Multi-trait genome-wide association analyses leveraging alcohol use disorder findings identify novel loci for smoking behaviors in the Million Veteran Program.
Multi-trait genome-wide association analyses leveraging alcohol use disorder findings identify novel loci for smoking behaviors in the Million Veteran Program.
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DOI：
10.1038/s41398-023-02409-2
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发表时间：
2023-05-05
影响因子：
6.8
通讯作者：
Xu, Ke
中科院分区：
文献类型：
--
作者：
Cheng, Youshu;Dao, Cecilia;Zhou, Hang;Li, Boyang;Kember, Rachel L.;Toikumo, Sylvanus;Zhao, Hongyu;Gelernter, Joel;Kranzler, Henry R.;Justice, Amy C.;Xu, Ke
吸烟行为和酒精使用障碍(AUD)都是适度遗传的特征，通常在普通人群中共同发生。单性状全基因组关联研究已经确定了吸烟和AUD的多个基因座。然而，旨在确定导致吸烟和AUD共同发生的基因的GWAS使用了小样本，因此没有提供很高的信息。应用GWASs的多性状分析(MTAG)，我们利用百万退伍军人计划(N = 318,694)的数据进行了吸烟和AUD的联合GWAS。通过利用GWASAUD的汇总统计数据，MTAG确定了21个与吸烟开始相关的全基因组显著(GWS)基因座和17个与戒烟相关的基因座，而单性状GWAs分别确定了16个和8个基因座。MTAG发现的新的吸烟行为基因包括那些以前与精神或药物使用特征相关的基因。共定位分析确定了AUD和吸烟状态性状共有的10个基因座，所有这些基因座都在MTAG中实现了GWS，包括Six3、NCAM1和Near DRD2上的变体。MTAG变异体的功能注释突出了ZBTB20、DRD2、PPP6C和GCKR上与吸烟行为有关的重要生物学区域。相比之下，吸烟行为和饮酒(AC)的MTAG与吸烟行为的单一性状GWAs相比并没有促进发现。我们的结论是，使用MTAG来增强GWAs的能力，能够识别常见共生表型的新的遗传变异，为研究它们对吸烟行为和AUD的多效性影响提供了新的见解。
Smoking behaviors and alcohol use disorder (AUD), both moderately heritable traits, commonly co-occur in the general population. Single-trait genome-wide association studies (GWAS) have identified multiple loci for smoking and AUD. However, GWASs that have aimed to identify loci contributing to co-occurring smoking and AUD have used small samples and thus have not been highly informative. Applying multi-trait analysis of GWASs (MTAG), we conducted a joint GWAS of smoking and AUD with data from the Million Veteran Program (N = 318,694). By leveraging GWAS summary statistics for AUD, MTAG identified 21 genome-wide significant (GWS) loci associated with smoking initiation and 17 loci associated with smoking cessation compared to 16 and 8 loci, respectively, identified by single-trait GWAS. The novel loci for smoking behaviors identified by MTAG included those previously associated with psychiatric or substance use traits. Colocalization analysis identified 10 loci shared by AUD and smoking status traits, all of which achieved GWS in MTAG, including variants on SIX3, NCAM1, and near DRD2. Functional annotation of the MTAG variants highlighted biologically important regions on ZBTB20, DRD2, PPP6C, and GCKR that contribute to smoking behaviors. In contrast, MTAG of smoking behaviors and alcohol consumption (AC) did not enhance discovery compared with single-trait GWAS for smoking behaviors. We conclude that using MTAG to augment the power of GWAS enables the identification of novel genetic variants for commonly co-occuring phenotypes, providing new insights into their pleiotropic effects on smoking behavior and AUD.
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来自1,092个人基因组的遗传变异的综合图。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
30.8
作者：
Das, Sayantan;Forer, Lukas;Schoenherr, Sebastian;Sidore, Carlo;Locke, Adam E.;Kwong, Alan;Vrieze, Scott I.;Chew, Emily Y.;Levy, Shawn;McGue, Matt;Schlessinger, David;Stambolian, Dwight;Loh, Po-Ru;Iacono, William G.;Swaroop, Anand;Scott, Laura J.;Cucca, Francesco;Kronenberg, Florian;Boehnke, Michael;Abecasis, Goncalo R.;Fuchsberger, Christian
通讯作者：
Fuchsberger, Christian
影响因子：
30.8
作者：
Bulik-Sullivan, Brendan K.;Loh, Po-Ru;Finucane, Hilary K.;Ripke, Stephan;Yang, Jian;Patterson, Nick;Daly, Mark J.;Price, Alkes L.;Neale, Benjamin M.
通讯作者：
Neale, Benjamin M.
影响因子：
16.6
作者：
Kranzler, Henry R.;Zhou, Hang;Gelernter, Joel
通讯作者：
Gelernter, Joel
影响因子：
158.5
作者：
CARMELLI, D;SWAN, GE;FABSITZ, R
通讯作者：
FABSITZ, R