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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	Mill J, 2004 (b)15007392
Citation	Mill J., Richards S., Knight J., Curran S., Taylor E. and Asherson P. (2004) "Haplotype analysis of SNAP-25 suggests a role in the aetiology of ADHD." Mol Psychiatry, 9(8): 801-10.
Study Design	family-based
Study Type	Candidate-gene association study and Mutational study
Sample Size	188 probands and their families
Predominant Ethnicity	Caucasian
Population	United Kingdom
Age Group	Children/Adolescents

Detail Info

Summary	They have screened the SNAP-25 gene using denaturing high-performance liquid chromatography and sequencing, and genotyped six polymorphic single-nucleotide polymorphisms and two microsatellites in a clinically ascertained sample of 188 probands. Several markers were found to show association with ADHD, both individually and in combination with other markers to form multimarker haplotypes. Analyses of transmission by parental sex suggested that the association of SNAP-25 with ADHD is largely due to transmission of alleles from paternal chromosomes to affected probands, suggesting that this locus may be subject to genomic imprinting. Overall their data provide some evidence for a role of this gene in ADHD, although the precise causal functional variant is yet to be ascertained.
Total Sample	In total, DNA from 188 probands and their families were used for this study. DNA was available from both parents for 121 of the families, and from only the mother in 64 families. In all, 113 of the affected families had at least one sibling who was also genotyped.
Diagnosis Description	Cases were included in this study if they had a diagnosis of ADHD under DSM-IV criteria. Out of 188 cases included in this study, 176 had the combined subtype, eight had the hyperactive/impulsive subtype, and four the inattentive subtype.
Technique	In this study, it was decided to screen 32 individuals which gives a probability of40.95 for the detection of a variant with a minor allele frequency of 0.05. DNA was obtained from volunteers using buccal swabs, and extracted using the method outlined in Freeman et al. Samples containing probable mutations were amplified by PCR and sequenced in both directions using the same primers as were used for DHPLC. Dye terminator sequencing was carried out using the ABI PRISM BigDye system and samples run on either an ABI 377 or 3100 machine. Sequencing traces were analysed using Sequencher software, and multiple samples aligned to aid mutation detection. Genotyping was performed using the ABI PRISM SNaPshot chemistry. Products were separated on an ABI 3100 Genetic Analyzer and analysed using GENOTYPER software.
Analysis Method	Family genotype data were primarily analysed using UNPHASED; Several tests were performed on the SNAP-25 genotype data: the extended transmission disequilibrium test (ETDT), the haplotype-based haplotype relative risk test (HHRR), and the pedigree disequilibrium test (PDT), which utilises extra genotype data (eg from siblings). David Clayton's program TRANSMIT (version 5.4) was also used to analyse this data.
Result Description	In this study, they report on 10 novel variants identified across SNAP-25 and detect some evidence for association of this gene with ADHD using eight of the markers that had minor allele frequencies greater than 5%. They found significant association with three individual polymorphisms in SNAP-25: the -2015 A/T SNP, the intron 1 microsatellite, and the 80609 G/A SNP. Stronger evidence for association resulted from the analysis of multimarker haplotypes.

SNPs reported by this study (count: 2)

SNP	Allele Change	Risk Allele	Statistical Values	Author Comments	Result of Statistical Analysis
rs1051312	T/C		allelic TDT P-value=0.16, X²=1.95; HHRR P-value=0.21, X²=1.56; PDT P-value=0.17, X²=1.90, TRANSMIT P-value=0.25, X²=1.33 in parental samples.	the marker was not individually associated with ADHD in this...... the marker was not individually associated with ADHD in this sample More...	Non-significant
rs3746544	T/G		allelic TDT P-value=0.24, X²=1.35; HHRR P-value=0.26, X²=1.26; PDT P-value=0.23, X²=1.42, TRANSMIT P-value=0.06, X²=0.27 in parental samples.	the marker was not individually associated with ADHD in this...... the marker was not individually associated with ADHD in this sample More...	Non-significant

Other variant reported by this study (count: 6)

