基于家系研究设计的2型糖尿病发病遗传培育效应研究

Environmental factors and genetic factors all contribute to the accelerating type 2 diabetes epidemic in China. So far, large-scale GWAS study have identified more than 100 genes that confer susceptibility to type 2 diabetes. Nonetheless, only around 15% of the risk attributable to genetic factors has been identified. Recently promising low-frequency and rare genetic variants studies made little contribution to filling the “loss of heritability” in type 2 diabetes. Genetic nurture effect study takes the sequence variants that are not transmitted to a child into consideration. This gives rise to a situation in which a child’s phenotype is influenced not only by the transmitted paternal and maternal alleles but also by the alleles that were not transmitted. Briefly, genetic nurture is a form of indirect genetic effect, which exert their influence via family environmentally mediated channels. During the project of family-based cohort study on the common non-communicable chronic diseases of the populations in the rural area of northern China in 2013, our research team have collected baseline demographics, clinical characteristics and blood samples in 2016 type 2 diabetic families. Based the above work, in the proposed research project, we aim to examine the parents’ direct genetic effect and genetic nurture effect on their child with type 2 diabetes. Polygenetic score construction and logistic regression will be employed in the further analysis. In order to explore the biological mechanism of genetic nurture effect, we will select genes which have strong genetic nurture effect to perform DNA methylation and analysis in type 2 diabetic probands and their 1:1 matched healthy subjects. Our proposed research may partly untangle the “loss of heritability” in type 2 diabetes and its potential mechanism. Besides, it will also provide new study designs and methods for the etiological study of complex diseases.

2型糖尿病的发生与环境和遗传因素相关，全基因组关联研究已发现的基因位点仅能解释15%左右的遗传度，近年来兴起的罕见突变研究也未能填补2型糖尿病“缺失的遗传度”。遗传培育是父母传递和未传递给子代的基因对子代表型所产生的间接影响，也就是通过父母提供的环境，间接影响子代的表型。本课题将依托2013年启动的北方农村地区居民常见慢性非传染性疾病家系队列研究收集的2016个2型糖尿病家系调查资料和血样本，首先，采用核心家系的研究设计和多基因评分模型，探讨2型糖尿病发病相关基因父母对子代的直接效应和遗传培育效应及其共同作用，在此基础上，采用1:1匹配病例对照研究设计，选择遗传培育效应较强的基因进行甲基化检测，探讨遗传培育效应潜在的表观遗传学机制。通过本研究，将有可能解开2型糖尿病“缺失的遗传度”及其作用机制。同时，为其它复杂性疾病病因学研究提供新的思路和方法学参考。

2型糖尿病不同于单基因变异所致的孟德尔遗传病，其发病原因可归纳为三条主要途径：（1）环境因素的作用；（2）遗传因素的直接传递作用；（3）遗传培育效应。遗传培育是父母传递或未传递给子代的等位基因通过影响子代的生活环境所产生的与子代表型的间接关联。本研究取得6个方面的主要结果1）：研究发现未传递给子代rs16861194 位点G 等位基因和 rs780094 位点 G 等位基因会增加子代 2 型糖尿病患病风险；2）：父母亲对子代2型糖尿病的遗传培育效应存在差异，母亲的遗传培育效应-0.204，父亲的遗传培育效应为-0.032， 母亲与父亲的遗传培育效应之比为6.394。3）：遗传的直接效应与间接效应存在大小与方向差异。2型糖尿病相关基因的遗传培育效应 η=-0.236，可释方差 19.17%。直接效应=0.438，遗传培育效应与直接效应之比为-0.538，可释方差 5.56%。4）：基于多效性的视角，发现糖尿病和睡眠相关的表型之间存在广泛的共享遗传。其中2型糖尿病和睡眠表型之间效应最强的共享位点是FTO，多效性基因ENSA和PMPCA在2型糖尿病中存在差异表达。5）：研究纳入16种与2型糖尿病发病相关的行为表型及对应的2607个遗传位点，最终筛选出了31个密集相互作用的关键基因，其中4个经验证在2型糖尿病患者的血液样本中呈现表达上调模式，提示这些关键基因可能通过中介作用或多效作用影响2型糖尿病的发病。6)：基于数据驱动的SNP集分析方法探索2型糖尿病与冠心病共病模式的遗传结构，分析发现共病组与仅患有糖尿病组的遗传结构间存在共享基因HMP19 和MSX2以及共享的富集通路，提示不同的共病模式的遗传结构存在关联性。通过本研究，验证了遗传培育效应在2型糖尿病的发病过程中发挥重要的作用，2型糖尿病与其它慢性复杂性疾病之间存在着复杂的相互作用关系。