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浙江大学学报（农业与生命科学版）
浙江大学学报（农业与生命科学版）
数量遗传与生物信息     
全基因组关联研究和条件分析揭示非加性效应和族系互作对冠心病的重要性(英文)
丁艺，朱军
浙江大学生物信息学研究所，杭州310058
Genome- wide association study and conditional analysis reveal the importance #br# of non-additive effects and ethnicity interaction for coronary heart disease
DING Yi, ZHU Jun
(Institute of Bioinformatics, Zhejiang University, Hangzhou 310058, China)
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摘要： 冠心病(coronary heart disease，CHD) 是一个复杂的遗传疾病，其发病率也受生活方式的影响,如吸烟和人体活动。全基因组关联研究已经检测到多个风险基因与冠心病相关联。然而报道的遗传变异仅占表现型变异的一小部分。生活方式对冠心病的影响机制仍然不清。本研究通过引入非加性效应的遗传分析，揭示非加性遗传的重要性，并用条件分析的方法研究了不同生活方式对种族人群遗传变异的影响。使用多族群研究动脉粥样硬化(Multi-Ethnic Study of Atherosclerosis，MESA)的数据，应用混合线性模型分析单核苷酸多态性(single nucleotide polymorphisms，SNPs) 变异与冠心病的关联。采用包括加性、显性、上位性及族群互作的遗传模型，研究了冠心病的复杂遗传体系。采用6种不同行为(步行，阅读、运输、运动、电视、吸烟)作为条件分析的协变量，探索了人类行为对冠心病的遗传影响。为实现个性化治疗的精准诊断，预测了人类不同行为对基因位点的特异遗传效应。总共检测到61个数量性状位点(quantitative trait SNPs，QTSs) 和23 对上位性位点，与表现型变异存在显著的相关性。采用不同模型估算的遗传率达64.58%～74.94%。我们观察到加性效应贡献只占总遗传率的一小部分(3.45%～5.72%)。相比之下，非加性效应占总遗传率的主要部分。基于不同生活方式的条件分析揭示，不同生活方式对冠心病遗传结构会产 生较大影响。4个族群基于7个不同模型的遗传分析揭示，不同种群的冠心病具有显著的遗传特异性。
关键词： 冠心病;  条件关联分析;  生活方式;  个体化医疗    
Abstract: Coronary heart disease (CHD) is a complex genetic etiology, and its incidence is also affected by life styles such as smoke and physical activities. Genome-wide association studies have identified multiple risk loci associated with CHD. However, genetic risk variants reported to date account for only a small fraction of heritability. Besides, the mechanism of how life styles affect CHD progression still remains vague. In this study, we aimed to explore the missing heritability via introducing non-additive effects into genetic analysis model and to investigate the impacts of life styles on genetic architectures among different ethnic populations. Mixed linear model (MLM) was conducted to identify causal single nucleotide polymorphisms (SNPs) associated with CHD using data from the Multi-Ethnic Study of Atherosclerosis (MESA) study. Saturated model including genetic effects of additive, dominance, epistasis and gene-ethnicity interaction was adopted to fit the complex genetic architecture of CHD. Each of the six life styles (walk, read, transportation, exercises, TV, and smoke) was set as a cofactor to explore the change of genetic architecture after removing their influences. To facilitate personalized medicine, we also predicted genotypic effects for each locus. There were 61 quantitative trait SNPs (QTSs) and 23 pairs of epistasis detected significantly (P＜ 0.05). The heritability explained from 64.58% to 74.94% across different models. We observed that additive effects (including both general and ethnicspecific additive effects) contributed only a small portion of heritability, ranging from 3.45% to 5.72%. In contrast, non-additive effects dominated large part of total heritability. Genetic effects attributed to life styles were analyzed by conditional analysis. The conditional analysis demonstrated that life styles exhibited significant impacts on the genetic architecture. In the meanwhile four ethnic groups exhibited notably distinctive genetic patterns under seven models, indicating genetic heterogeneity for CHD among four races.
Key words: coronary heart disease    conditional GWAS    life styles    personalized medicine
出版日期: 2017-01-25
CLC:  Q 811.4  
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丁艺，朱军. 全基因组关联研究和条件分析揭示非加性效应和族系互作对冠心病的重要性(英文)[J]. 浙江大学学报（农业与生命科学版）, 10.3785/j.issn.1008-9209.2016.12.301.

DING Yi, ZHU Jun. Genome- wide association study and conditional analysis reveal the importance #br# of non-additive effects and ethnicity interaction for coronary heart disease. Journal of Zhejiang University (Agriculture and Life Sciences), 10.3785/j.issn.1008-9209.2016.12.301.

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http://www.zjujournals.com/agr/CN/10.3785/j.issn.1008-9209.2016.12.301    或    http://www.zjujournals.com/agr/CN/Y2017/V43/I1/1

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