Korhonen Tellervo, Loukola Anu, Wedenoja Juho, Nyman Emma, Latvala Antti, Broms Ulla, Häppölä Anja, Paunio Tiina, Schrage Andrew J, Vink Jaqueline M, Mbarek Hamdi, Boomsma Dorret I, Penninx Brenda W J H, Pergadia Michele L, Madden Pamela A F, Kaprio Jaakko
Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland; Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki, Finland; Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.
Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland; Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki, Finland.
PLoS One. 2014 Jun 13;9(6):e98199. doi: 10.1371/journal.pone.0098199. eCollection 2014.
The aims of this study were to analyze associations of dopamine receptor genes (DRD1-5) with Major Depressive Disorder (MDD) and nicotine dependence (ND), and to investigate whether ND moderates genetic influences on MDD.
The sample was ascertained from the Finnish Twin Cohort. Twin pairs concordant for smoking history were recruited along with their family members, as part of the multisite Nicotine Addiction Genetics consortium. Genetic association analyses were based on 1428 adults. Total of 70 tagging single nucleotide polymorphisms within the dopamine receptor genes were genotyped and analyzed for association with MDD, ND, and MD-ND co-morbidity. Individual level logistic regression analyses were based on 1296 adults with data on ND and MDD diagnoses, as well as on dopamine receptor genotypes adjusted for sex, age, and alcohol use. Four independent samples, such as population-based and case-control samples, were used for replication.
Rs2399496, located 1.5 kb downstream of DRD3, showed suggestive association for MDD (p = 0.00076) and significant association for MDD-ND co-morbidity (p = 0.000079). Suggestive gene-(rs2399496) by-ND-interaction justified analyses by genetic risk variant and ND status. Individuals with ND and two minor alleles (AA) of rs2399496 had almost six-fold risk for MDD (OR 5.74, 95%CI 3.12-10.5, p = 9.010e-09) compared to individuals without ND and with two major alleles (TT).
Significant association between a variant downstream of DRD3 and a co-morbid MDD-ND phenotype was detected. Our results further suggest that nicotine dependence may potentiate the influence of the DRD3 genetic variant on MDD.
本研究旨在分析多巴胺受体基因（DRD1 - 5）与重度抑郁症（MDD）及尼古丁依赖（ND）之间的关联，并探讨ND是否会调节基因对MDD的影响。
样本来自芬兰双胞胎队列。作为多中心尼古丁成瘾遗传学联盟的一部分，招募了吸烟史一致的双胞胎对及其家庭成员。基因关联分析基于1428名成年人。对多巴胺受体基因内总共70个标签单核苷酸多态性进行基因分型，并分析其与MDD、ND及MDD - ND共病的关联。个体水平的逻辑回归分析基于1296名有ND和MDD诊断数据以及经性别、年龄和饮酒情况调整后的多巴胺受体基因型的成年人。使用四个独立样本，如基于人群的样本和病例对照样本进行重复验证。
位于DRD3下游1.5 kb处的Rs2399496与MDD显示出提示性关联（p = 0.00076），与MDD - ND共病显示出显著关联（p = 0.000079）。提示性的基因 -（rs2399496）- ND - 相互作用证明了按遗传风险变异和ND状态进行分析的合理性。与没有ND且有两个主要等位基因（TT）的个体相比，有ND且rs2399496的两个次要等位基因（AA）的个体患MDD的风险几乎高出六倍（OR 5.74，95%CI 3.12 - 10.5，p = 9.010e - 09）。
检测到DRD3下游的一个变异与共病的MDD - ND表型之间存在显著关联。我们的结果进一步表明，尼古丁依赖可能会增强DRD3基因变异对MDD的影响。
