A genomewide linkage scan of cocaine dependence and major depressive episode in two populations

Abstract

Cocaine dependence (CD) and major depressive episode (MDE) frequently co-occur with poorer treatment outcome and higher relapse risk. Shared genetic risk was affirmed; to date, there have been no reports of genomewide linkage scans (GWLSs) surveying the susceptibility regions for comorbid CD and MDE (CD-MDE). We aimed to identify chromosomal regions and candidate genes susceptible to CD, MDE, and CD-MDE in African Americans (AAs) and European Americans (EAs). A total of 1896 individuals were recruited from 384 AA and 355 EA families, each with at least a sibling-pair with CD and/or opioid dependence. Array-based genotyping of about 6000 single-nucleotide polymorphisms was completed for all individuals. Parametric and non-parametric genomewide linkage analyses were performed. We found a genomewide-significant linkage peak on chromosome 7 at 183.4 cM for non-parametric analysis of CD-MDE in AAs (lod=3.8, genomewide empirical p=0.016; point-wise p=0.00001). A nearly genomewide significant linkage was identified for CD-MDE in EAs on chromosome 5 at 14.3 cM (logarithm of odds (lod)=2.95, genomewide empirical p=0.055; point-wise p=0.00012). Parametric analysis corroborated the findings in these two regions and improved the support for the peak on chromosome 5 so that it reached genomewide significance (heterogeneity lod=3.28, genomewide empirical p=0.046; point-wise p=0.00053). This is the first GWLS for CD-MDE. The genomewide significant linkage regions on chromosomes 5 and 7 harbor four particularly promising candidate genes: SRD5A1, UBE3C, PTPRN2, and VIPR2. Replication of the linkage findings in other populations is warranted, as is a focused analysis of the genes located in the linkage regions implicated here.

Figure 1

Lod scores on 22 autosomal chromosomes resulting from non-parametric linkage analyses including African-American families with cocaine dependence (CD), major depressive episode (MDE), and comorbid CD with MDE (CD–MDE). The dashed lines denote the thresholds of lod scores for the three phenotypes for genomewide-‘suggestive' linkage. (Some of these thresholds appear as one dashed line because they are very close).

Figure 2

Lod scores on 22 autosomal chromosomes resulting from non-parametric linkage analyses including European-American families with cocaine dependence (CD), major depressive episode (MDE), and comorbid CD and MDE (CD–MDE). The dashed lines denote the thresholds of lod scores for the three phenotypes for genomewide suggestive linkage. (Some of these thresholds appear as one dashed line because they are very close).

Figure 3

Hlod scores on chromosome 7 for African Americans and chromosome 5 for European Americans resulting from the parametric linkage analysis of all possible sibling pairs with cocaine dependence (CD), major depressive episode (MDE), and comorbid CD and MDE (CD–MDE). The dash lines denoted the thresholds of hlod scores for the three phenotypes for genomewide suggestive linkage. (Some of these thresholds appear as one dashed line because they are very close).