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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

Detail ...

Study Report

Basic Info

Reference	Kim JW, 200717455213
Citation	Kim J. W., Biederman J., Arbeitman L., Fagerness J., Doyle A. E., Petty C., Perlis R. H., Purcell S., Smoller J. W., Faraone S. V. and Sklar P. (2007) "Investigation of variation in SNAP-25 and ADHD and relationship to co-morbid major depressive disorder." Am J Med Genet B Neuropsychiatr Genet, 144B(6): 781-90.
Study Design	family-based
Study Type	Candidate-gene association study
Sample Size	229 families
Predominant Ethnicity	USA
Population	USA
Gender	214 (60%) males and 138 (40%) females
Age Group	Children/Adolescents

Detail Info

Summary	Synaptosomal-associated protein of 25 kDa (SNAP-25), a protein involved in presynaptic neurotransmitter release, is a candidate gene for ADH). Previous investigators have reported association initially with two single nucleotide polymorphisms (SNPs) (rs3746544, rs1051312) and their associated haplotypes. Subsequently, additional SNPs across the region were also reported to be associated with ADHD. This study attempted to replicate these observations in a sample of 229 families with ADHD offspring by genotyping 61 SNPs spanning the region containing SNAP-25. A single SNP (rs3787283) which is in strong linkage disequilibrium (LD) with rs3746544 and rs1051312 resulted in a nominally significant association (P-value=0.002). When they pooled their data with those from prior studies, results were modestly significant for rs3746544 (P-value=0.048) and rs6077690 (P-value=0.031). As an attempt to determine if specific ADHD-related phenotypesmay be more relevant to SNAP-25 than the categorical diagnosis, they carried out exploratory subgroup analysis in ADHD sample according to co-morbid status. They found the strongest association result in the ADHD patients with co-morbid major depressive disorder (MDD). Six SNPs were nominally associated with the ADHD and co-morbid MDD cases (P-value=0.012-0.045). Furthermore, a haplotype block located 11 kb 3' of the gene showed positive evidence for association with this phenotype (global P-value=0.013). In conclusion, this study report some evidence supporting the association of previously implicated SNPs (rs3746544, rs1051312) of SNAP-25 to ADHD. They further suggest that comorbidity with MDD may enhance detection of the association between SNAP-25 and ADHD.
Total Sample	The 229 families included in this report comprised 130 parent-child trios, 61 affected siblings 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.
Sample Collection	Families including offspring with ADHD were recruited from several ongoing family studies of ADHD conducted at the Massachusetts General Hospital as pre- viously described [Smoller et al., 2005]. The largest number (90 families) was ascertained from longitudinal case-control family studies of boys and girls with ADHD [Biederman et al., 1992b, 1999]. In these studies, probands were recruited from either consecutive referral to the MGH Pediatric Psychopharmacology program or by pediatric referral from a large Health Maintenance Organization (HMO) in the Boston area. The majority of children was Caucasian (95% Caucasian, 5% other)
Diagnosis Description	Affection status for probands and their relatives was based on DSM-IIIR criteria. During the screening phase, mothers were administered a telephone questionnaire containing criteria for DSM-IIIR ADHD and exclusionary criteria for their referred child. Potential probands were excluded if they were adopted, if their nuclear family was not available for study or if they had major sensorimotor handicaps, psychosis, autism or a Full Scale IQ less than 70. Individuals who screened positive for DSM-IIIR ADHD were invited to enroll in the study along with their first-degree relatives. Probands with subthreshold ADHD diagnoses were excluded. Those classified as having ADHD at both the screen and the interview (described below) were included as index cases. Families were also ascertained from a family study of adults with ADHD, an affected sibling pair linkage study of ADHD, family studies of bipolar disorder and family studies of ADHD and substance abuse. The screening methods for these studies were similar to the methods for the family studies of ADHD boys and girls with the following exceptions: (1) ADHD cases were obtained from the