The Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, NY, USA.
Dr. Miriam and Sheldon G. Adelson Clinic for Drug Abuse Treatment and Research, Las Vegas, NV, USA.
Transl Psychiatry. 2021 May 25;11(1):316. doi: 10.1038/s41398-021-01439-y.
Several OPRD1 intronic variants were associated with opioid addiction (OD) in a population-specific manner. This follow-up study aims to further characterize the OPRD1 haplotype pattern of the risk variants in different populations and apply in silico analysis to identify potential causal variants. A population-specific haplotype pattern was revealed based on six OPRD1 eQTL SNPs and five common haplotypes were identified in a sample of European ancestry (CEU). A European-specific haplotype ('Hap 3') that includes SNPs previously associated with OD and is tagged by SNP rs2236861 is more common in subjects with OD. It is quite common (10%) in CEU but is absent in the African sample (YRI) and extends upstream of OPRD1. SNP rs2236857 is most probably a non-causal variant in LD with the causal SNP/s in a population-specific manner. The study provides an explanation for the lack of association in African Americans, despite its high frequency in this population. OD samples homozygous for 'Hap 3' were reanalyzed using a denser coverage of the region and revealed at least 25 potentially regulatory SNPs in high LD. Notably, GTEx data indicate that some of the SNPs are eQTLs for the upstream phosphatase and actin regulator 4 (PHACTR4), in the cortex, and others are eQTLs for OPRD1 and the upstream lncRNA ENSG00000270605, in the cerebellum. The study highlights the limitation of single SNP analysis and the sensitivity of association studies of OPRD1 to a genetic background. It proposes a long-range functional connection between OPRD1 and PHACTR4. PHACTR4, a mediator of cytoskeletal dynamics, may contribute to drug addiction by modulating synaptic plasticity.
几种 OPRD1 内含子变体以特定于人群的方式与阿片类药物成瘾（OD）相关。本后续研究旨在进一步描述不同人群中风险变体的 OPRD1 单倍型模式，并应用计算机分析来识别潜在的因果变体。基于六个 OPRD1 eQTL SNPs 和五个常见单倍型，在欧洲血统（CEU）样本中揭示了一种特定于人群的单倍型模式。一种欧洲特有的单倍型（“Hap 3”）包含先前与 OD 相关的 SNP，并且由 SNP rs2236861 标记，在 OD 患者中更为常见。它在 CEU 中很常见（10%），但在非洲样本（YRI）中不存在，并且延伸到 OPRD1 的上游。SNP rs2236857 很可能是一种非因果变体，以特定于人群的方式与因果 SNP 处于 LD 状态。该研究解释了为什么非洲裔美国人缺乏关联，尽管它在该人群中的频率很高。使用该区域更密集的覆盖范围重新分析 OD 样本的“Hap 3”纯合子，并揭示了至少 25 个潜在的高度连锁的调节 SNP。值得注意的是，GTEx 数据表明，一些 SNP 是皮质中磷酸酶和肌动蛋白调节因子 4（PHACTR4）的 eQTL，而其他 SNP 是小脑中 OPRD1 和上游长链非编码 RNA ENSG00000270605 的 eQTL。该研究强调了单 SNP 分析的局限性和 OPRD1 关联研究对遗传背景的敏感性。它提出了 OPRD1 和 PHACTR4 之间的长程功能连接。PHACTR4 是细胞骨架动力学的调节剂，可能通过调节突触可塑性而导致药物成瘾。
