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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	Kim SJ, 200516082698
Citation	Kim S. J., Badner J., Cheon K. A., Kim B. N., Yoo H. J., Cook E., Jr., Leventhal B. L. and Kim Y. S. (2005) "Family-based association study of the serotonin transporter gene polymorphisms in Korean ADHD trios." Am J Med Genet B Neuropsychiatr Genet, 139B(1): 14-8.
Study Design	case-control and family-based
Study Type	Candidate-gene association study
Sample Size	104 completed trios for the 5-HTTLPR and 106 trios for the intron 2 VNTR; Normal control N=211 (Kim et al. [2004a] (Korean)), N=208 (Pae et al. [2003] (Korean)), N=252 (Kim et al. [2000] (Korean))
Predominant Ethnicity	Mongoloid
Population	Korea
Gender	110 probands were boys (87.3%) and 16 probands were girls (12.7%)
Age Group	Children/Adolescents : mean age: 8.3 (SD=1.8) years

Detail Info

Summary	In this study, they examined the genotypes of two polymorphisms, 5-HTTLPR and the intron 2 VNTR, in 126 Korean ADHD families and investigated linkage disequilibrium (LD) between SLC6A4 and ADHD, using the transmission disequilibrium test (TDT) and haplotype analysis. Additionally, association with quantitative measures of inattention, hyperactivity-impulsivity, and overall severity was tested using logistic regression and QTDT analysis. TDT of both polymorphisms and haplotype analysis failed to detect LD. However, after excluding ADHD NOS subtype, TDT revealed nominally significant LD between 5- HTTLPR and ADHD. QTDT revealed positive association between 12 repeats of the intron 2 VNTR and attention, but case-control and TDT logistic regression analyses were negative. These markers have low heterozygosity in the Korean population, which would be expected to reduce the power of association.
Total Sample	One hundred twenty-six children with ADHD were ascertained by K-SADS-PL-K. Among 126 families, 19 trios did not have complete genotyping, because one or two of family members did not complete blood collection (1 family with missing proband, 15 families with 1 missing parent, 3 families with 2 missing parents). Three trios were incompatible for the 5- HTTLPR and one trio for the intron 2 VNTR. Dropping these trios from further analysis resulted in 104 completed trios for the 5-HTTLPR and 106 trios for the intron 2 VNTR. Normal control N=211 (Kim et al. [2004a] (Korean)), N=208 (Pae et al. [2003] (Korean)), N=252 (Kim et al. [2000] (Korean))
Sample Collection	Consecutive subjects consenting to participate in a family-based association study for ADHD, and their biological parents, were studied between September 2000 and August 2002 at four, university-based, child psychiatry outpatient clinics (Seoul, Anyang, and Jinju) in South Korea.
Diagnosis Description	The included children met DSM-IV diagnostic criteria on the Diagnostic Interview Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime-Korean Version (K-SADS-PL-K). The ADHD subtypes included inattentive type 27.8% (n=35), hyperactive-impulsive type 7.9% (n=10), combined type 28.6% (n=36), and NOS 35.7% (n=45).
Technique	DNA was extracted from whole blood using the PureGene DNA isolation procedure. PCR for 5-HTTLPR was carried out in a 10 ul volume containing 50 ng of genomic template, 0.5 uM of each primer, 200 uM of each dNTP, 1X PCR buffer, 1.5 mM MgCl₂, and 0.3 U of DyNAzyme^TM EXT DNA polymerase, with 0.5MGC-melt. For the intron 2 VNTR, 0.25 U of HotStar Taq DNA polymerase was used instead of DyNAzyme^TM EXT DNA polymerase and 0.5 M GC-melt. Primer sequences were as follows: For 5-HTTLPR, 5'-FAM-CTGAATGCCAGCACCTAACCCCTAATGT- 3' and 5'-GGGGAATACTGGTAGGGTGCAAGGAGAA- 3'. For the intron 2 VNTR, primer sequences were 5'-HEX-TGGATTTCCTTCTCTCAGTGATTGG-3' and 5'- TCATGTTCCTAGTCTTACGCCAGTG-3'. Post PCR products were injected and detected by laser-induced fluorescence on an ABI PRISM 3700 Genetic Analyzer at the University of Chicago DNA Sequencing and Genotyping Core. Electropherograms were processed and alleles called with Genotyper software.
Analysis Method	Sib_tdt test was used for TDT, and TDTPHASE was used for the haplotype analysis. The odds ratio (OR) was calculated using the method of Lohmueller et al. [2003]. They assumed hypothetical control group that is very large population (10,000) with equal numbers of each allele (to reflect the expected 50:50 transmission ratio). For the quantitative analysis, symptom severity was computed from each ADHD item in K-SADS-PL-K. The quantitative traits were the independent variables and the dependent variable was either the genotype an individual carried (case-control) or the allele that was transmitted from a heterozygous parent (TDT). Additionally, quantitative transmission disequilibrium test (QTDT) was performed to examine the association between the genotypes and the ADHD subscale severity scores.
Result Description	TDT of both polymorphisms and haplotype analysis failed to detect LD. However, after excluding ADHD NOS subtype, TDT revealed nominally significant LD between 5-HTTLPR and ADHD (X²=4.9, P=0.036). QTDT revealed positive association between 12 repeats of the intron 2 VNTR and attention (P=0.031), but case-control and TDT logistic regression analyses were negative.

Other variant reported by this study (count: 2)

Variant Name	Allele Change	Risk Allele	Statistical Values	Author Comments	Result of Statistical Analysis
SLC6A4 intron2 VNTR			allelic TDT P-value=0.72 for ADHD pooled together, TDT P-val...... allelic TDT P-value=0.72 for ADHD pooled together, TDT P-value=0.2 for ADHD without ADHD NOS subtype; compared to the previous reports from Korean populations [Kim et al., 2000, 2004a; Pae et al.,2003], Intron 2 VNTR allele frequencies: X²=0.001, df=1, P-value=0.97; Intron 2 VNTR allele frequencies: X²=0.64, df=2, P-value=0.73 among ADHD subtype groups excluding ADHD NOS subtype More...	no significant association was detected in the family-based study and no significant difference compared to the previous study	Non-significant
5HTTLPR	short/long		allelic TDT P-value=0.11 for ADHD pooled together, TDT P-val...... allelic TDT P-value=0.11 for ADHD pooled together, TDT P-value=0.036 for ADHD without ADHD NOS subtype; 5-HTTLPR allele frequencies: X²=2.60, df=1, P-value=0.11 compared to the previous reports [Kim et al., 2000, 2004a; Pae et al.,2003]; 5-HTTLPR allele frequencies: X²=2.70, df=2, P-value=0.60 among ADHD subtype groups excluding ADHD NOS subtype More...	TDT revealed nominally significant LD between 5-HTTLPR and ADHD; the frequencies of the alleles and genotypes did not differ significantly compared to the previous reports	Significant

Genes reported by this study (count: 1)