psychiatry clinics at MGH (and for the linkage study, the child psychiatry clinic at Children's Hospital in Boston) as well as referrals from individual child psychiatrists in the commu- nity and advertisements; (2) ascertainment was based on DSM-IV diagnoses; (3) the pediatric bipolar studies ascertained cases for bipolar disorder and did not screen out cases with psychosis. Affection status for these studies was based on DSM-IV criteria for ADHD. Individuals 18 years of age or older provided written informed consent for themselves. Mothers provided written informed consent for minor children, and children provided written assent. In addition to the ADHD diagnosis, they examined DSM-IV diagnostic subtypes of ADHD and co-morbidities for all subjects. For more details about diagnostic assessment, please refer to the original publication.
Technique	The primers and probes for the assays were designed using SpectroDESIGNER software (Sequenom, San Diego, CA) and genotyping was performed using a single base extension reaction with allele discrimination by MassArray mass spectrometry system (Sequenom). The resulting spectra were analyzed by using SPECTROTYPER software (Sequenom) [Sklar et al., 2002]. For information about selection of SNP markers, please refer to the original publication.
Analysis Method	Data analysis for single marker association were performed using the Family Based Association Test (FBAT) Program, version 1.5.5 [Laird et al., 2000]. For association analysis of single markers, they selected a subset of tagging SNPs using the program Tagger [Paul de Bakker et al., www.broad.mit. edu/mpg/tagger). The tag SNPs were chosen such that the intermarker LD between the SNPs tested for association and those not tested for association was at least r²>0.8 (average r²=0.97). All SNPs previously reported were included. Haplotypes were reconstructed using the Haploview software [Barrett et al., 2005] which implements the E-M algorithm. Haplotype blocks were constructed according to the block criteria of Gabriel et al. [2002] using 61 SNPs. Haplotype analyses were conducted using the haploFBAT extension of FBAT [Horvath et al., 2004]. HaploFBAT estimates haplotype frequencies using the EM algorithm and uses a weighted conditional approach to test for haplotype association.
Result Description	Combined TDT analysis for previously reported SNPs and haplotypes found none of the 7 individual SNPs in this study reached statistical significance, although a combined analysis of the data from the five independent studies produced some evidence of association for rs3746544 (P-value=0.048) and rs6077690 (P-value=0.031). The haplotypes defined by rs3746544 and rs1051312 were tested by TDT using the complete nuclear families, but did not find statistically significant associations. However, combined data also showed support for the association of this locus in ADHD (global P-value=0.01). Single marker association analysis were performed by FBAT for tag SNPs tested spanning SNAP-25. rs3787283 (P-value=0.002) and rs2327269 (P-value=0.013) showed evidence of significant association. Haplotype blocks were tested in those regions with positive single markers. 13 haplotype blocks were generated for the total ADHD families. Blocks 10, 11, and 12 were tested for association to ADHD. No significant haplotype blocks results were found. Exploratory analyses for subgroups of ADHD were conducted. Association results revealed evidence for an association between six SNPs and the co-morbid MDD phenotype. There was only one SNP associated with co-morbid BPD and no SNPs were associated with CD. However, none of these SNPs remained significant after Bonferroni correction for multiple testing. Exploratory haplotype analysis on these phenotypes with blocks 10, 11, and 12 were also performed. This revealed a significant association between block 12 (P-value=0.01) and ADHD with co-morbid MDD. No association was detected between these haplotype blocks and ADHD with co-morbid bipolar disorder or conduct disorder. Further haplotype-specific tests in block 12 showed a significant undertransmission of haplotype GCT (P-value=0.004) and overtransmission of GCC in co-morbidMDD(P-value=0.027). The association results for the GCT haplotype (P-value=0.004) in MDD survived the Bonferroni correction for testing of multiple haplotypes (N=9) but did not when including multiple haplotypes and phenotypes (N=27).

