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, 200312687500
Citation	Ogdie M. N., Macphie I. L., Minassian S. L., Yang M., Fisher S. E., Francks C., Cantor R. M., McCracken J. T., McGough J. J., Nelson S. F., Monaco A. P. and Smalley S. L. (2003) "A genomewide scan for attention-deficit/hyperactivity disorder in an extended sample: suggestive linkage on 17p11." Am J Hum Genet, 72(5): 1268-79.
Study Design	affected sib pairs
Study Type	Genome-wide linkage study
Sample Size	270 possible ASPs from 204 families
Predominant Ethnicity	Caucasian
Population	USA
Gender	315 (72%) males, 123 (28%) females
Age Group	Children/Adolescents : mean age 11.1 years (SD=3.6)

Detail Info

Summary	As part of an ongoing study of the genetic etiology of ADHD, they performed a genomewide linkage scan in 204 nuclear families comprising 853 individuals and 270 affected sibling pairs (ASPs). Previously, they reported genomewide linkage analysis of a first wave of these families composed of 126 ASPs. A follow-up investigation of one region on 16p yielded significant linkage in an extended sample. The current study extends the original sample of 126 ASPs to 270 ASPs and provides linkage analyses of the entire sample, using polymorphic microsatellite markers that define an ~10cM map across the genome. Maximum LOD score (MLS) analysis identified suggestive linkage for 17p11 (MLS=2.98) and four nominal regions with MLS values >1.0, including 5p13, 6q14, 11q25, and 20q13. These data, taken together with the fine mapping on 16p13, suggest two regions as highly likely to harbor risk genes for ADHD: 16p13 and 17p11. Interestingly, both regions, as well as 5p13, have been highlighted in genomewide scans for autism.
Total Sample	The total sample includes 204 families, comprising 270 possible ASPs and 234 independent pairs. The initial set of 104 families, termed wave 1 included 126 ASPs. The sample was extended with an additional set of 101 families, termed wave 2 and comprising 140 ASPs. Together, the wave 1 and wave 2 families constitute the combined set. Family 580, a four-sibling family, contributed a single ASP to both wave 1 and wave 2. The average full-scale IQ being 105.9 (SD=14.2). The majority of the sample met definite diagnostic criteria (95%), with 24 affected siblings classified as probable (5%). All ASP families had at least one member with a definite diagnosis. The distribution of subtypes and comorbid conditions in the sample is similar to that expected on the basis of clinical and epidemiological studies of ADHD. The extended sample of 277 ASPs reported elsewhere for fine-mapping on 16p overlaps with the current data set by 237 ASPs. Specifically, 40 ASPs unique to the 16p fine-mapping sample were not genotyped for the 10-cM grid, and 33 ASPs included in the 10-cM genotyping were not genotyped for the fine-mapping analyses.
Sample Collection	Families that included at least two children with ADHD were recruited from multiple sources, including previous research studies of ADHD, clinics, hospitals, and schools in the greater Los Angeles area.
Diagnosis Description	Assessment of psychiatric disorders was performed using semistructured interviews, the Schedule for Affective Disorders and Schizophrenia for School-Age Children- Present and Lifetime version (KSADS-PL) for subjects 5-17 years of age and the Schedule fo Affective Disorders and Schizophrenia-Lifetime Version, modified for the study of anxiety disorder, with the Disruptive Disorders section of the KSADS-PL for subjects aged >=18years. Interviews were conducted by clinical psychologists and highly trained interviewers and were administered to the mother as well as the child if the child was >=8 years of age. In addition, the Swanson, Nolan, and Pelham, version IV (SNAP-IV) (parent and teacher versions), the Child Behavior Checklist, and the Teacher's Report Form were utilized to supplement information obtained in the direct interviews. Diagnosis was determined using a best-estimate procedure, with senior psychiatrists reviewing all positive diagnoses. ADHD was diagnosed according to DSM-IV criteria and was defined as definite when all criteria were met or as probable when the subject met only five criteria, instead of the six required for definite diagnosis, but was accompanied by significant impairment. In the present study, they qualitatively assigned all individuals with definite and probable diagnoses as affected, similar to the broad definition used in the first genomewide scan. Families were excluded from analysis if an affected child met criteria for autism or schizophrenia. Full-scale IQ was measured using the Wechsler Intelligence Scale for Children, 3rd edition, and academic achievement was determined using the Peabody Individual Achievement Test-Revised. Affected children were excluded from analysis if their full-scale IQ was <70. A thorough description of the cohort and all associated procedures has been reported elsewhere (Smalley et al. 2000).
