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Study Report
Reference | Friedel S, 200717579611 |
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Citation | Friedel S., Saar K., Sauer S., Dempfle A., Walitza S., Renner T., Romanos M., Freitag C., Seitz C., Palmason H., Scherag A., Windemuth-Kieselbach C., Schimmelmann B. G., Wewetzer C., Meyer J., Warnke A., Lesch K. P., Reinhardt R., Herpertz-Dahlmann B., Linder M., Hinney A., Remschmidt H., Schafer H., Konrad K., Hubner N. and Hebebrand J. (2007) "Association and linkage of allelic variants of the dopamine transporter gene in ADHD." Mol Psychiatry, 12(10): 923-33. |
Study Design | family-based |
Study Type | Candidate-gene association study |
Sample Size | 523 cases from 329 families |
Predominant Ethnicity | Caucasian |
Population | Germany |
Gender | 404 males (77.25%) and 119 females |
Age Group | Children/Adolescents : mean age 11.1 years (SD=3.0) |
Summary | Previously, they had reported a genome-wide scan for ADHD in 102 families with affected sibs of German ancestry; the highest multipoint LOD score of 4.75 was obtained on chromosome 5p13 near the dopamine transporter gene (DAT1). They genotyped 30 SNPs in this candidate gene and its 50 region in 329 families (including the 102 initial families) with 523 affected offspring. They have accumulated evidence that genetic variation at the DAT1 locus underlies their ADHD linkage peak on chromosome 5; additionally solid association for a single SNP and a haplotype were shown. Future studies are required to assess if variation at this locus also explains other positive linkage results obtained for chromosome 5p. |
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Total Sample | In total, 523 ADHD children from 329 families were included. In 173, 123, 28 and 5 families, one, two, three and four affected children were recruited, respectively. |
Sample Collection | Samples were collected from six child psychiatric outpatient units (Aachen, Marburg, Homburg, Trier, Regensburg and Wuerzburg) in Germany. All families were of Caucasian descent; the vast majority of families were of German origin. |
Diagnosis Description | Families were included if at least one child was diagnosed with ADHD according to DSM- IV. The ascertainment strategy and inclusion criteria have been described previously (Hebebrand J. et al., 2006). DSM-IV diagnosis of ADHD in children from Homburg and Trier (n=72) was derived from a semi-structured standardized interview with parents (Kinder-DIPS) and the Conners' Parent and Teacher Rating Scales. |
Technique | Genotyping of 7 SNPs was performed using the GOOD assay and matrix assisted laser disorption/ionisation (MALDI) mass spectrometry negative ion mode detection. PCR, primer extension, phosphodiesterase II digestion, alkylation and sample preparation were performed as described using MTP AnchorChip 400/384 targets from BrUnited Kingdomer Daltonics (Bremen, Germany). Data analysis was performed as described recently using the GenoTools SNP Manager software (BrUnited Kingdomer Daltonics). The other 5 SNPs were genotyped using TaqMan assays (Applied Biosystems, Foster City, CA, USA) using FAM and VIC reporter dyes. All TaqMan probes and primers were purchased from Applied Biosystems. They used the ABI Prism 7900HT Sequence detection instrument (Applied Biosystems, Darmstadt, Germany) for thermocycling and data collection. Frag- ments DAT1 8, 10 and 11 (according to 25) were resequenced.DNA sequences were determined using ABI BigDye Terminator 3.1 chemistry and 3730xl ABI 96-capillary sequencer systems. Sequences were processed for quality clipping and assembled using an in-house software package based on the poly-phred system. |
Analysis Method | Marker data were checked for Mendelian inconsistencies using PedCheck. Hardy-Weinberg equilibrium was checked on parental genotypes by chi-square tests as implemented in Pedstats. Likely genotyping errors were checked using FAMHAP. Haploview was used to calculate linkage disequilibrium. A family-based association test (TDT) was performed for the 23 SNPs with a MAF>3% in the DAT1 by using a permutation test as implemented in FAMHAP. Allele frequencies for linkage analysis were estimated from all parental alleles. Multipoint nonparametric linkage analysis was performed on the qualitative affection status ADHD using the Sall statistic that can be converted to a nonparametric LOD score as implemented in Merlin. Post hoc analyses were performed both for the original 102 GS families and the 156 families with affected sib pairs (ASPs). The genotype-IBD sharing test (GIST) was used to test whether probands with a certain genotype (under a dominant model) contributed more than expected to the linkage signal. LAMP software was used to test whether one of the SNPs is in complete or partial LD with a putative disease locus in this region, for example, whether it can explain the observed linkage. |
Result Description | They found that (1) SNP rs463379 was significantly associated with ADHD upon correction for multiple testing (P-value=0.0046); (2) the global P-value for association of haplotypes was significant for block two upon correction for all (n=3) tested blocks (P-value=0.0048); (3) within block two they detected a nominal P-value=0.000034 for one specific marker combination. This CGC haplotype showed relative risks of 1.95 and 2.43 for heterozygous and homozygous carriers, respectively; and (4) finally, their linkage data and the genotype-IBD sharing test (GIST) suggest that genetic variation at the DAT1 locus explains their linkage peak and that rs463379 (P-value<0.05) is the only SNP of the above haplotype that contributed to the linkage signal. |