Variant Name	Allele Change	Risk Allele	Statistical Values	Author Comments	Result of Statistical Analysis
SNAP25 promoter (TG)n			allelic TDT P-value=0.28, X²=16.54, 14df; HHRR P-...... allelic TDT P-value=0.28, X²=16.54, 14df; HHRR P-value=0.34, X²=15.56, 14df; PDT P-value=0.26, X²=16.92, 14df; TRANSMIT P-value=0.6, X²=12.043, 14df in parental samples. More...	the marker was not individually associated with ADHD in this sample	Non-significant
SNAP25 promoter -2015A/T	A/T		allelic TDT P-value=0.03, X²=4.55; HHRR P-value=0...... allelic TDT P-value=0.03, X²=4.55; HHRR P-value=0.04, X²=4.20; PDT P-value=0.04, X²=4.37, TRANSMIT P-value=0.06, X²=3.68 in parental samples. maternal TDT X²=1.73, 1 df, P-value=0.19; paternal TDT X²=4.76, 1 df, P-value=0.03 More...	evidence for association using TDT, HHRR, PDT, and TRANSMIT analyses was found; was more significantly associated when paternal transmissions were analysed compared to maternal transmissions	Significant
SNAP25 promoter -900G/T	G/T		allelic TDT P-value=0.59, X²=0.29; HHRR P-value=0...... allelic TDT P-value=0.59, X²=0.29; HHRR P-value=0.52, X²=0.42; PDT P-value=0.57, X²=0.33, TRANSMIT P-value=0.81, X²=0.06 in parental samples. More...	the marker was not individually associated with ADHD in this sample	Non-significant
SNAP25 5'-UTR (ATTT)n			allelic TDT P-value=0.01, X²=14.80, 5df; HHRR P-v...... allelic TDT P-value=0.01, X²=14.80, 5df; HHRR P-value=0.01, X²=15.07, 5df; PDT P-value=0.005, X²=16.56, 5df; TRANSMIT P-value=0.001, X²=21.66, 5df in parental samples. maternal TDT X²=6.18, 5 df, P-value=0.29; paternal TDT X²=15.13, 5 df, P-value=0.01 More...	evidence for association using TDT, HHRR, PDT, and TRANSMIT analyses was found; was more significantly associated when paternal transmissions were analysed compared to maternal transmissions	Significant
SNAP25 3'-UTR 88268T/C	T/C		allelic TDT P-value=0.51, X²=0.43; HHRR P-value=0...... allelic TDT P-value=0.51, X²=0.43; HHRR P-value=0.6, X²=0.28; PDT P-value=0.59, X²=0.3, TRANSMIT P-value=0.55, X²=0.35 in parental samples. More...	the marker was not individually associated with ADHD in this sample	Non-significant
SNAP25 exon7 80609G/A	G/A		allelic TDT P-value=0.03, X²=4.74; HHRR P-value=0...... allelic TDT P-value=0.03, X²=4.74; HHRR P-value=0.04, X²=4.34; PDT P-value=0.03, X²=4.46, TRANSMIT P-value=0.001, X²=11.36 in parental samples. maternal TDT X²=1.79, 1df, P-value=0.18; paternal TDT X²=4.28, 1df, P-value=0.04 More...	evidence for association using TDT, HHRR, PDT, and TRANSMIT analyses was found; was more significantly associated when paternal transmissions were analysed compared to maternal transmissions	Significant

Genes reported by this study (count: 1)

Gene	Statistical Values/Author Comments	Result of Statistical Analysis
SNAP25	3 variants were significantly associated with ADHD in this s...... 3 variants were significantly associated with ADHD in this study; the most significant haplotype G-4-G, TDT P-value=0.05 for the third haplotype window; the most significant haplotype 4-G-T, TDT P-value=0.04 for the fourth haplotype window; the most significant haplotype G-T-T, TDT P-value=0.04 for the fifth haplotype window; the most significant haplotype T-T-C, TDT P-value=0.03 for the sixth haplotype window; global TDT P-value=0.001 of a three-marker haplotype gave individual significant evidence for association with ADHD; two-marker haplotype (87610T/G and 87614T/C) TDT P-value=0.01, X²=6.22 showed some suggestive evidence for haplotypes of these SNPs being involved in ADHD with the T-T haplotype being over transmitted to ADHD probands More...	Significant