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	Smoller JW, 200616197923
Citation	Smoller J. W., Biederman J., Arbeitman L., Doyle A. E., Fagerness J., Perlis R. H., Sklar P. and Faraone S. V. (2006) "Association between the 5HT1B receptor gene (HTR1B) and the inattentive subtype of ADHD." Biol Psychiatry, 59(5): 460-7.
Study Design	family-based
Study Type	Candidate-gene association study
Sample Size	229 families
Predominant Ethnicity	USA
Population	USA
Age Group	Children/Adolescents and Adults

Detail Info

Summary	To examine haplotype structure, they genotyped 21 SNPs in and around the gene in 12 multigenerational CEPH pedigrees. They identified a haplotype block encompassing HTR1B and performed haplotype and single-marker association analyses for the eight SNPs within or flanking this block in 229 families of ADHD probands. In light of previous studies suggesting distinct genetic influences on ADHD subtypes, they also examined association with the inattentive and combined subtypes. They observed nonsignificant overtransmission of the G861 allele to ADHD offspring. Single-marker and haplotype tests of a haplotype block encompassing HTR1B revealed no other associations with ADHD. However, this haplotype block was associated with the inattentive subtype. Additionally, three SNPs in this block were nominally associated with the inattentive subtype, although these did not remain significant after correction for multiple testing. As reported in previous studies, they found paternal overtransmission of the G861 allele to offspring with ADHD; this appeared to be largely attributable to inattentive cases.
Total Sample	They selected 229 families included in this report comprising 130 parent-child trios: 61 affected sibling pairs with both parents, 8 families with both parents and 3 affected offspring, 1 family with both parents and 4 affected offspring, 22 affected sibling pairs with 1 parent, 5 families with 1 parent and 3 affected offspring, and 2 families with 1 parent and 4 affected offspring. A total of 229 families including offspring with ADHD were recruited from several ongoing family studies of ADHD conducted at the Massachusetts General Hospital (MGH).
Diagnosis Description	ADHD was defined using DSM-III-R criteria for families enrolled in the Boys and Girls Studies of ADHD and using DSM-IV criteria for all other families. In addition to the ADHD diagnosis, they examined DSM-IV diagnostic subtypes of ADHD (inattentive, hyperactive/impulsive, and combined) for all subjects in light of evidence that they may reflect genetically distinguishable forms of ADHD. For the longitudinal study of girls, although ascertainment was based on DSM-III-R, information on all 18 DSM-IV symptom criteria were obtained at the time of assessment, permitting subtype assignment. For families in the longitudinal family study of boys, subtypes were assigned based on a 10-year follow-up reassessment at which lifetime DSM-IV diagnoses were obtained. The sample included 107 offspring with the inattentive subtype of ADHD, 203 with the combined subtype, and 20 with the hyperactive/impulsive subtype.
Technique	Genotyping of SNPs was performed using a MassARRAY RT mass spectrometer (BrUnited Kingdomer-Sequenom, San Diego, California; Buetow et al 2001) as previously described (Sklar et al 2002). SNPs were selected for testing in the ADHD family sample if they met the following quality control metrics: 1) genotyping call rate>90%; 2) genotypes in Hardy-Weinberg equilibrium; and 3) no Mendel errors. Twenty-one SNPs spanning 112 kb (average ~1SNP/5 kb) in and around the HTR1B locus were used to define haplotype blocks in the region. Haplotypes were reconstructed from the CEPH data using an E-M algorithm and the haplotype block criteria of Gabriel et al (2002) as implemented in the Haploview program.
Analysis Method	Our primary family-based association analyses were performed using the Family Based Association Test (FBAT) program, version 1.5.3. Haplotype analyses were conducted using the haploFBAT extension of FBAT.
Result Description	They observed nonsignificant overtransmission of the G861 allele to ADHD offspring. Single-marker and haplotype tests of a haplotype block encompassing HTR1B revealed no other associations with ADHD. However, this haplotype block was associated with the inattentive subtype. Additionally, three SNPs in this block were nominally associated with the inattentive subtype, although these did not remain significant after correction for multiple testing. As reported in previous studies, they found paternal overtransmission of the G861 allele to offspring with ADHD; this appeared to be largely attributable to inattentive cases. These analyses suggest that variation in the HTR1B gene may primarily affect the inattentive subtype of ADHD.

SNPs reported by this study (count: 8)

SNP	Allele Change	Risk Allele	Statistical Values	Author Comments	Result of Statistical Analysis
rs6298	C/T		allelic P-value=0.05 in inattentive; allelic P-value=0.25 in ADHD; allelic P-value=0.96 in combined	displayed no significant association displayed no significant association	Non-significant
rs2000292	C/T		allelic P-value=0.022 in inattentive; allelic P-value=0.21 in ADHD; allelic P-value=0.74 in combined	displayed nominally significant association with the inatten...... displayed nominally significant association with the inattentive subtype More...	Significant
rs130060	T/G		alpha=0.0083	displayed no significant association displayed no significant association	Non-significant
rs6297	A/G		allelic P-value=0.039 in inattentive; allelic P-value=0.35 in ADHD; allelic P-value=0.61 in combined	displayed nominally significant association with the inatten...... displayed nominally significant association with the inattentive subtype More...	Significant
rs6296	G/C		TDT P-value=0.12, X²=2.46, OR=1.24 in total sample; TDT P-value=0.013, X²=6.13, OR=1.69 among paternal transmission; TDT P-value=0.91, X²=0.012, OR=0.98 among maternal transmission in this study; TDT P-value=0.0009, X²=11, OR=1.35 in total sample; TDT P-value=0.00005, X²=16.5, OR=1.81 among paternal transmission; TDT P-value=0.22, X²=1.48, OR=1.19 among maternal transmission in combined data; allelic P-value=0.025 in inattentive, P-value=0.070 in ADHD, P-value=0.93 in combined	evidence of significant overtransmission of the G allele in ...... evidence of significant overtransmission of the G allele in combined data, significant evidence of association with the G allele among paternal transmissions, but not among maternal transmissions in this study; displayed nominally significant association with the inattentive subtype More...	Significant
rs11568817	T/G		allelic P-value=0.86 in inattentive; allelic P-value=0.9 in ADHD; allelic P-value=0.96 in combined	displayed no significant association displayed no significant association	Non-significant
rs130058	A/T		allelic P-value=0.24 in inattentive; allelic P-value=1 in ADHD; allelic P-value=0.82 in combined	displayed no significant association displayed no significant association	Non-significant
rs130056	C/T		alpha=0.0083	displayed no significant association displayed no significant association	Non-significant

Genes reported by this study (count: 1)