SNPs reported by this study (count: 33)

SNP	Allele Change	Risk Allele	Statistical Values	Author Comments	Result of Statistical Analysis
rs6104571	A/G	G	Single marker analysis FBAT P-value=0.807; Exploratory analyses FBAT P-value=0.789 for co-morbid CD, P-value=0.761 for co-morbid MDD, P-value=0.842 for co-morbid BD	No association was found between ADHD or co-morbidities of A...... No association was found between ADHD or co-morbidities of ADHD and this SNP More...	Non-significant
rs6077699	A/C	C	Single marker analysis FBAT P-value=0.839; Exploratory analyses FBAT P-value=0.571 for co-morbid CD, P-value=0.412 for co-morbid MDD, P-value=0.73 for co-morbid BD	No association was found between ADHD or co-morbidities of A...... No association was found between ADHD or co-morbidities of ADHD and this SNP More...	Non-significant
rs6077690	T/A	A	Combined TDT P-value=0.03 (OR=0.80); Single marker analysis FBAT P-value=0.375; Exploratory analyses FBAT P-value=0.301 for co-morbid CD, P-value=0.489 for co-morbid MDD, P-value=0.728 for co-morbid BD	Combined analysis showed evidence of significant association...... Combined analysis showed evidence of significant association with ADHD More...	Significant
rs6074121	T/C	C	Single marker analysis FBAT P-value=0.327; Exploratory analyses FBAT P-value=0.555 for co-morbid CD, P-value=0.313 for co-morbid MDD, P-value=0.962 for co-morbid BD	No association was found between ADHD or co-morbidities of A...... No association was found between ADHD or co-morbidities of ADHD and this SNP More...	Non-significant
rs6074109	A/G	G	Single marker analysis FBAT P-value=0.075; Exploratory analyses FBAT P-value=0.079 for co-morbid CD, P-value=0.201 for co-morbid MDD, P-value=0.426 for co-morbid BD	No association was found between ADHD or co-morbidities of A...... No association was found between ADHD or co-morbidities of ADHD and this SNP More...	Non-significant
rs4813023	C/T	T	Single marker analysis FBAT P-value=0.507; Exploratory analyses FBAT P-value=0.781 for co-morbid CD, P-value=0.63 for co-morbid MDD, P-value=0.596 for co-morbid BD	No association was found between ADHD or co-morbidities of A...... No association was found between ADHD or co-morbidities of ADHD and this SNP More...	Non-significant
rs4642009	C/T	T	Single marker analysis FBAT P-value=0.384; Exploratory analyses FBAT P-value=0.449 for co-morbid CD, P-value=0.639 for co-morbid MDD, P-value=0.91 for co-morbid BD	No association was found between ADHD or co-morbidities of A...... No association was found between ADHD or co-morbidities of ADHD and this SNP More...	Non-significant
rs3787283	A/G	G	Single marker analysis FBAT P-value=0.002; Exploratory analyses FBAT P-value=0.101 for co-morbid CD, P-value=0.012 for co-morbid MDD, P-value=0.085 for co-morbid BD	Combined and exploratory analysis showed evidence of signifi...... Combined and exploratory analysis showed evidence of significant association with ADHD and co-morbid MDD More...	Significant
rs3746544	T/G	G	Combined TDT P-value=0.048 (OR=1.14); Single marker analysis FBAT P-value=0.101; Exploratory analyses FBAT P-value=0.233 for co-morbid CD, P-value=0.012 for co-morbid MDD, P-value=0.082 for co-morbid BD	Combined and exploratory analysis showed evidence of signifi...... Combined and exploratory analysis showed evidence of significant association with ADHD and co-morbid MDD More...	Significant
rs363040	G/T	T	Single marker analysis FBAT P-value=0.518; Exploratory analyses FBAT P-value=0.408 for co-morbid CD, P-value=0.289 for co-morbid MDD, P-value=0.517 for co-morbid BD	No association was found between ADHD or co-morbidities of A...... No association was found between ADHD or co-morbidities of ADHD and this SNP More...	Non-significant
rs363035	C/T	T	Single marker analysis FBAT P-value=0.717; Exploratory analyses FBAT P-value=0.405 for co-morbid CD, P-value=0.841 for co-morbid MDD, P-value=0.763 for co-morbid BD	No association was found between ADHD or co-morbidities of A...... No association was found between ADHD or co-morbidities of ADHD and this SNP More...	Non-significant
