Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
Neuropsychopharmacology. 2011 Nov;36(12):2422-30. doi: 10.1038/npp.2011.122. Epub 2011 Aug 17.
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.
可卡因依赖（CD）和重度抑郁发作（MDE）常同时发生，治疗效果较差，复发风险较高。共享的遗传风险已经得到证实；迄今为止，还没有全基因组连锁扫描（GWLS）报告调查合并 CD 和 MDE（CD-MDE）的易感区域。我们旨在鉴定非洲裔美国人（AA）和欧洲裔美国人（EA）中对 CD、MDE 和 CD-MDE 易感的染色体区域和候选基因。共有 1896 名个体来自 384 个 AA 和 355 个 EA 家族，每个家族至少有一个 CD 和/或阿片类药物依赖的兄弟姐妹对。对所有个体完成了大约 6000 个单核苷酸多态性的基于阵列的基因分型。对 CD-MDE 进行了参数和非参数全基因组连锁分析。我们发现，在 AA 中非参数分析 CD-MDE 的染色体 7 上有一个全基因组显著的连锁峰，在 183.4cM 处（对数优势（lod）=3.8，全基因组经验 p=0.016；逐点 p=0.00001）。在 EA 中，在染色体 5 上 14.3cM 处也发现了一个接近全基因组显著的 CD-MDE 连锁，在 2.95cM 处（对数优势（lod）=2.95，全基因组经验 p=0.055；逐点 p=0.00012）。参数分析证实了这两个区域的发现，并提高了对 5 号染色体峰的支持，使其达到全基因组显著水平（异质性 lod=3.28，全基因组经验 p=0.046；逐点 p=0.00053）。这是第一次对 CD-MDE 进行全基因组连锁分析。染色体 5 和 7 上的全基因组显著连锁区域包含四个特别有希望的候选基因：SRD5A1、UBE3C、PTPRN2 和 VIPR2。需要在其他人群中复制连锁发现，也需要对这里涉及的连锁区域中的基因进行集中分析。
