A large-scale genome-wide association study meta-analysis of cannabis use disorder.
A large-scale genome-wide association study meta-analysis of cannabis use disorder.
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DOI：
10.1016/s2215-0366(20)30339-4
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发表时间：
2020-12
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影响因子：
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通讯作者：
Agrawal A
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Johnson EC;Demontis D;Thorgeirsson TE;Walters RK;Polimanti R;Hatoum AS;Sanchez-Roige S;Paul SE;Wendt FR;Clarke TK;Lai D;Reginsson GW;Zhou H;He J;Baranger DAA;Gudbjartsson DF;Wedow R;Adkins DE;Adkins AE;Alexander J;Bacanu SA;Bigdeli TB;Boden J;Brown SA;Bucholz KK;Bybjerg-Grauholm J;Corley RP;Degenhardt L;Dick DM;Domingue BW;Fox L;Goate AM;Gordon SD;Hack LM;Hancock DB;Hartz SM;Hickie IB;Hougaard DM;Krauter K;Lind PA;McClintick JN;McQueen MB;Meyers JL;Montgomery GW;Mors O;Mortensen PB;Nordentoft M;Pearson JF;Peterson RE;Reynolds MD;Rice JP;Runarsdottir V;Saccone NL;Sherva R;Silberg JL;Tarter RE;Tyrfingsson T;Wall TL;Webb BT;Werge T;Wetherill L;Wright MJ;Zellers S;Adams MJ;Bierut LJ;Boardman JD;Copeland WE;Farrer LA;Foroud TM;Gillespie NA;Grucza RA;Harris KM;Heath AC;Hesselbrock V;Hewitt JK;Hopfer CJ;Horwood J;Iacono WG;Johnson EO;Kendler KS;Kennedy MA;Kranzler HR;Madden PAF;Maes HH;Maher BS;Martin NG;McGue M;McIntosh AM;Medland SE;Nelson EC;Porjesz B;Riley BP;Stallings MC;Vanyukov MM;Vrieze S;Psychiatric Genomics Consortium Substance Use Disorders Workgroup;Davis LK;Bogdan R;Gelernter J;Edenberg HJ;Stefansson K;Børglum AD;Agrawal A
对大麻使用障碍的易感性的变化具有很强的遗传成分（估计双胞胎和家庭遗传率约为50-70%），并与负面结果相关，包括精神病理学风险增加。该研究的目的是进行一项大型全基因组关联研究（GWAS），以确定与大麻使用障碍相关的新型遗传变异。为了进行大麻使用障碍的GWAS荟萃分析并确定与遗传基因座的关联，我们使用了来自精神病基因组学联盟物质使用障碍工作组，iPSYCH和deCODE的样本（20916例病例样本，共363116例对照样本），将大麻使用障碍病例与对照进行对比。 为了检查大麻使用障碍和22个感兴趣的性状之间的遗传重叠（选择是因为先前发表的表型相关性[例如，精神疾病]或假设的大麻使用障碍相关性[例如，时间型]），我们使用连锁不平衡评分回归来计算遗传相关性。我们确定了两个全基因组显著的基因座：一个新的7号染色体基因座（FOXP 2，前导单核苷酸多态性[SNP] rs7783012;比值比[OR] 1·11，95% CI 1·07-1·15，p=1·84 × 10−9）和先前确定的8号染色体基因座（靠近CHRNA 2和EPHX 2，前导SNP rs 4732724; OR 0·89，95% CI 0·86-0·93，p=6·46 × 10−9）。 大麻使用障碍和大麻使用存在遗传相关性（rg 0·50，p=1·50 × 10−21），但它们与我们测试的22个性状中的12个性状表现出显著不同的遗传相关性，这表明大麻使用和大麻使用障碍的遗传基础至少部分不同。 大麻使用障碍与其他精神病理学呈正相关，包括ADHD，重度抑郁症和精神分裂症。这些发现支持了大麻使用障碍与其他精神病理学共享遗传责任的理论，并且大麻使用的遗传责任和大麻使用障碍之间存在区别。国家精神卫生研究所;国家酒精滥用和酒精中毒研究所;国家药物滥用研究所;基因组学和个性化医学中心和综合测序中心;欧洲联盟委员会，地平线2020;国家儿童健康和人类发展研究所;新西兰健康研究理事会;国家老龄问题研究所;惠康信托病例控制联合会;英国研究与创新医学研究理事会（UKRI MRC）;大脑和行为研究基金会;国家耳聋和其他交流障碍研究所;物质滥用和精神卫生服务管理局（SAMHSA）;国家生物医学成像和生物工程研究所;澳大利亚国家卫生和医学研究理事会（NHMRC）;加州大学烟草相关疾病研究计划;边缘型人格障碍家庭研究（Beth和Rob Elliott）2018年NARSAD青年研究者补助金;国家儿童健康研究基金会（治愈儿童）;坎特伯雷医学研究基金会;新西兰彩票赠款委员会;奥塔哥大学;卡尼药物基因组学中心;詹姆斯·休谟遗赠基金会;美国国立卫生研究院：基因、环境和健康倡议;美国国立卫生研究院;国家癌症研究所;威廉·T·格兰特基金会;澳大利亚研究理事会;弗吉尼亚烟草定居基金会;美国退伍军人事务部的VISN 1和VISN 4精神疾病研究、教育和临床中心;第五框架计划（FP-5）GenomEUtwin项目; Lundbeck基金会; NIH资助的共享仪器补助金S10 RR 025141;临床转化科学奖赠款;国家神经疾病和中风研究所;国家心脏，肺和血液研究所;国家普通医学科学研究所。
