| Summary |
OBJECTIVE:Attention-deficit/hyperactivity disorder (ADHD) is an etiologically complex heterogeneous behavioral disorder. Several studies have reported that ADHD subjects are more likely to be overweight/obese and that this comorbidity may be due to shared genetic factors. The objective of this study is to explore the association between ADHD and FTO, a gene strongly associated with obesity in genome-wide studies. DESIGN AND METHODS: One tag SNP (single-nucleotide polymorphism, rs8050136, risk allele A) in the FTO gene was selected and its association with ADHD was tested. Family-based association tests (FBATs) were conducted with the categorical diagnosis of ADHD as well as behavioral and cognitive phenotypes related to ADHD. Furthermore, stratified FBAT analyses based on maternal smoking during pregnancy (MSDP) status were conducted. RESULTS: Statistically significant associations were observed between rs8050136 and several of the traits tested in the total sample. These associations were stronger when the analysis was restricted to children who were not exposed to MSDP. CONCLUSIONS: These exploratory results suggest the involvement of the FTO SNP rs8050136 in modulating the risk for ADHD, particularly in those children who were not exposed to MSDP. If confirmed, they may explain, at least in part, the complex links between obesity and ADHD. |
| Total Sample |
This study included a total of 380 nuclear families having one or more child with a DSM-IV diagnosis of ADHD.Of the 380, 184 were trios with information from both parents, 18 were trios with two affected children, 49 were trios with information from one parent and one or more unaffected sibling, 115 were duos including the proband and one parent, whereas 14 were families with two affected siblings and one parent. This study included a total of 380 nuclear families having one or more child with a DSM-IV diagnosis of ADHD. Of the 380,184 were trios with information from both parents, 18 were trios with two affected children, 49 were trios with information from one parent and one or more unaffected sibling, 115 were duos including the proband and one parent, whereas 14 were families with two affected siblings and one parent. |
| Sample Collection |
Subjects were recruited from the Disruptive Behaviour Disorders Program and the children outpatient clinic at the Douglas Mental Health University Institute. |
| Diagnosis Description |
Children included in this study met DSM-IV diagnosis criteria for ADHD.A comprehensive clinical evaluation was used to establish the diagnosis of ADHD (see details in Ref.15).Briefly,ADHD diagnosis was based on clinical examination of the child and an interview of at least one of his or her parents by a child psychiatrist (RJ or NG). In addition, a structured clinical interview with parents using the Diagnostic Interview Schedule for Children-version IV,DISC-IV, was used to corroborate the diagnosis.Children were excluded from this study if they had an IQ<70 on the Wechsler Intelligence Scale for Children-III/IV(WISC-III or WISC-IV),Tourette syndrome,pervasive developmental disorder,or psychosis.Among the total sample, 78.1% were male, 86.9% were of Caucasian ethnicity, and 28.9% belonged to families with an annual income of less than CAD$ 20,000.A total of 52.8% met DSM-IV criteria for the combined subtype,whereas 37.3 and 9.9% were diagnosed with the inattentive and hyperactive subtypes, respectively. A total of 38.8% were previously receiving medication for their ADHD symptoms;2.1% were underweight, 57.9% were of normal weight, 19.7% were overweight, and 20.3% were obese as per BMI category according to WHO classification (this distribution of weight categories was not significantly different between the three genotype groups). Comorbid disorders such as oppositional defiant disorder (40.4%),conduct disorder (21.7%),anxiety disorder (44.1%),and mood disorder (8.3%) were present in proportions similar to those reported in previous studies.All he behavioral and neurocognitive assessments were completed while the children were not taking any medication.In cases,where children were on medication prior to their inclusion in the study,all clinical,behavioral,neuro-cognitive,and task-engagement assessments were carried out at the end of a 1-week washout period. |
| Technique |
DNA was extracted for each participant and his/her associated family member, using a blood sample, a buccal swab,or a saliva sample.rs8050136 SNP was genotyped using Sequenom iPlex Gold Technology(26); genotyping error was estimated using duplicates of two reference samples included in each plate. |
| Analysis Method |
Genotypes for all the samples included in the study were read with 100% accuracy and the genotype distribution (AA=13.4%, AC =48.7%, and CC=38.0%) of this marker did not depart from Hardy-Weinberg equilibrium (P>0.05)The family-based association test (FBAT) statistical package (version 2.0.3) (27) was used to examine the overtransmission of a specific allele from parent to affected offspring.Genetic association of rs8050136 with ADHD diagnosis and behavioral, cognitive, and task engagement quantitative traits/phenotypes were examined. All the analyses were conducted under the assumption of an additive model, with the null hypothesis of no linkage and no association. At the first level, FBAT analysis was conducted with the total sample.However, given the results of earlier studies indicating that MSDP is the environmental risk factor most consistently associated with ADHD(2)and the fact that the FTO gene was associated with smoking behavior, possible modulation of the association between the FTO genotype and ADHD-related phenotypes was explored by stratifying participants into two groups based on MSDP status.At the time of submission of this manuscript,this was,to our knowledge,the first study exploring possible association between FTO candidate gene and ADHD as a diagnostic entity,and given the previous literature indicating that mutations in this gene may cause attention and cognitive deficits, the significance level of association with ADHD as a diagnosis was set at P=0.05 and not corrected for multiple testing. |
| Result Description |
Statistically significant associations were observed between rs8050136 and several of the traits tested in the total sample. These associations were stronger when the analysis was restricted to children who were not exposed to MSDP. CONCLUSIONS: These exploratory results suggest the involvement of the FTO SNP rs8050136 in modulating the risk for ADHD, particularly in those children who were not exposed to MSDP. If confirmed, they may explain, at least in part, the complex links between obesity and ADHD. |
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