rs363021	C/T	T	Single marker analysis FBAT P-value=0.508; Exploratory analyses FBAT P-value=0.627 for co-morbid CD, P-value=0.405 for co-morbid MDD, P-value=0.47 for co-morbid BD	No association was found between ADHD or co-morbidities of A...... No association was found between ADHD or co-morbidities of ADHD and this SNP More...	Non-significant
rs363014	A/G	G	Single marker analysis FBAT P-value=0.558; Exploratory analyses FBAT P-value=1 for co-morbid CD, P-value=0.697 for co-morbid MDD, P-value=0.561 for co-morbid BD	No association was found between ADHD or co-morbidities of A...... No association was found between ADHD or co-morbidities of ADHD and this SNP More...	Non-significant
rs363012	A/G	G	Single marker analysis FBAT P-value=1; Exploratory analyses FBAT P-value=0.405 for co-morbid CD, P-value=0.421 for co-morbid MDD, P-value=0.963 for co-morbid BD	No association was found between ADHD or co-morbidities of A...... No association was found between ADHD or co-morbidities of ADHD and this SNP More...	Non-significant
rs363006	G/A	A	Combined TDT P-value=0.43 (OR=1.09); Single marker analysis FBAT P-value=0.741; Exploratory analyses FBAT P-value=0.369 for co-morbid CD, P-value=0.858 for co-morbid MDD, P-value=0.688 for co-morbid BD	No association was found between ADHD or co-morbidities of A...... No association was found between ADHD or co-morbidities of ADHD and this SNP More...	Non-significant
rs362998	C/T	T	Combined TDT P-value=0.09 (OR=1.36); Single marker analysis FBAT P-value=0.446; Exploratory analyses FBAT P-value=0.592 for co-morbid CD, P-value=0.179 for co-morbid MDD, P-value=0.345 for co-morbid BD	No association was found between ADHD or co-morbidities of A...... No association was found between ADHD or co-morbidities of ADHD and this SNP More...	Non-significant
rs362987	A/C	C	Combined TDT P-value=0.25 (OR=1.11); Single marker analysis FBAT P-value=0.699; Exploratory analyses FBAT P-value=1 for co-morbid CD, P-value=0.169 for co-morbid MDD, P-value=0.723 for co-morbid BD	No association was found between ADHD or co-morbidities of A...... No association was found between ADHD or co-morbidities of ADHD and this SNP More...	Non-significant
rs362993	C/T	T	Single marker analysis FBAT P-value=1; Exploratory analyses FBAT P-value=0.275 for co-morbid CD, P-value=0.53 for co-morbid MDD, P-value=0.046 for co-morbid BD	Exploratory analysis showed evidence of significant associat...... Exploratory analysis showed evidence of significant association with ADHD and co-morbid BD More...	Significant
rs362585	G/T	T	Single marker analysis FBAT P-value=0.886; Exploratory analyses FBAT P-value=0.248 for co-morbid CD, P-value=0.045 for co-morbid MDD, P-value=0.196 for co-morbid BD	Exploratory analysis showed evidence of significant associat...... Exploratory analysis showed evidence of significant association with ADHD and co-morbid MDD More...	Significant
rs362599	A/C	C	Single marker analysis FBAT P-value=1; Exploratory analyses FBAT P-value=1 for co-morbid CD, P-value=0.969 for co-morbid MDD, P-value=0.705 for co-morbid BD	No association was found between ADHD or co-morbidities of A...... No association was found between ADHD or co-morbidities of ADHD and this SNP More...	Non-significant
rs362562	G/A	A	Single marker analysis FBAT P-value=1; Exploratory analyses FBAT P-value=0.896 for co-morbid CD, P-value=0.356 for co-morbid MDD, P-value=0.764 for co-morbid BD	No association was found between ADHD or co-morbidities of A...... No association was found between ADHD or co-morbidities of ADHD and this SNP More...	Non-significant
rs362584	G/A	A	Single marker analysis FBAT P-value=0.456; Exploratory analyses FBAT P-value=0.763 for co-morbid CD, P-value=0.791 for co-morbid MDD, P-value=0.439 for co-morbid BD	No association was found between ADHD or co-morbidities of A...... No association was found between ADHD or co-morbidities of ADHD and this SNP More...	Non-significant
rs362553	G/A	A	Single marker analysis FBAT P-value=0.781; Exploratory analyses FBAT P-value=0.038 for co-morbid MDD, P-value=0.563 for co-morbid BD	Exploratory analysis showed evidence of significant associat...... Exploratory analysis showed evidence of significant association with ADHD and co-morbid MDD More...	Significant