Technique	Affected siblings and their parents were genotyped with 423 polymorphic microsatellite markers, spanning the entire human genome. The majority of autosomal markers represent the ABI Prism Linkage Mapping Set (LMS) 2.5 panels, supplemented with additional markers to compensate for large intervals and/or poorly amplifying markers. X-chromosome markers were taken from the LMS 2.5 panels and from the Cooperative Human Linkage Center (CHLC)/Weber Human Screening Set version 6 (Research Genetics). Sex-averaged marker maps were determined from CHLC, Genethon, Marshfield, and maps generated from recombination fractions within the sample, using both Genehunter version 2.1 and ASPEX version 2.3. The average intermarker interval was 9.2cM. PCR was performed in 9¦Ìl volumes in 96-well plates. PCR products were run on ABI 3700 capillary-action sequencers, and trace files were analyzed in Genotyper version 3.7. Random subsets of trace files were independently analyzed and reviewed by two persons to ensure accurate and consistent allele designation. GAS version 2.0 was used to eliminate violations of Mendelian inheritance and to assign global allele designations. Haplotypes were generated in Genehunter version 2.1 and all double recombinants, as well as any chromosome with an excessive number of crossovers, were reviewed extensively. LINKAGE format files were generated with the use of MAKEPED and RECODE version 1.4.
Analysis Method	MLS analysis was performed under a multiplicative model, utilizing the restrictions of the possible triangle. Autosomal single-point MLSs were generated in Genehunter version 2.1, using Mapmaker/SIBS options. X-chromosome single-point MLS values were generated in Mapmaker/SIBS. All allele frequencies were derived from founders and random inidividuals in RECODE version 1.4 (Dan Weeks). Multipoint MLS analysis was performed using ASPEX 2.3 sib_ibd, with incremental estimates set to ~1-cM intervals. Values for locus-specific sibling relative-risk ratios (theta_s) were calculated from the Z₀ parameter, assuming a recombination fraction of 0. Simulations to determine the empirical significance of MLS values attained in the current study were performed using Simulate. Exclusion mapping was performed in ASPEX sib_ibd under defined theta_s values, assuming no dominance variance. Any region yielding a LOD score <= -2.00 was considered excluded. Exclusion mapping compares the likelihood of the genotype data under the assumption of specified values of theta_s with the likelihood under the null hypothesis of no linkage.
Result Description	Multipoint MLS analysis of the combined data set yielded six genomic regions with values >1.0: 5p13, 6q14, 11q25, 16p13, 17p11, and 20q13. Regions 16p13 (MLS=3.73) and 17p11 (MLS=2.98) yielded the strongest evidence for linkage in the present sample. Separate analyses of wave 1, wave 2, and the combined data sets are presented. Region 17p11 is the only one that yields nominal evidence of linkage in the multipoint analysis of both wave 1 (MLS=0.79) and wave 2 (MLS=2.33) data sets. Single-point MLS analysis in the combined set supports the multipoint MLS findings for four of the regions highlighted: 5p13, 6p12-6q14, 16p13, 17p11. In addition, 11q13 and 15q26 both yielded single-point MLS values >1.0, but the multipoint MLS values were <1.0. The most striking single-point MLS was on chromosome 5 at marker D5S418 (MLS=3.09). Exclusion mapping under a theta_s of 1.5 excluded 56.3% of the genome. Exclusion mapping under a theta_s of 2.0 excluded 94.3% of the genome. Under a theta_s of 2.5, 99.8% of the genome was excluded, with only four intervals yielding LOD scores > -2.00: 5p13, 6p21-6q14, 16p13, and 17p11.