SNP | Allele Change | Risk Allele | Statistical Values | Author Comments | Result of Statistical Analysis |
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rs8179029 | G/A | G | FAMHAP P-value=0.14 in single marker association analysis | No association was found with ADHD No association was found with ADHD | Non-significant |
rs7732456 | A/C | A | FAMHAP P-value=0.77 in single marker association analysis | No association was found with ADHD No association was found with ADHD | Non-significant |
rs37022 | T/A | T | FAMHAP P-value=0.15 in single marker association analysis | No association was found with ADHD No association was found with ADHD | Non-significant |
rs28362317 | A/T | A | FAMHAP P-value=0.13 in single marker association analysis | No association was found with ADHD No association was found with ADHD | Non-significant |
rs403636 | G/T | G | FAMHAP P-value=0.01 in single marker association analysis | not significantly associated with ADHD after multiple test c...... not significantly associated with ADHD after multiple test correction More... | Significant |
rs3756450 | T/C | T | FAMHAP P-value=0.03 in single marker association analysis | not significantly associated with ADHD after multiple test c...... not significantly associated with ADHD after multiple test correction More... | Significant |
rs464049 | T/C | T | FAMHAP P-value=0.13 in single marker association analysis | No association was found with ADHD No association was found with ADHD | Non-significant |
rs463379 | C/G | C | FAMHAP P-value=0.0002 in single marker association analysis | significantly associated with ADHD upon correction for multi...... significantly associated with ADHD upon correction for multiple testing (P-value=0.0046) More... | Significant |
rs6350 | C/T | C | FAMHAP P-value=0.008 in single marker association analysis | not significantly associated with ADHD after multiple test c...... not significantly associated with ADHD after multiple test correction More... | Significant |
rs6347 | A/G | A | FAMHAP P-value=1 in single marker association analysis | No association was found with ADHD No association was found with ADHD | Non-significant |
rs1316830 | G/A | G | FAMHAP P-value=0.03 in single marker association analysis | not significantly associated with ADHD after multiple test c...... not significantly associated with ADHD after multiple test correction More... | Significant |
rs2042449 | C/T | C | FAMHAP P-value=0.78 in single marker association analysis | No association was found with ADHD No association was found with ADHD | Non-significant |
rs2550956 | C/T | T | FAMHAP P-value=0.66 in single marker association analysis | No association was found with ADHD No association was found with ADHD | Non-significant |
rs2617595 | A/G | A | FAMHAP P-value=0.29 in single marker association analysis | No association was found with ADHD No association was found with ADHD | Non-significant |
rs2652509 | C/T | C | FAMHAP P-value=0.35 in single marker association analysis | No association was found with ADHD No association was found with ADHD | Non-significant |
rs2652510 | G/A | A | FAMHAP P-value=0.43 in single marker association analysis | No association was found with ADHD No association was found with ADHD | Non-significant |
rs27048 | C/T | G | FAMHAP P-value=0.24 in single marker association analysis | No association was found with ADHD No association was found with ADHD | Non-significant |
rs27072 | C/T | C | FAMHAP P-value=0.85 in single marker association analysis | No association was found with ADHD No association was found with ADHD | Non-significant |
rs11133767 | G/A | A | FAMHAP P-value=0.74 in single marker association analysis | No association was found with ADHD No association was found with ADHD | Non-significant |
rs11564750 | C/G | C | FAMHAP P-value=0.19 in single marker association analysis | No association was found with ADHD No association was found with ADHD | Non-significant |
rs11564752 | G/T | G | FAMHAP P-value=0.56 in single marker association analysis | No association was found with ADHD No association was found with ADHD | Non-significant |
rs11564774 | C/G | G | FAMHAP P-value=0.59 in single marker association analysis | No association was found with ADHD No association was found with ADHD | Non-significant |
Variant Name | Allele Change | Risk Allele | Statistical Values | Author Comments | Result of Statistical Analysis |
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SLC6A3 intron1 sid1153 | ins(C) | WT | FAMHAP P-value=0.1 in single marker association analysis FAMHAP P-value=0.1 in single marker association analysis | No association was found with ADHD | Non-significant |
Gene | Statistical Values/Author Comments | Result of Statistical Analysis |
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SLC6A3 | nominal P-value=0.000034 for family-based association study ...... nominal P-value=0.000034 for family-based association study of haplotypes of SNPs rs6350-rs403636-rs463379. solid association for a single SNP and a haplotype in this gene were shown. More... | Significant |
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Last update: Feb 26, 2014