Association analysis of rs4906902 with heroin dependence.

<p>Association analysis of rs4906902 with heroin dependence.</p

Predicted changes of transcription factor binding sites of 3 SNPs identified in this study.

<p>Predicted changes of transcription factor binding sites of 3 SNPs identified in this study.</p

Association Analysis of <i>GABRB3</i> Promoter Variants with Heroin Dependence

<div><p><i>GABRB3</i> encoding the β3 subunit of GABAA receptor has been implicated in multiple neuropsychiatric disorders, including substance abuse. Previous studies reported that SNPs at the 5′ regulatory region of <i>GABRB3</i> could regulate <i>GABRB3</i> gene expression and associated with childhood absence epilepsy (CAE). The study aimed to investigate whether SNPs at the 5′ regulatory region of <i>GABRB3</i> were associated with heroin dependence in our population. We first re-sequenced 1.5 kb of the 5′regulatory region of <i>GABRB3</i> gene to examine the SNP profile in the genomic DNA of 365 control subjects. Then, we conducted a case-control association analysis between 576 subjects with heroin dependence (549 males, 27 females) and 886 controls (472 males, 414 females) by genotyping the rs4906902 as a tag SNP. We also conducted a reporter gene assay to assess the promoter activity of two major haplotypes derived from SNPs at this region. We detected 3 common SNPs (rs4906902, rs8179184 and rs20317) at this region that had strong pair-wise linkage disequilibrium. The C allele of rs4906902 was found to be associated with increased risk of heroin dependence (odds ratio:1.27, p = 0.002). Two major haplotypes (C-A-G and T-G-C) derived from these 3 SNPs accounted for 99% of this sample, and reporter gene activity assay showed that haplotype C-A-G that contained the C allele of the tag SNP rs4906902 had higher activity than haplotype T-G-C. Our data suggest that <i>GABRB3</i> might be associated with heroin dependence, and increased expression of <i>GABRB3</i> might contribute to the pathogenesis of heroin dependence.</p></div

The genotype and allele frequency of three SNPs identified in 386 control subjects in his study.

<p>The genotype and allele frequency of three SNPs identified in 386 control subjects in his study.</p

A representative genotyping results of rs4906902 using RFLP.

<p>After digestion with AseI, the T allele yielded 262 and 427(689 bp); M indicates DNA marker 100 bp ladder.</p

Stop signal performance.

<p>Abbreviations: RT: reaction time; SSRT: stop signal reaction time; PES: post-error slowing.</p>†<p><i>P</i><.05 between HC and OD-combined groups (post-hoc Tukey tests).</p>#<p><i>P</i><.05 between MMT and OD-combined groups (post-hoc Tukey tests).</p>‡<p><i>P</i><.05 between MMT vs. OD-long, MMT vs. OD-short, and OD-long vs. OD-short subgroups (post-hoc Tukey tests).</p

Graphical summary of genome-wide association analysis for TRS in a Han Chinese population.

<p><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0033598#s2" target="_blank">Results</a> (−log₁₀<i>P</i>) are shown in chromosomal order for 694,436 SNPs which were tested in 522 cases and 806 controls by using Affymetrix SNP 6.0 Array. The horizontal line indicates a <i>P</i>-value of 10⁻⁵.</p

Refined regional association plots.

<p>For each plot of the four clusters ((A) <i>SLAMF1</i>, (B) <i>NFKB1</i>, (C) <i>DOCK4</i>, and (D) <i>RIPK4</i>), the −log₁₀<i>P</i> values for the trend test from Affymetrix SNP 6.0 Array in 522 cases and 806 controls are plotted as red diamond according to their genomic position (NCBI Build 36.3). The SNPs with the strongest signal are represented as blue diamonds. The recombination rates (right y-axis) based on the Chinese HapMap population is plotted as green lines to reflect the local LD structure around the SNPs. The dashed horizontal line indicates a <i>P</i>-value of 10⁻⁵.</p

Results of GWAS for TRS in Han population.

<p>SNP position were indexed to the forward of NCBI Build 36.3.</p><p>ch: chromosome.</p><p>RA: Risk allele, the allele with higher frequency in schizophrenia as compared with controls;</p><p>RAF: risk allele frequency.</p><p>F: frequency.</p><p><i>P</i>_trend: P values obtained from the initial GWA analysis on 522 cases and 806 controls.</p><p><i>P</i>_joint: P values calculated from joint analysis on 804 cases and 806 controls.</p><p>OR, odds ratio for risk allele.</p

Variants identified in NFKB1 by direct sequencing in 94 TRS cases and controls.

<p>Risk allele means the allele with higher frequency in schizophrenia as compared with controls;</p><p>RAF: risk allele frequency.</p><p>P: promoter, I : intron.</p