ADHDgene Database

Hot Results

Quick Search

Keyword:
Type:

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	Asherson P, 200818180756
Citation	Asherson P., Zhou K., Anney R. J., Franke B., Buitelaar J., Ebstein R., Gill M., Altink M., Arnold R., Boer F., Brookes K., Buschgens C., Butler L., Cambell D., Chen W., Christiansen H., Feldman L., Fleischman K., Fliers E., Howe-Forbes R., Goldfarb A., Heise A., Gabriels I., Johansson L., Lubetzki I., Marco R., Medad S., Minderaa R., Mulas F., Muller U., Mulligan A., Neale B., Rijsdijk F., Rabin K., Rommelse N., Sethna V., Sorohan J., Uebel H., Psychogiou L., Weeks A., Barrett R., Xu X., Banaschewski T., Sonuga-Barke E., Eisenberg J., Manor I., Miranda A., Oades R. D., Roeyers H., Rothenberger A., Sergeant J., Steinhausen H. C., Taylor E., Thompson M. and Faraone S. V. (2008) "A high-density SNP linkage scan with 142 combined subtype ADHD sib pairs identifies linkage regions on chromosomes 9 and 16." Mol Psychiatry, 13(5): 514-21.
Study Design	affected sib pairs
Study Type	Genome-wide linkage study
Sample Size	276 affected siblings
Predominant Ethnicity	Caucasian
Population	Belgium, United Kingdom, Germany, Ireland, Israel, the Netherlands, Spain, Switzerland
Gender	78.6% male
Age Group	Children/Adolescents : mean age 10.6 years (SD=3.1)

Detail Info

Summary	As part of the International Multi-centre ADHD Genetics project they completed an affected sibling pair study of 142 narrowly defined Diagnostic and Statistical Manual of Mental Disorders, fourth edition combined type ADHD proband-sibling pairs. No linkage was observed on the most established ADHD-linked genomic regions of 5p and 17p. They found suggestive linkage signals on chromosomes 9 and 16, respectively, with the highest multipoint nonparametric linkage signal on chromosome 16q23 at 99 cM (LOD=3.1) overlapping data published from the previous UCLA (University of California, Los Angeles) (LOD>1, ~95cM) and Dutch (LOD>1, ~100cM) studies. The second highest peak in this study was on chromosome 9q22 at 90 cM (LOD=2.13); both the previous UCLA and German studies also found some evidence of linkage at almost the same location (UCLA LOD=1.45 at 93 cM; German LOD=0.68 at 100 cM). The overlap of these two main peaks with previous findings suggests that loci linked to ADHD may lie within these regions. Meta-analysis or reanalysis of the raw data of all the available ADHD linkage scan data may help to clarify whether these represent true linked loci.
Total Sample	After pedigree correction using the linkage markers to check for expected family relationships, the final sample in this study consisted of 577 subjects, including 276 ADHD combined subtype cases from 134 nuclear families. With eight families having three affected children, a total of 142 independent sibling pairs with combined subtype ADHD were formed.
Sample Collection	Families were identified by the IMAGE consortium through clinically diagnosed combined subtype ADHD cases at specialist clinics in eight European countries: Belgium, United Kingdom, Germany, Ireland, Israel, the Netherlands, Spain and Switzerland. To ensure the genetic homogeneity of the sample only white Caucasians of European ancestry were included based on information on ethnicity going back to grand-parents of the affected sibling pairs.
Diagnosis Description	Entry criteria for research assessments were (1) a proband with the ADHD combined subtype, (2) availability of one or more siblings of each affected proband and (3) both the probands and siblings aged between 5 and 17 at the time of assessment, both the children and at least one of their biological parents were available for DNA collection. Eligible families were then invited to the research centers or assessed during home assessments by qualified child psychiatrists or trained interviewers using clinical research assessments. Exclusion criteria applied to both probands and siblings: (1) IQ<70, (2) a diagnosis of schizophrenia or autism that might confound the diagnosis of ADHD and (3) neurological disorders such as epilepsy and brain injury, as well as any genetic or medical disorder associated with externalizing behaviors that might mimic ADHD. Details for clinical procedures, please refer to the original paper.
Technique	The genotyping service was provided by the Center for Inherited Disease Research using the Illumina BeadArray technology on a BeadLab system. A total of 5873 SNPs from the Illumina Linkage IVB SNP panel were successfully assayed with a reproduction rate of 99.994%. The markers were ordered and placed on the physical map according to Genome Build 35. Interpolated genetic distances from the deCODE genetic map were used to estimate genetic map distances. Pedigree errors were identified and corrected by testing pairwise subject relationships with the program Relpair. Genotypes causing Mendelian inconsistencies were identified by Pedcheck and removed by a custom script. Hardy-Weinberg equilibrium (HWE) for each marker was calculated using Pedstats and 138 SNP markers with significant departure from HWE were dropped from the analysis. Unlikely genotype combinations leading to double recombinations over short genetic distance in a few cases were removed by Merlin.
Analysis Method	Nonparametric linkage was examined by Merlin using Whittemore and Halpern's Sall statistics and Kong and Cox's log of the odds (LOD) score transformation. Linkage disequilibrium has been shown between tightly linked markers on the Illumina Linkage IV SNP panels and treating them as independent markers can inflate LOD scores. Merlin overcomes this problem by clustering markers that are in LD and estimating the haplotype frequencies to perform multipoint linkage analysis with the composite markers. They implemented the 'rsq 0.05' constraint which requires a pairwise LD measure of r²<0.05 between adjacent markers to create marker clusters; as suggested by a comprehensive simulation study.
Result Description	Nominal linkage signals were found on chromosome 2, 11, 14, 21 and the X chromosome. There are two suggestive linkage signals with multipoint LOD scores exceeding 2.0 on chromosome 9 (LOD=2.13) and chromosome 16 (LOD = 3.1).

Regions reported by this study (count: 9)

Region	Statistical Values	Author Comments	Result of Statistical Analysis
Chr2:181.5cM	nonparametric multipoint LOD=1.16 for marker rs2033866	Nominal linkage signals (LOD>1.0) Nominal linkage signals (LOD>1.0)	Non-significant
Chr2:34.5cM	nonparametric multipoint LOD=1.64 for marker rs1510834	Nominal linkage signals (LOD>1.0) Nominal linkage signals (LOD>1.0)	Non-significant
ChrX:141.9cM	nonparametric multipoint LOD=1.25 for marker rs728186	Nominal linkage signals (LOD>1.0) Nominal linkage signals (LOD>1.0)	Non-significant
Chr21:61.4cM	nonparametric multipoint LOD=1.53 for marker rs875060	Nominal linkage signals (LOD>1.0) Nominal linkage signals (LOD>1.0)	Non-significant
16q23	nonparametric multipoint LOD=3.1 for marker rs424074	suggestive linkage signals suggestive linkage signals	Trend
16q12	nonparametric multipoint LOD=1.51 for marker rs837529	Nominal linkage signals (LOD>1.0) Nominal linkage signals (LOD>1.0)	Non-significant
Chr14:100cM	nonparametric multipoint LOD=1.75 for marker rs1361525	Nominal linkage signals (LOD>1.0) Nominal linkage signals (LOD>1.0)	Non-significant
Chr11:69cM	nonparametric multipoint LOD=1.31 for marker rs630759	Nominal linkage signals (LOD>1.0) Nominal linkage signals (LOD>1.0)	Non-significant
9q22	nonparametric multipoint LOD=2.13 for marker rs7043803	suggestive linkage signals suggestive linkage signals	Trend