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	Rommelse NN, 2008 (b)18599010
Citation	Rommelse N. N., Arias-Vasquez A., Altink M. E., Buschgens C. J., Fliers E., Asherson P., Faraone S. V., Buitelaar J. K., Sergeant J. A., Oosterlaan J. and Franke B. (2008) "Neuropsychological endophenotype approach to genome-wide linkage analysis identifies susceptibility loci for ADHD on 2q21.1 and 13q12.11." Am J Hum Genet, 83(1): 99-105.
Study Design	affected sib pairs
Study Type	Genome-wide linkage study (neuropsychological endophenotype approach)
Sample Size	238 ADHD probands and their 112 affected and 195 nonaffected siblings
Predominant Ethnicity	Caucasian
Population	the Netherlands
Age Group	Children/Adolescents

Detail Info

Summary	ADHD linkage findings have not all been consistently replicated, suggesting that other approaches to linkage analysis in ADHD might be necessary, such as the use of (quantitative) endophenotypes (heritable traits associated with an increased risk for ADHD). Genome-wide linkage analyses were performed in the Dutch subsample of the International Multi-Center ADHD Genetics (IMAGE) study comprising 238 DSM-IV combined-type ADHD probands and their 112 affected and 195 nonaffected siblings. Eight candidate neuropsychological ADHD endophenotypes with heritabilities >0.2 were used as quantitative traits. In addition, an overall component score of neuropsychological functioning was used. A total of 5407 autosomal single nucleotide polymorphisms (SNPs) were used to run multipoint regression-based linkage analyses. Two significant genome-wide linkage signals were found, one for Motor Timing on chromosome 2q21.1 (LOD score: 3.944) and one for Digit Span on 13q12.11 (LOD score: 3.959). Ten suggestive linkage signals were found (LOD scores R 2) on chromosomes 2p, 2q, 3p, 4q, 8q, 12p, 12q, 14q, and 17q. The suggestive linkage signal for the component score that was found at 2q14.3 (LOD score: 2.878) overlapped with the region significantly linked to Motor Timing. Endophenotype approaches may increase power to detect susceptibility loci in ADHD and possibly in other complex disorders.
Total Sample	Endophenotypes were available for the Dutch subsample of the International Multi-Center ADHD Genetics (IMAGE) study comprising 238 DSM-IV combined-type ADHD probands and their 112 affected and 195 nonaffected siblings. The study was approved by the local medical-ethics committee.
Sample Collection	IMAGE
Diagnosis Description	DSM-IV (for screening and diagnostic details, please see Kuntsi, J. et al, 2006 (The IMAGE project)).
Technique	The full description of DNA extraction is provided by Brookes et al. As described in Asherson et al., a total of 5545 autosomal single-nucleotide polymorphisms (SNPs) from the Illumina Linkage IVb SNP panel were successfully assayed, with a call rate of 99.6% and a reproduction rate of 99.994%. After data cleaning, 5407 autosomal SNPs with an average resolution of 1.66 SNPs/centimorgan (cM) were entered into the linkage analyses.
Analysis Method	To select endophenotypes for linkage analysis, heritability of the traits was estimated. Heritability estimates were estimated with the use of the linear mixed model implemented in SOLAR. Models were adjusted for age, sex, and scores on Conners' Inattention and Hyperactivity/Impulsivity subscales. QTL linkage was examined for eight of the ten individual task measures that showed a heritability estimate >20%, as well as for the component score. Age was used as a covariate. In addition, subscale (ADHD combined) totals of Conners' Parent Rating Scale and Conner's Teacher Rating Scale were used as covariates. Linkage analysis was performed with the use of Merlin-regress software, which implements a regression-based procedure using trait-squared sums and differences to predict identity by descent (IBD) sharing between relative pairs. Since the linkage disequilibrium (LD) between adjacent SNPs can lead to inflated LOD scores, the criteria of r² <0.05 was applied between SNPs to cluster SNPs into combined markers. Empirical p values were derived with the use of Merlin software by the running of 1000 simulations under the null hypothesis of no linkage while preser ving the original phenotypes, family structures, allele frequencies, LD structures and missing-data patterns. The estimated thresholds for significant linkage for the individual neuropsychological traits plus the combined score ranged from 3.615 to 4.049. The thresholds for suggestive linkage for the individual neuropsychological traits plus the combined score ranged from 1.785 to 2.011. All linkage signals above this value of 2.011 were reported.
Result Description	Six of the eight measures (stop task, time test, visuo-spatial sequencing, digit span, pursuit, tapping, motor timing) with an estimated heritability of >0.2 showed at least one linkage signal with a LOD score above 2.011. Motor Timing, the ability to produce a 1 s interval, showed genome-wide significant linkage to chromosome 2q21.1 (LOD score: 3.944). Digit Span, a measure of verbal working memory, showed genome-wide significant linkage to chromosome 13q12.11 (LOD score 3.959). In addition, eight suggestive linkage signals with LOD scores between 2.022 and 2.627 were found on chromosomes 2p (twice), 3p, 4q, 8q, 12q, 14q, and 17q. Most of these findings did not overlap between measures, except for the suggestive findings for Motor Timing and Digit Span on chromosome 2p25. The component score showed two suggestive linkage signals with LOD scores of 2.516 and 2.878 on 2q14.3 and 12p13.33, respectively, the former overlapping with the regions linked to Motor Timing on chromosome 2.

Regions reported by this study (count: 13)

Region	Statistical Values	Author Comments	Result of Statistical Analysis
2p25.2	LOD = 2.022 , P=0.0011 for task Digit span.	A suggestive linkage signal was found. A suggestive linkage signal was found.	Trend
3p24.3	LOD = 2.112 , P=0.0009 for task Visuo-spatial sequencing.	A suggestive linkage signal was found. A suggestive linkage signal was found.	Trend
14q32.13	LOD = 2.471 , P=0.0004 for task Digit span.	A suggestive linkage signal was found. A suggestive linkage signal was found.	Trend
13q12.11	LOD = 3.959 , P=0.00001 , empirical P=0.025 for task Digit span.	A genome-wide significant linkage was found for Digit Span. A genome-wide significant linkage was found for Digit Span.	Significant
9p21.2	LOD = 2.337 , P=0.0005 for task Tapping.	A suggestive linkage signal was found. A suggestive linkage signal was found.	Trend
8q22.3	LOD = 2.57 , P=0.0003 for task Pursuit.	A suggestive linkage signal was found. A suggestive linkage signal was found.	Trend
2p25.1	LOD = 2.195 , P=0.0007 for task Motor timing.	A suggestive linkage signal was found. A suggestive linkage signal was found.	Trend
2q21.1	LOD = 3.944 , P=0.00001 , empirical P=0.042 for task Motor timing.	A genome-wide significant linkage was found for Motor Timing...... A genome-wide significant linkage was found for Motor Timing. More...	Significant
4q35.2	LOD = 2.111 , P=0.0009 for task Time test.	A suggestive linkage signal was found. A suggestive linkage signal was found.	Trend
12q23.3	LOD = 2.627 , P=0.0003 for task Stop task.	A suggestive linkage signal was found. A suggestive linkage signal was found.	Trend
17q12	LOD = 2.338 , P=0.0005 for task Motor timing.	A suggestive linkage signal was found. A suggestive linkage signal was found.	Trend
2q14.3	LOD = 2.516 , P=0.0003 for task Combined score.	A suggestive linkage signal was found. A suggestive linkage signal was found.	Trend
12p13.33	LOD = 2.878 , P=0.00014 for task Combined score.	A suggestive linkage signal was found. A suggestive linkage signal was found.	Trend