Regions reported by this study (count: 10)

Region	Statistical Values	Author Comments	Result of Statistical Analysis
11q25	Multipoint MLS Linkage Analysis: with marker D11S1320, MLS=0.85 (P=0.02394) for wave 1, MLS=0.34 (P=0.10541) for wave 2, MLS=1.27 (P=0.00779) for combined	show support (MLS>1) in only one of the two waves of familie...... show support (MLS>1) in only one of the two waves of families More...	Non-significant
20q13	Multipoint MLS Linkage Analysis: with marker D20S196, MLS=0.01 (P=0.41504) for wave 1, MLS=1.68 (P=0.00271) for wave 2, MLS=1.19 (P=0.00962) for combined	show support (MLS>1) in only one of the two waves of familie...... show support (MLS>1) in only one of the two waves of families More...	Non-significant
17p12	Single-Point MLS Linkage Analysis: with marker D17S799, MLS=0.625 (P=0.04493) for wave 1, MLS=0.477 (P=0.06917) for wave 2, MLS=1.061 (P=0.01355) for combined	no evidence no evidence	Non-significant
17p11	Multipoint MLS Linkage Analysis: with marker D17S1857, MLS=0.79 (P=0.02824) for wave 1, MLS=2.33 (P=0.00053) for wave 2, MLS=2.98 (P=0.00011) for combined; Single-Point MLS Linkage Analysis: with marker D17S1857, MLS=0.441 (P=0.07708) for wave 1, MLS=1.247 (P=0.00771) for wave 2, MLS=1.326 (P=0.00637) for combined	suggestive evidence suggestive evidence	Trend
11q13	Single-Point MLS Linkage Analysis: with marker D11S987, MLS=0.137 (P=0.21336) for wave 1, MLS=1.057 (P=0.01369) for wave 2, MLS=1.172 (P=0.01009) for combined	no evidence no evidence	Non-significant
6q14	Multipoint MLS Linkage Analysis: with marker D6S460, MLS=0.19 (P=0.17479) for wave 1, MLS=2.42 (P=0.00042) for wave 2, MLS=1.75 (P=0.00226) for combined; Single-Point MLS Linkage Analysis: with marker D6S460, MLS=0.267 (P=0.13357) for wave 1, MLS=0.638 (P=0.04327) for wave 2, MLS=1.067 (P=0.01333) for combined	show support (MLS>1) in only one of the two waves of familie...... show support (MLS>1) in only one of the two waves of families More...	Non-significant
16p13	Multipoint MLS Linkage Analysis: with marker D16S3060, MLS=3.13 (P=0.00007) for wave 1, MLS=0.5 (P=0.06458) for wave 2, MLS=3.73 (P=0.00002) for combined; Single-Point MLS Linkage Analysis: with marker D16S3114, MLS=1.942 (P=0.00139) for wave 1, MLS=0.043 (P=0.32778) for wave 2, MLS=1.738 (P=0.00233) for combined; with marker D16S3047, MLS=1.741 (P=0.00232) for wave 1, MLS=0.257 (P=0.13831) for wave 2, MLS=1.501 (P=0.00427) for combined; with marker rs153783, MLS=0.645 (P=0.04231) for wave 1, MLS=1.409 (P=0.00543) for wave 2, MLS=2.436 (P=0.0004) for combined; with marker rs127293, MLS=1.014 (P=0.01536) for wave 1, MLS=0.253 (P=0.14016) for wave 2, MLS=1.555 (P=0.00373) for combined; with marker D16S3060, MLS=1.268 (P=0.00784) for wave 1, MLS=0.053 (P=0.31297) for wave 2, MLS=1.421 (P=0.00526) for combined	significant linkage significant linkage	Significant
15q26	Single-Point MLS Linkage Analysis: with marker D15S127, MLS=0.444 (P=0.07634) for wave 1, MLS=1.176 (P=0.00998) for wave 2, MLS=1.287 (P=0.00745) for combined	no evidence no evidence	Non-significant
6p12	Single-Point MLS Linkage Analysis: with marker D6S257, MLS=0.617 (P=0.04587) for wave 1, MLS=1.581 (P=0.00349) for wave 2, MLS=1.837 (P=0.00181) for combined	no evidence no evidence	Non-significant
5p13	Multipoint MLS Linkage Analysis: with marker D5S418, MLS=0.82 (P=0.02599) for wave 1, MLS=0.61 (P=0.04686) for wave 2, MLS=1.77 (P=0.00215) for combined; Single-Point MLS Linkage Analysis: with marker D5S418, MLS=2.089 (P=0.00094) for wave 1, MLS=1.158 (P=0.01046) for wave 2, MLS=3.091 (P=0.00008) for combined	show support in wave 1 and wave 2, with a combined multipoin...... show support in wave 1 and wave 2, with a combined multipoint MLS of 1.77, falling short of suggestive linkage. More...	Non-significant