CNV_Williams[2010]_49 | Sample ID: 50 (case) | Gain | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... | |
| CNV_Williams[2010]_50 | Sample ID: 52 (case) | Gain | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... | |
| CNV_Williams[2010]_51 | Sample ID: 53 (case) | Gain | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... | |
| CNV_Williams[2010]_52 | Sample ID: 54 (case) | Gain | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... | |
| CNV_Williams[2010]_53 | Sample ID: 55 (case) | Gain | De novo | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... |
| CNV_Williams[2010]_54 | Sample ID: 56 (case) | Gain | Maternal | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... |
| CNV_Williams[2010]_55 | Sample ID: 57 (case) | Gain | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... | |
| CNV_Williams[2010]_56 | Sample ID: 58 (case) | Loss | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... | |
| CNV_Williams[2010]_57 | Sample ID: 59 (case) | Gain | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... | |
| CNV_Williams[2010]_15 | Sample ID: 16 (case) | Loss | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... | |
| CNV_Williams[2010]_16 | Sample ID: 17 (case) | Loss | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... | |
| CNV_Williams[2010]_13 | Sample ID: 14 (case) | Gain | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... | |
| CNV_Williams[2010]_14 | Sample ID: 15 (case) | Gain | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... | |
| CNV_Williams[2010]_11 | Sample ID: 12 (case) | Gain | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... | |
| CNV_Williams[2010]_12 | Sample ID: 13 (case) | Gain | Paternal | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... |
| CNV_Williams[2010]_9 | Sample ID: 9 (case) | Gain | Maternal | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... |
| CNV_Williams[2010]_10 | Sample ID: 10 (case) | Gain | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... | |
| CNV_Williams[2010]_7 | Sample ID: 6 (case) | Gain | Paternal | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... |
| CNV_Williams[2010]_8 | Sample ID: 8 (case) | Loss | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... | |
| CNV_Williams[2010]_5 | Sample ID: 5 (case) | Gain | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... | |
| CNV_Williams[2010]_6 | Sample ID: 6 (case) | Loss | Paternal | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... |
| CNV_Williams[2010]_3 | Sample ID: 3 (case) | Gain | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... | |
| CNV_Williams[2010]_4 | Sample ID: 4 (case) | Gain | Maternal | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... |
| CNV_Williams[2010]_1 | Sample ID: 1 (case) | Gain | Maternal | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... |
| CNV_Williams[2010]_2 | Sample ID: 2 (case) | Gain | Rare CNV larger than 500kb identified in children with ADHD....... Rare CNV larger than 500kb identified in children with ADHD. More... |
| Region | Statistical Values | Author Comments | Result of Statistical Analysis |
|---|---|---|---|
| 16p13.11 | Locus-specific test P=0.0008 (corrected for multiple testing; OR=13.88, 95%CI=2.3-82.2). Case-control test P=0.031 (after correction for relatedness and potential population stratification) in the replicate sample. | This locus showed a significant excess of rare CNVs larger t...... This locus showed a significant excess of rare CNVs larger than 500kb in children with ADHD. There was also a significant excess of 16p13.11 duplications in the ADHD group compared with controls in the replication sample. More... | Significant |
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Last update: Feb 26, 2014