rs362555	A/G	G	Single marker analysis FBAT P-value=0.949; Exploratory analyses FBAT P-value=0.571 for co-morbid CD, P-value=0.714 for co-morbid MDD, P-value=0.619 for co-morbid BD	No association was found between ADHD or co-morbidities of A...... No association was found between ADHD or co-morbidities of ADHD and this SNP More...	Non-significant
rs3025873	G/C	C	Single marker analysis FBAT P-value=1; Exploratory analyses FBAT P-value=0.723 for co-morbid CD, P-value=0.021 for co-morbid MDD, P-value=0.952 for co-morbid BD	Exploratory analysis showed evidence of significant associat...... Exploratory analysis showed evidence of significant association with ADHD and co-morbid MDD More...	Significant
rs362549	G/A	A	Combined TDT P-value=0.11 (OR=1.16); Single marker analysis FBAT P-value=0.466; Exploratory analyses FBAT P-value=0.892 for co-morbid CD, P-value=0.429 for co-morbid MDD, P-value=0.465 for co-morbid BD	No association was found between ADHD or co-morbidities of A...... No association was found between ADHD or co-morbidities of ADHD and this SNP More...	Non-significant
rs2327269	T/C	C	Single marker analysis FBAT P-value=0.013; Exploratory analyses FBAT P-value=0.248 for co-morbid CD, P-value=0.013 for co-morbid MDD, P-value=0.127 for co-morbid BD	Single marker and exploratory analysis showed evidence of si...... Single marker and exploratory analysis showed evidence of significant association with ADHD and co-morbid MDD More...	Significant
rs2423486	C/T	T	Single marker analysis FBAT P-value=0.481; Exploratory analyses FBAT P-value=0.731 for co-morbid CD, P-value=0.256 for co-morbid MDD, P-value=0.249 for co-morbid BD	No association was found between ADHD or co-morbidities of A...... No association was found between ADHD or co-morbidities of ADHD and this SNP More...	Non-significant
rs2076240	T/C	C	Single marker analysis FBAT P-value=0.241; Exploratory analyses FBAT P-value=0.405 for co-morbid CD, P-value=0.251 for co-morbid MDD, P-value=0.345 for co-morbid BD	No association was found between ADHD or co-morbidities of A...... No association was found between ADHD or co-morbidities of ADHD and this SNP More...	Non-significant
rs2206161	T/C	C	Single marker analysis FBAT P-value=0.295; Exploratory analyses FBAT P-value=0.66 for co-morbid CD, P-value=0.265 for co-morbid MDD, P-value=0.283 for co-morbid BD	No association was found between ADHD or co-morbidities of A...... No association was found between ADHD or co-morbidities of ADHD and this SNP More...	Non-significant
rs1051312	T/C	C	Combined TDT P-value=0.69 (OR=1.03); Single marker analysis FBAT P-value=0.894; Exploratory analyses FBAT P-value=0.475 for co-morbid CD, P-value=0.211 for co-morbid MDD, P-value=0.219 for co-morbid BD	No association was found between ADHD or co-morbidities of A...... No association was found between ADHD or co-morbidities of ADHD and this SNP More...	Non-significant
rs6108464	T/C	C	Single marker analysis FBAT P-value=0.1; Exploratory analyses FBAT P-value=0.257 for co-morbid CD, P-value=0.117 for co-morbid MDD, P-value=0.388 for co-morbid BD	No association was found between ADHD or co-morbidities of A...... No association was found between ADHD or co-morbidities of ADHD and this SNP More...	Non-significant
rs8636	C/T	T	Single marker analysis FBAT P-value=0.113; Exploratory analyses FBAT P-value=0.345 for co-morbid CD, P-value=0.114 for co-morbid MDD, P-value=0.105 for co-morbid BD	No association was found between ADHD or co-morbidities of A...... No association was found between ADHD or co-morbidities of ADHD and this SNP More...	Non-significant

Other variant reported by this study (count: 1)

Variant Name	Allele Change	Risk Allele	Statistical Values	Author Comments	Result of Statistical Analysis
SNAP25 hCV27368320 T/C	T/C	C	Single marker analysis FBAT P-value=0.218; Exploratory analy...... Single marker analysis FBAT P-value=0.218; Exploratory analyses FBAT P-value=0.647 for co-morbid CD, P-value=0.477 for co-morbid MDD, P-value=0.342 for co-morbid BD More...	No association was found between ADHD or co-morbidities of ADHD and this SNP	Non-significant

Genes reported by this study (count: 1)