ABSTRACT
We studied 261 ADHD probands and 354 of their siblings to assess quantitative trait loci associated with autism spectrum disorder symptoms (as measured by the Children's Social Behavior Questionnaire (CSBQ)) using a genome-wide linkage approach, followed by locus-wide association analysis. A genome-wide significant locus for the CSBQ subscale addressing social interaction was found on chromosome 7q11, with suggestive signals supporting this locus on three other CSBQ subscales. We identified two other suggestive loci for the CSBQ total scale and individual subscales on chromosomes 4q35 and 7p12. Fine-mapping the significantly linked locus resulted in interesting candidate genes, although their association was not significant after permutation testing.
Subject(s)
Attention Deficit Disorder with Hyperactivity/genetics , Child Development Disorders, Pervasive/genetics , Chromosomes, Human, Pair 7/genetics , Genetic Linkage , Attention , Child , Child Development Disorders, Pervasive/physiopathology , Chromosome Mapping , Female , Humans , Male , Surveys and QuestionnairesABSTRACT
BACKGROUND: Symptoms of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) often co-occur. Given the previously found familiality of ASD symptoms in children with ADHD, addressing these symptoms may be useful for genetic association studies, especially for candidate gene findings that have not been consistently replicated for ADHD. METHODS: We studied the association of the catechol O-methyltransferase (COMT) Val158Met polymorphism and the serotonin transporter (SLC6A4/SERT/5-HTT) 5-HTTLPR insertion/deletion polymorphism with ASD symptoms in children with ADHD, and whether these polymorphisms would interact with pre- and perinatal risk factors, i.e., maternal smoking during pregnancy and low birth weight. Analyses were performed using linear regression in 207 Dutch participants with combined type ADHD of the International Multicenter ADHD Genetics (IMAGE) study, and repeated in an independent ADHD sample (n =439) selected from the TRracking Adolescents' Individual Lives Survey (TRAILS). Dependent variables were the total and subscale scores of the Children's Social Behavior Questionnaire (CSBQ). RESULTS: No significant main effects of COMT Val158Met, 5-HTTLPR, maternal smoking during pregnancy and low birth weight on ASD symptoms were found. However, the COMT Val/Val genotype interacted with maternal smoking during pregnancy in increasing stereotyped behavior in the IMAGE sample (p =.008); this interaction reached significance in the TRAILS sample after correction for confounders (p =.02). In the IMAGE sample, the 5-HTTLPR S/S genotype interacted with maternal smoking during pregnancy, increasing problems in social interaction (p =.02), and also interacted with low birth weight, increasing rigid behavior (p =.03). Findings for 5-HTTLPR in the TRAILS sample were similar, albeit for related CSBQ subscales. CONCLUSIONS: These findings suggest gene-environment interaction effects on ASD symptoms in children with ADHD.
Subject(s)
Attention Deficit Disorder with Hyperactivity/genetics , Catechol O-Methyltransferase/genetics , Child Development Disorders, Pervasive/genetics , Interpersonal Relations , Serotonin Plasma Membrane Transport Proteins/genetics , Stereotyped Behavior , Adolescent , Attention Deficit Disorder with Hyperactivity/epidemiology , Attention Deficit Disorder with Hyperactivity/psychology , Birth Weight , Child , Child Development Disorders, Pervasive/epidemiology , Child Development Disorders, Pervasive/psychology , Female , Genetic Predisposition to Disease , Genotype , Humans , INDEL Mutation , Linear Models , Male , Maternal Behavior , Methionine , Netherlands/epidemiology , Polymorphism, Single Nucleotide , Pregnancy , Risk Factors , Sampling Studies , Smoking , Surveys and Questionnaires , ValineABSTRACT
OBJECTIVE: The genetic basis for autism spectrum disorder (ASD) symptoms in children with attention-deficit/hyperactivity disorder (ADHD) was addressed using a genome-wide linkage approach. METHOD: Participants of the International Multi-Center ADHD Genetics study comprising 1,143 probands with ADHD and 1,453 siblings were analyzed. The total and subscale scores of the Social Communication Questionnaire (SCQ) were used as quantitative traits for multipoint regression-based linkage analyses on 5,407 autosomal single-nucleotide polymorphisms applying MERLIN-regress software, both without and with inclusion of ADHD symptom scores as covariates. RESULTS: The analyses without ADHD symptom scores as covariates resulted in three suggestive linkage signals, i.e., on chromosomes 15q24, 16p13, and 18p11. Inclusion of ADHD symptom scores as covariates resulted in additional suggestive loci on chromosomes 7q36 and 12q24, whereas the LOD score of the locus on chromosome 15q decreased below the threshold for suggestive linkage. The loci on 7q, 16p, and 18p were found for the SCQ restricted and repetitive subscale, that on 15q was found for the SCQ communication subscale, and that on 12q for the SCQ total score. CONCLUSIONS: Our findings suggest that QTLs identified in this study are ASD specific, although the 15q QTL potentially has pleiotropic effects for ADHD and ASD. This study confirms that genetic factors influence ASD traits along a continuum of severity, as loci potentially underlying ASD symptoms in children with ADHD were identified even though subjects with autism had been excluded from the IMAGE sample, and supports the hypothesis that differential genetic factors underlie the three ASD dimensions.
Subject(s)
Attention Deficit Disorder with Hyperactivity/diagnosis , Attention Deficit Disorder with Hyperactivity/genetics , Child Development Disorders, Pervasive/diagnosis , Child Development Disorders, Pervasive/genetics , Chromosome Mapping , Genome-Wide Association Study , Quantitative Trait Loci/genetics , Adolescent , Attention Deficit Disorder with Hyperactivity/psychology , Child , Child Development Disorders, Pervasive/psychology , Chromosome Aberrations , Chromosomes, Human, Pair 15/genetics , Chromosomes, Human, Pair 16/genetics , Chromosomes, Human, Pair 18/genetics , Communication , Comorbidity , Female , Genetic Predisposition to Disease/genetics , Genetic Testing , Humans , Lod Score , Male , Personality Assessment/statistics & numerical data , Polymorphism, Single Nucleotide/genetics , Psychometrics/statistics & numerical data , Social BehaviorABSTRACT
Attention-deficit/hyperactivity disorder (ADHD) is associated with functional impairments in different areas of daily life. One such area is social functioning. The purpose of this paper is to critically review research on social dysfunctioning in children with ADHD. Children with ADHD often have conflicts with adults and peers, and suffer from unpopularity, rejection by peers, and a lack of friendships, in part as a consequence of their ADHD symptoms. Comorbid oppositional defiant or conduct disorder aggravates these impairments. In some cases the inadequate social behavior of children with ADHD may be phenomenologically and etiologically related to pervasive developmental disorders (PDD). However, the causes and consequences of PDD symptoms in ADHD are understudied. Also, the relative contributions of ADHD, on the one hand, and comorbid disorders, on the other, to the course of social impairments are unknown. Social dysfunctioning in children with ADHD appears to increase their risk of later psychopathology other than ADHD. Thus far effective treatment for social dysfunctioning is lacking. Future research should address the exact nature and long-term consequences of social dysfunctioning in children with ADHD, and focus on development of effective treatment strategies.
