Study Report

Basic Info
Reference |
Smoller JW, 200616197923
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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.
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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
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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 |
rs130056 |
C/T |
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alpha=0.0083 |
displayed no significant association
displayed no significant association
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Non-significant
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rs11568817 |
T/G |
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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
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Non-significant
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rs6298 |
C/T |
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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
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Non-significant
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rs6296 |
G/C |
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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...
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Significant
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rs6297 |
A/G |
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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...
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Significant
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rs2000292 |
C/T |
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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...
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Significant
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rs130060 |
T/G |
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alpha=0.0083 |
displayed no significant association
displayed no significant association
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Non-significant
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rs130058 |
A/T |
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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
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Non-significant
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Genes reported by this study (count: 1)
Gene |
Statistical Values/Author Comments |
Result of Statistical Analysis |
HTR1B |
block 3, FBAT P-value=0.009, X2 (5df)=15.4, signi......
block 3, FBAT P-value=0.009, X2 (5df)=15.4, significant association with inattentive subtype; undertransmitted haplotype 3B-ACTTAT FBAT P-value=0.026, overtransmitted haplotype 3D-GGTCAT FBAT P-value=0.016 in inattentive
More...
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Significant
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