美国人群尼古丁依赖的全基因组关联研究：非裔美国人和欧裔美国人中新型风险位点的鉴定
Genome-wide association study of nicotine dependence in American populations: identification of novel risk loci in both African-Americans and European-Americans.
作者信息
Gelernter Joel, Kranzler Henry R, Sherva Richard, Almasy Laura, Herman Aryeh I, Koesterer Ryan, Zhao Hongyu, Farrer Lindsay A
机构信息
Department of Psychiatry, Division of Human Genetics, Yale University School of Medicine, New Haven; Departments of Genetics and Neurobiology, Veterans Affairs Connecticut Healthcare Center, West Haven, Connecticut.
Department of Psychiatry, Center for Studies of Addiction, University of Pennsylvania Perelman School of Medicine, and Veterans Integrated Service Network 4 Mental Illness Research, Educational, and. Clinical Center, Philadelphia Veterans Affairs Medical Center, Philadelphia, Pennsylvania.
出版信息
Biol Psychiatry. 2015 Mar 1;77(5):493-503. doi: 10.1016/j.biopsych.2014.08.025. Epub 2014 Sep 16.
BACKGROUND
We report a genome-wide association study (GWAS) of nicotine dependence defined on the basis of scores on the Fagerström Test for Nicotine Dependence in European-American (EA) and African-American (AA) populations.
METHODS
Our sample, from the one used in our previous GWAS, included only subjects who had smoked >100 cigarettes lifetime (2114 EA and 2602 AA subjects) and an additional 927 AA and 2003 EA subjects from the Study of Addiction: Genetics and Environment project [via the database of Genotypes and Phenotypes (dbGAP)]. GWAS analysis considered Fagerström Test for Nicotine Dependence score as an ordinal trait, separately in each population and sample and by combining the results in meta-analysis. We also conducted analyses that were adjusted for other substance use disorder criteria in a single nucleotide polymorphism (SNP) subset.
RESULTS
In EAs, one chromosome 7 intergenic region was genome-wide significant (GWS): rs13225753, p = 3.48 × 10(-8) (adjusted). In AAs, GWS associations were observed at numerous SNPs mapped to a region on chromosome 14 of >305,000 base pairs (minimal p = 4.74 × 10(-10)). Two chromosome 8 regions were associated: p = 4.45 × 10(-8) at DLC1 SNP rs289519 (unadjusted) and p = 1.10 × 10(-9) at rs6996964 (adjusted for other substances), located between CSGALNACT1 and INTS10. No GWS associations were observed at the chromosome 15 nicotinic receptor gene cluster (CHRNA5-CHRNA3-CHRNB4) previously associated with nicotine dependence and smoking quantity traits. TSNAX-DISC1 SNP rs821722 (p = 1.46 × 10(-7)) was the most significant result with substantial contributions from both populations; we previously identified DISC1 associations with opioid dependence. Pathway analysis identified association with nitric oxide synthase and adenosine monophosphate-activated protein kinase pathways in EAs.
CONCLUSIONS
The key risk loci identified, which require replication, offer novel insights into nicotine dependence biology.
背景
我们报告了一项基于欧美（EA）和非裔美国人（AA）人群中尼古丁依赖的Fagerström测试得分所定义的全基因组关联研究（GWAS）。
方法
我们的样本取自之前GWAS研究中的样本，仅纳入了终生吸烟超过100支的受试者（2114名EA受试者和2602名AA受试者），以及来自成瘾：遗传学与环境研究项目（通过基因型和表型数据库（dbGAP））的另外927名AA受试者和2003名EA受试者。GWAS分析将Fagerström尼古丁依赖测试得分视为一个有序性状，在每个群体和样本中分别进行分析，并通过荟萃分析合并结果。我们还在一个单核苷酸多态性（SNP）子集中进行了针对其他物质使用障碍标准进行调整的分析。
结果
在EA人群中，一个7号染色体基因间区域达到全基因组显著水平（GWS）：rs13225753，p = 3.48 × 10⁻⁸（调整后）。在AA人群中，在映射到14号染色体上一个超过305,000碱基对区域的众多SNP处观察到GWS关联（最小p = 4.74 × 10⁻¹⁰）。两个8号染色体区域存在关联：DLC1 SNP rs289519处p = 4.45 × 10⁻⁸（未调整），以及位于CSGALNACT1和INTS10之间的rs6996964处p = 1.10 × 10⁻⁹（针对其他物质进行调整）。在先前与尼古丁依赖和吸烟量性状相关的15号染色体烟碱受体基因簇（CHRNA5 - CHRNA3 - CHRNB4）处未观察到GWS关联。TSNAX - DISC1 SNP rs821722（p = 1.46 × 10⁻⁷）是最显著的结果，两个群体都有显著贡献；我们之前已确定DISC1与阿片类药物依赖有关联。通路分析在EA人群中确定了与一氧化氮合酶和腺苷单磷酸激活的蛋白激酶通路的关联。
结论
所确定的关键风险位点需要进行重复验证，它们为尼古丁依赖生物学提供了新的见解。
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