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Whole genome sequence study of cannabis dependence in two independent cohorts

机译：全基因组序列研究大麻依赖于两个独立队列

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Abstract Recent advances in genome wide sequencing techniques and analytical methods allow for more comprehensive examinations of the genome than microarray‐based genome‐wide association studies (GWAS). The present report provides the first application of whole genome sequencing (WGS) to identify low frequency variants involved in cannabis dependence across two independent cohorts. The present study used low‐coverage whole genome sequence data to conduct set‐based association and enrichment analyses of low frequency variation in protein‐coding regions as well as regulatory regions in relation to cannabis dependence. Two cohorts were studied: a population‐based Native American tribal community consisting of 697 participants nested within large multi‐generational pedigrees and a family‐based sample of 1832 predominantly European ancestry participants largely nested within nuclear families. Participants in both samples were assessed for Diagnostic and Statistical Manual of Mental Disorders‐IV (DSM‐IV) lifetime cannabis dependence, with 168 and 241 participants receiving a positive diagnosis in each sample, respectively. Sequence kernel association tests identified one protein‐coding region, C1orf110 and one regulatory region in the MEF2B gene that achieved significance in a meta‐analysis of both samples. A regulatory region within the PCCB gene, a gene previously associated with schizophrenia, exhibited a suggestive association. Finally, a significant enrichment of regions within or near genes with multiple splice variants or involved in cell adhesion or potassium channel activity were associated with cannabis dependence. This initial study demonstrates the potential utility of low pass whole genome sequencing for identifying genetic variants involved in the etiology of cannabis use disorders.
机译：摘要基因组宽测序技术和分析方法的最新进展允许比微阵列的基因组 - 宽协会研究（GWAs）更全面的基因组检查。本报告提供了全基因组测序（WGS）的第一次应用，以识别在两个独立队列中涉及大麻依赖的低频变体。本研究使用低覆盖的全基因组序列数据来进行基于组的关联和富集蛋白质编码区的低频变化的富集分析以及与大麻依赖性相关的调节区域。研究了两名队列：一个基于人口的原生部族群岛，由697名与会者组成，嵌套在大型多世代章程中，一个基于家庭的7832年的样本，主要是欧洲祖先参与者在很大程度上嵌套在核心家庭中。评估两种样品中的参与者进行精神障碍-4- IV（DSM-IV）终身大麻依赖性的诊断和统计手册，分别在每个样品中接受阳性诊断的168和241名参与者。序列核关联试验鉴定了一个蛋白质编码区，C1orF110和一个调节区，其在MEF2B基因中达到了两种样品的META分析中的意义。 PCCB基因内的调节区是先前与精神分裂症相关的基因，表现出暗示协会。最后，在具有多种剪接变体或涉及细胞粘附或钾通道活性的基因内或附近的区域的显着富集与大麻依赖性有关。该初步研究表明，低通环形全基因组测序的潜在效用用于鉴定大麻使用障碍病因的遗传变异。

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