Department of Psychiatry and Human Behavior, Alpert Medical School, Brown University, Providence, Rhode Island.
Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, School of Public Health, Brown University, Providence, Rhode Island.
J Stud Alcohol Drugs. 2019 May;80(3):319-330. doi: 10.15288/jsad.2019.80.319.
The opioid epidemic in the United States has led to unprecedented increases in morbidity and mortality, posing a serious public health crisis. Although twin and family studies, as well as genome-wide association studies (GWAS), all identify significant genetic factors contributing to opioid dependence, no studies to date have estimated marker-based heritability estimates of opioid dependence. The goal of the current study was to use a large, genetically imputed, case/control sample of 4,064 participants (after quality control and imputation) with genome-wide data to estimate the unbiased heritability tagged by single nucleotide polymorphisms (SNPs).
Study data were part of the Genome-wide Study of Heroin Dependence obtained via the Database for Genotypes and Phenotypes (dbGaP). Genomic-Relatedness-Matrix Restricted Maximum Likelihood with adjustment for minor allele frequency (MAF) and linkage disequilibrium (LD; GREML-LDMS) was used to determine the variation in opioid dependence attributable to common SNPs from imputed data. Mixed linear models were used in an exploratory GWAS to assess effects of single SNPs.
At least 45% of the variance in opioid dependence according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, was attributable to common SNPs, after stratifying to account for differences in MAF and LD across the genome. Most of the genetic variance was tagged by SNPs in the 1%-9% MAF range and in low LD with other SNPs in the region. Two markers in LOC101927293 survived multiple-testing correction (i.e., q value < .05).
Nearly half of the variation in opioid dependence can be attributed to common SNPs. Most of this variation is due to rare variants in low LD with other markers in the region.
美国的阿片类药物流行导致发病率和死亡率空前上升，构成了严重的公共卫生危机。尽管双胞胎和家系研究以及全基因组关联研究（GWAS）都确定了对阿片类药物依赖有重大遗传因素，但迄今为止尚无研究估计阿片类药物依赖的基于标记的遗传率估计值。本研究的目的是利用具有全基因组数据的 4064 名参与者（经过质量控制和插补）的大型，遗传导入，病例/对照样本，估计由单核苷酸多态性（SNP）标记的无偏遗传率。
研究数据是通过基因型和表型数据库（dbGaP）获得的海洛因依赖全基因组研究的一部分。使用与最小等位基因频率（MAF）和连锁不平衡（LD）调整相关的基因组相关性矩阵限制最大似然法（GREML-LDMS），从导入数据中确定归因于常见 SNP 的阿片类药物依赖变化。混合线性模型用于探索性 GWAS 以评估单 SNP 的影响。
根据《精神障碍诊断与统计手册》第四版，至少有 45％的阿片类药物依赖变异归因于常见 SNP，在分层考虑到整个基因组中 MAF 和 LD 的差异后。遗传变异的大部分由 MAF 范围为 1％-9％且与该区域中其他 SNP 低度连锁的 SNP 标记。 LOC101927293 中的两个标记在多次测试校正后仍保留下来（即 q 值<0.05）。
阿片类药物依赖的近一半变异可以归因于常见 SNP。这种变异的大部分是由于该区域中其他标记低度连锁的罕见变异引起的。
