[Show abstract][Hide abstract] ABSTRACT: Previously we reported the results of Wave One of a genome-wide search for heroin dependence susceptibility loci in Han Chinese families from Yunnan Province, China, near Asia's "Golden Triangle". Our initial analysis of 194 independent affected sibling-pairs from 192 families identified two regions with nonparametric linkage (NPL) Z-scores greater than 2.0, which were suggestive of linkage. Presently we have supplemented our sample with additional individuals and families, bringing the total number of genotyped individuals to 1513 and the number of independent sibling-pairs to 397. Upon repeating our analyses with this larger sample, we found that the evidence for linkage at our most strongly implicated locus from Wave One (marker D17S1880; 53.4cM on 17q11.2; NPL Z=2.36; uncorrected p=0.009) was completely abolished (Z=-1.13; p=0.900). In contrast, the evidence for linkage at the second-most strongly implicated locus from Wave One (D4S1644; 143.3cM on 4q31.21; NPL Z=2.19; uncorrected p=0.014) increased in its magnitude and significance (Z=2.64; uncorrected p=0.004), becoming the most strongly implicated locus overall in our full sample. Other loci on chromosomes 1, 2, 4, 12, 16, and X also displayed nominally significant evidence for linkage (p< or =0.05). These loci appear to be entirely distinct from opioid-linked loci reported by other groups; however, meta-analyses of all available linkage data may reveal common sites of interest and promising candidate genes that can be further evaluated as risk factors for the illness.
Full-text · Article · Jul 2008 · Drug and Alcohol Dependence
[Show abstract][Hide abstract] ABSTRACT: OPRM1, which codes for the mu-opioid receptor, is the most frequently studied candidate gene for opioid dependence. Despite numerous allelic association studies, no definitive conclusion has been reached regarding the role of OPRM1 polymorphisms in determining risk for opioid dependence. We attempted to resolve this by conducting a family-based association study and meta-analysis which may be more robust and powerful, respectively, than traditional case-control analyses. First, we genotyped three single nucleotide polymorphisms (SNPs) of OPRM1 in 1208 individuals from 473 Han Chinese families ascertained on the basis of having two or more siblings with DSM-IV-defined opioid dependence. The Val6Ala and Arg111His SNPs were detected, but with low minor allele frequencies (0.002 and 0.001, respectively). The Asn40Asp SNP was more informative (minor allele frequency: 0.419), but no significant evidence was observed for either a dominant (p=0.810) or additive (p=0.406) effect of this polymorphism on risk for opioid dependence. In addition, a meta-analysis of case-control studies of opioid dependence was performed, and found a similar lack of evidence for an association with the Asn40Asp SNP (p=0.859). Although a role of OPRM1 polymorphisms in determining risk for opioid dependence cannot be entirely discounted, a major contribution of the Asn40Asp polymorphism seems unlikely. Further analysis is warranted in samples from specific ancestral groups. In addition, it is critical that other OPRM1 variants, including all haplotype-tagging and amino-acid-coding SNPs, be tested for an influence on risk for opioid dependence, since the Asn40Asp polymorphism is only one of several hundred known mutations in the gene.
Full-text · Article · Nov 2007 · Drug and Alcohol Dependence
[Show abstract][Hide abstract] ABSTRACT: The contribution of genes to the etiology of heroin dependence is greater than for any other illicit drug. The specific genes mediating this effect remain unknown, despite several candidate gene association studies of the condition. Here we report the results of a genome-wide search for heroin dependence susceptibility loci using multipoint linkage analysis. In phase I, we ascertained 207 independent affected sibling pairs from 202 Han Chinese families from Yunnan Province, China (near Asia's "Golden Triangle"). After data-cleaning, 194 fully independent sibling pairs (i.e., with no overlapping individuals) from 192 families were genotyped on 404 short tandem-repeat markers spaced at an average inter-marker distance of 9 cM. Although none of our findings achieved genome-wide significance, we found two regions with non-parametric linkage (NPL) Z-scores greater than 2.0. An NPL Z-score of 2.19 (uncorrected P-value = 0.014) was observed at D4S1644, located at 143.3 cM on chromosomal region 4q31.21. The highest NPL Z-score of 2.36 (uncorrected P-value = 0.009) was observed at 53.4 cM on chromosomal region 17q11.2 at marker D17S1880. This is among the first published reports of a genome-wide linkage analysis of heroin dependence. Forthcoming results from other groups and from two additional waves of ascertainment (one planned, one currently ongoing) for our own study should be able to support or refute the putative susceptibility loci we have identified, after which positional candidate genes can be further evaluated as risk factors for the illness.
Full-text · Article · Sep 2006 · American Journal of Medical Genetics Part B Neuropsychiatric Genetics