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	Hebebrand J, 200616222334
Citation	Hebebrand J., Dempfle A., Saar K., Thiele H., Herpertz-Dahlmann B., Linder M., Kiefl H., Remschmidt H., Hemminger U., Warnke A., Knolker U., Heiser P., Friedel S., Hinney A., Schafer H., Nurnberg P. and Konrad K. (2006) "A genome-wide scan for attention-deficit/hyperactivity disorder in 155 German sib-pairs." Mol Psychiatry, 11(2): 196-205.
Study Design	affected sib pairs
Study Type	Genome-wide linkage study
Sample Size	155 sib-pairs
Predominant Ethnicity	Caucasian
Population	Germany
Gender	86 males and 16 females in index patients; 79 males and 48 females in siblings
Age Group	Children/Adolescents : mean age 11.1 in index patients, mean age 12.0 in siblings

Detail Info

Summary	In the current study, they performed a whole-genome scan with 102 German families with two or more offspring who currently fulfilled the diagnostic criteria for ADHD. Including subsequent fine mapping on chromosome 5p, a total of 523 markers were genotyped. The highest nonparametric multipoint LOD score of 2.59 (empirical genome-wide significance 0.1) was obtained for chromosome 5p at 17cM (according to the Marshfield map). Subsequent analyses revealed (a) a higher LOD score of 3.37 at 39cM for a quantitative severity score based on symptoms of inattention than for hyperactivity/impulsivity (LOD score of 1.11 at 59 cM), and (b) an HLOD of 4.75 (empirical genome-wide significance 0.001) based on a parametric model assuming dominant inheritance. The locus of the solute carrier 6A3 (SLC6A3; dopamine transporter 1; DAT1) localizes to 5p15.33; the gene has repeatedly been implicated in the etiology of ADHD. However, in their sample the DAT1 VNTR did not show association with ADHD. They additionally identified nominal evidence for linkage to chromosomes 6q, 7p, 9q, 11 q, 12q and 17p, which had also been identified in previous scans. Despite differences in ethnicity, ascertainment and phenotyping schemes, linkage results in ADHD appear remarkably consistent.
Total Sample	Of the 155 sib-pairs, 127 were independent; four of the sib-pairs were based on half-sibs. In 94 families, both parents of the index patient were ascertained, and in the remaining eight only the mother was included.
Sample Collection	Caucasian ethnicity
Diagnosis Description	The 102 families were ascertained and phenotypically characterized by physicians either in the outpatient units of the Departments of Child and Adolescent Psychiatry of the Universities of Aachen, Lubeck, Marburg and Wurzburg and of the district Oberpfalz in Regensburg for ADHD. The children all currently fulfilled diagnostic criteria for ADHD according to DSM-IV;14 index patients were required to fulfill lifetime criteria for the combined type. The original publication contains more diagnostic details.
Technique	They performed a genome-wide scan based on a total of 425 individuals with initially 475 autosomal, 24 X chromosomal and two pseudoautosomal STR markers spanning the entire genome with an average (maximum) distance of 7(13)cm. Briefly, markers were amplified in multiplex reactions in 384-well microtiter plates on ABI GeneAmp PCR 9700 machines (Applied Biosystems, Darmstadt, Germany). An aliquot of the PCR reaction was submitted to analysis on ABI 3730 sequencers. Semi-automated genotyping was performed with the help of the GeneMapper software version 3.0 (ABI).
Analysis Method	Allele frequencies for linkage analysis were estimated from all parental alleles. Data handling and preparation of files was done with Mega2 version 3.0. Both the NPL score and the nonparametric LOD score were given, using the Kong-Cox transformation as implemented in Merlin. Linkage analysis was performed on the quantitative DSM-IV scores using Merlin-regress, and parametric HLOD linkage analysis was also performed with Merlin under a dominant model. Post-hoc analyses as to whether the evidence for nonparametric linkage on chromosome 5p could be explained by the investigated DAT1 VNTR was done using the genotype-IBD sharing test GIST. Additionally, the pedigree disequilibrium test (PDT), a test for allelic association in pedigrees, was used.
Result Description	The highest nonparametric multipoint LOD score of 2.59 was obtained for chromosome 5p at 17cM. Subsequent analyses revealed (a) a higher LOD score of 3.37 at 39cM for a quantitative severity score based on symptoms of inattention than for hyperactivity/impulsivity, and (b) an HLOD of 4.75 based on a parametric model assuming dominant inheritance. The locus of the solute carrier 6A3 localizes to 5p15.33; the gene has repeatedly been implicated in the etiology of ADHD. However, in their sample the DAT1 VNTR did not show association with ADHD. They additionally identified nominal evidence for linkage to chromosomes 6q, 7p, 9q, 11 q, 12q and 17p, which had also been identified in previous scans.

Regions reported by this study (count: 8)

Region	Statistical Values	Author Comments	Result of Statistical Analysis
12q	LOD score=2.1	identified nominal evidence for linkage identified nominal evidence for linkage	Non-significant
17p	LOD score=1.39	identified nominal evidence for linkage identified nominal evidence for linkage	Non-significant
9q	LOD score=0.68	identified nominal evidence for linkage identified nominal evidence for linkage	Non-significant
11q	LOD score=0.41	identified nominal evidence for linkage identified nominal evidence for linkage	Non-significant
6q	LOD score=0.58	identified nominal evidence for linkage identified nominal evidence for linkage	Non-significant
5p	LOD score=2.59; LOD score=3.37 for symptoms of inattention; HLOD=4.75 under a dominant model	identified nominal evidence for linkage identified nominal evidence for linkage	Significant
8	LOD score=1.29	no significant evidence for linkage was identified no significant evidence for linkage was identified	Non-significant
7p	LOD score=0.92	identified nominal evidence for linkage identified nominal evidence for linkage	Non-significant