文献类型： 外文期刊
作者： Cai, Xiaodian 1 ; Teng, Jinyan 1 ; Ren, