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	Ogdie MN, 200415297934
Citation	Ogdie M. N., Fisher S. E., Yang M., Ishii J., Francks C., Loo S. K., Cantor R. M., McCracken J. T., McGough J. J., Smalley S. L. and Nelson S. F. (2004) "Attention deficit hyperactivity disorder: fine mapping supports linkage to 5p13, 6q12, 16p13, and 17p11." Am J Hum Genet, 75(4): 661-8.
Study Design	affected sib pairs
Study Type	Linkage study
Sample Size	308 ASPs
Predominant Ethnicity	Caucasian
Population	USA
Gender	73% male
Age Group	Children/Adolescents

Detail Info

Summary	They completed fine mapping of nine positional candidate regions for ADHD in an extended population sample of 308 affected sibling pairs (ASPs). The candidate chromosomal regions were selected from all three published genomewide scans for ADHD, and fine mapping was done to comprehensively validate these positional candidate regions in their sample. Multipoint maximum LOD score (MLS) analysis yielded significant evidence of linkage on 6q12 (MLS 3.30; empiric P=0.024) and 17p11 (MLS 3.63; empiric P=0.015), as well as suggestive evidence on 5p13 (MLS 2.55; empiric P=0.091). In conjunction with the previously reported significant linkage on the basis of fine mapping 16p13 in the same sample as this report, the analyses presented here indicate that four chromosomal regions-5p13, 6q12, 16p13, and 17p11-are likely to harbor susceptibility genes for ADHD. The refinement of linkage within each of these regions lays the foundation for subsequent investigations using association methods to detect risk genes of moderate effect size.
Total Sample	The sample of 308 ASPs with ADHD is derived from 226 multiplex families (194 two-sib families, 26 three-sib families, and 6 four-sib families), containing a total of 490 affected children and 308 ASPs (all possible pairs). Parents of all ASPs were genotyped, with both parents available for 289 (94%) ASPs and one parent available for 19 (6%) ASPs. The affected individuals in the sample are fairly representative of the subtype proportions evident in epidemiological studies of ADHD (49% combined, 44% inattentive, and 7% hyperactive-impulsive).
Sample Collection	The current sample contains 269 of the 270 ASPs reported in the previous genomewide scans (Fisher et al. 2002; Ogdie et al. 2003) and an independent set of 39 ASPs. The affected individuals in the sample are 78% white.
Diagnosis Description	ADHD was diagnosed in accordance with DSM-IV criteria, by use of a best-estimate procedure (USAn Psychiatric Association 1994). A definite ADHD diagnosis was made for 95% of the ASP members, whereas a probable ADHD diagnosis (i.e., the individual showed one less symptom than the diagnosis requirement but met criteria of impairment and age at onset) was made in 5% of the sample. All ASPs have at least one member with a definite diagnosis. Details of the sample characteristics are published elsewhere (Smalley et al. 2000). Expected psychiatric comorbidity is present in the sample and includes oppositional-defiant disorder (46%), conduct disorder (11%), mood disorders (major depression, dysthymia, and bipolar disorder) (17%), and anxiety disorders (8%). Although five of the ASP members had a comorbid diagnosis of bipolar disorder, none came from the same family. They tested the impact these cases might have had on the MLS results by removing them from the data set and rerunning the MLS analysis. There were no significant changes in the MLS values for any of the chromosomes of interest in the sample from which the five cases were excluded.
Technique	Genotyping was performed in accordance with standard procedures (Ogdie et al. 2003). Mendelian inheritance errors were identified and removed using GAS 2.0 (A. Young, Ox-ford University), and improbable genotypes, as determined by the presence of unlikely recombination events, were identified and removed using Simwalk2 (Sobel and Lange 1996).
Analysis Method	Multipoint MLS analysis was conducted by ASPEX sib_ibd v2.3, under the multiplicative model with parameters restricted to the possible triangle. MLSs were calculated at 1cM increments, with all possible pairs treated as independent. Single-point MLS analysis was performed by Genehunter v2.1 with the use of Map-maker/Sibs commands. ASPEX sib_ibd uses only fully informative transmissions, whereas single-point MLS analysis in Genehunter uses all inheritance information for the reconstruction of missing parental genotypes and for the determination of identity-by-descent (IBD) and thus maximizes the number of ASPs contributing to a single-point MLS. MLS values were converted to pointwise P values by the derivation for MLS calculated under the possible triangle.
Result Description	Multipoint MLS analysis yielded significant evidence of linkage for the regions on 6q12-6q14 and 17p11. Region 5p13, the only region presenting evidence of linkage in both current sample and the Dutch sample, yielded suggestive evidence. Evidence of linkage to 11q25 and 20q13 remained below the suggestive threshold and did not increase above that of the 10-cM data set. Region 13q33 yielded evidence of linkage above the nominal threshold, whereas analysis of the other three regions identified by Bakker et al. (2003) failed to yield even nominal evidence of linkage in current sample and did not vary appreciably from the evidence provided by the 10-cM data set, indicating that the 10-cM genomewide scan provided an accurate estimate of IBD sharing in these unlinked regions. A separate multipoint MLS analysis of the independent set of 39 ASPs was performed. The trend of excess sharing continues, and evidence of linkage is present: 5p13 (sharing 63.55%, MLS 0.22), 6q12 (sharing 70.09%, MLS 1.27), and 17p11 (sharing 59.79%, MLS 0.18). Results from single-point MLS analyses were highly consistent with multi-point findings. Of note, in fine-mapping regions on chromosomes 5, 6, and 17, several markers yielded MLSs >1 under each peak (three markers in 5p13, seven markers in 6q12, and nine markers in 17p11).

Regions reported by this study (count: 16)

Region	Statistical Values	Author Comments	Result of Statistical Analysis
15q15	multipoint MLS=0.28 (nominal P=0.18, empiric P=1) for marker D15S146	little evidence of linkage (MLS>1) little evidence of linkage (MLS>1)	Non-significant
17p11	multipoint MLS=3.63 (nominal P=0.000045, empiric P=0.015) for marker D17S947; single-point MLS=1.84 (nominal P=0.0032) for marker D17S839; single-point MLS=1.23 (nominal P=0.014) for marker D17S953; single-point MLS=2.06 (nominal P=0.0019) for marker D17S1857; single-point MLS=1.7 (nominal P=0.0045) for marker D17S2196	significant evidence of linkage significant evidence of linkage	Significant
11q25	multipoint MLS=1 (nominal P=0.026, empiric P=0.931) for marker D11S4126; single-point MLS=1.19 (nominal P=0.016) for marker D11S4126	evidence of linkage remained below the suggestive threshold evidence of linkage remained below the suggestive threshold	Non-significant
13q33	multipoint MLS=0.84 (nominal P=0.039, empiric P=0.972) for marker D13S796	evidence of linkage above the nominal threshold evidence of linkage above the nominal threshold	Non-significant
6p12	single-point MLS=2.46 (nominal P=0.00072) for marker D6S465; single-point MLS=1.05 (nominal P=0.022) for marker D6S1960; single-point MLS=1.83 (nominal P=0.0033) for marker D6S257	little evidence of linkage (MLS>1) little evidence of linkage (MLS>1)	Non-significant
6q12	multipoint MLS=3.3 (nominal P=0.000098, empiric P=0.024) for marker D6S430; single-point MLS=1.72 (nominal P=0.0043) for marker D6S430	significant evidence of linkage significant evidence of linkage	Significant
5p13	multipoint MLS=2.55 (nominal P=0.00058, empiric P=0.091) for marker D5S418; single-point MLS=3.24 (nominal P=0.00011) for marker D5S418	suggestive evidence suggestive evidence	Trend
5q11	single-point MLS=1.26 (nominal P=0.013) for marker D5S1968	little evidence of linkage (MLS>1) little evidence of linkage (MLS>1)	Non-significant
20q13	multipoint MLS=1.09 (nominal P=0.02, empiric P=0.871) for marker D20S1106; single-point MLS=2.11 (nominal P=0.0017) for marker D20S1106	evidence of linkage remained below the suggestive threshold evidence of linkage remained below the suggestive threshold	Trend
5p12	single-point MLS=1.24 (nominal P=0.014) for marker D5S1958	little evidence of linkage (MLS>1) little evidence of linkage (MLS>1)	Non-significant
17p12	single-point MLS=1.72 (nominal P=0.0043) for marker D17S947; single-point MLS=1.54 (nominal P=0.0067) for marker D17S799; single-point MLS=2.51 (nominal P=0.00064) for marker D17S1856	little evidence of linkage (MLS>1) little evidence of linkage (MLS>1)	Non-significant
17q11	single-point MLS=1.35 (nominal P=0.011) for marker D17S1824; single-point MLS=1.41 (nominal P=0.0092) for marker D17S798	little evidence of linkage (MLS>1) little evidence of linkage (MLS>1)	Non-significant
9q33	multipoint MLS=0 (nominal P=0.6, empiric P=1) for marker D9S1825	little evidence of linkage (MLS>1) little evidence of linkage (MLS>1)	Non-significant
7p13	multipoint MLS=0 (nominal P=0.6, empiric P=1) for marker D7S1818	little evidence of linkage (MLS>1) little evidence of linkage (MLS>1)	Non-significant
6q14	single-point MLS=1.06 (nominal P=0.022) for marker D6S460; single-point MLS=1.5 (nominal P=0.0074) for marker D6S1609	little evidence of linkage (MLS>1) little evidence of linkage (MLS>1)	Non-significant
6q13	single-point MLS=1.97 (nominal P=0.0023) for marker D6S1557	little evidence of linkage (MLS>1) little evidence of linkage (MLS>1)	Non-significant