Variation in liability to cannabis use disorder has a strong genetic component (estimated twin and family heritability about 50–70%) and is associated with negative outcomes, including increased risk of psychopathology. The aim of the study was to conduct a large genome-wide association study (GWAS) to identify novel genetic variants associated with cannabis use disorder. To conduct this GWAS meta-analysis of cannabis use disorder and identify associations with genetic loci, we used samples from the Psychiatric Genomics Consortium Substance Use Disorders working group, iPSYCH, and deCODE (20 916 case samples, 363 116 control samples in total), contrasting cannabis use disorder cases with controls. To examine the genetic overlap between cannabis use disorder and 22 traits of interest (chosen because of previously published phenotypic correlations [eg, psychiatric disorders] or hypothesised associations [eg, chronotype] with cannabis use disorder), we used linkage disequilibrium score regression to calculate genetic correlations. We identified two genome-wide significant loci: a novel chromosome 7 locus (FOXP2, lead single-nucleotide polymorphism [SNP] rs7783012; odds ratio [OR] 1·11, 95% CI 1·07–1·15, p=1·84 × 10−9) and the previously identified chromosome 8 locus (near CHRNA2 and EPHX2, lead SNP rs4732724; OR 0·89, 95% CI 0·86–0·93, p=6·46 × 10−9). Cannabis use disorder and cannabis use were genetically correlated (rg 0·50, p=1·50 × 10−21), but they showed significantly different genetic correlations with 12 of the 22 traits we tested, suggesting at least partially different genetic underpinnings of cannabis use and cannabis use disorder. Cannabis use disorder was positively genetically correlated with other psychopathology, including ADHD, major depression, and schizophrenia. These findings support the theory that cannabis use disorder has shared genetic liability with other psychopathology, and there is a distinction between genetic liability to cannabis use and cannabis use disorder. National Institute of Mental Health; National Institute on Alcohol Abuse and Alcoholism; National Institute on Drug Abuse; Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing; The European Commission, Horizon 2020; National Institute of Child Health and Human Development; Health Research Council of New Zealand; National Institute on Aging; Wellcome Trust Case Control Consortium; UK Research and Innovation Medical Research Council (UKRI MRC); The Brain & Behavior Research Foundation; National Institute on Deafness and Other Communication Disorders; Substance Abuse and Mental Health Services Administration (SAMHSA); National Institute of Biomedical Imaging and Bioengineering; National Health and Medical Research Council (NHMRC) Australia; Tobacco-Related Disease Research Program of the University of California; Families for Borderline Personality Disorder Research (Beth and Rob Elliott) 2018 NARSAD Young Investigator Grant; The National Child Health Research Foundation (Cure Kids); The Canterbury Medical Research Foundation; The New Zealand Lottery Grants Board; The University of Otago; The Carney Centre for Pharmacogenomics; The James Hume Bequest Fund; National Institutes of Health: Genes, Environment and Health Initiative; National Institutes of Health; National Cancer Institute; The William T Grant Foundation; Australian Research Council; The Virginia Tobacco Settlement Foundation; The VISN 1 and VISN 4 Mental Illness Research, Education, and Clinical Centers of the US Department of Veterans Affairs; The 5th Framework Programme (FP-5) GenomEUtwin Project; The Lundbeck Foundation; NIH-funded Shared Instrumentation Grant S10RR025141; Clinical Translational Sciences Award grants; National Institute of Neurological Disorders and Stroke; National Heart, Lung, and Blood Institute; National Institute of General Medical Sciences.