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Am J Med Genet B Neuropsychiatr Genet. 2017 Apr;174(3):261-268. doi: 10.1002/ajmg.b.32507. Epub 2016 Oct 20.

Sex-specific linkage scans in opioid dependence.

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Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.
VA CT Healthcare Center, West Haven, Connecticut.
Department of Psychiatry, University of Iowa, Iowa City, Iowa.
Department of Psychiatry, University of Pennsylvania Perelman School of Medicine and VISN 4 MIRECC, Crescenz VAMC, Philadelphia, Pennsylvania.
Department of Psychiatry, University of California San Diego, La Jolla, California.
Departments of Genetics and Neuroscience, Yale University School of Medicine, New Haven, Connecticut.


Sex influences risk for opioid dependence (OD). We hypothesized that sex might interact with genetic loci that influence the risk for OD. Therefore we performed an analysis to identify sex-specific genomic susceptibility regions for OD using linkage. Over 6,000 single nucleotide polymorphism (SNP) markers were genotyped for 1,758 African- and European-American (AA and EA) individuals from 739 families, ascertained via affected sib-pairs with OD and/or cocaine dependence. Autosomewide non-parametric linkage scans, stratified by sex and population, were performed. We identified one significant linkage region, segregating with OD in EA men, at 71.1 cM on chromosome 4 (LOD = 3.29; point-wise P = 0.00005; empirical autosome-wide P = 0.042), which significantly differed from the linkage signal at the same location in EA women (empirical P = 0.002). Three suggestive linkage signals were identified at 181.3 cM on chromosome 7 (LOD = 2.18), 104 cM on chromosome 11 (LOD = 1.85), and 60.9 cM on chromosome 16 (LOD = 1.93) in EA women. In AA men, four suggestive linkage signals were detected at 201.1 cM on chromosome 3 (LOD = 2.32), 152.9 cM on chromosome 6 (LOD = 1.86), 16.8 cM on chromosome 7 (LOD = 1.95), and 36.1 cM on chromosome 17 (LOD = 1.99). The significant region, mapping to 4q12-4q13.1, harbors several OD candidate genes with interconnected functionality, including VEGFR, CLOCK, PDCL2, NMU, NRSF, and IGFBP7. In conclusion, these results provide an evidence for the existence of sex-specific and population-specific differences in OD. Furthermore, these results provide positional information that will facilitate the use of targeted next-generation sequencing to search for genes that contribute to sex-specific differences in OD.


4q12; 4q13.1; linkage analysis; opioid dependence; sex-specific

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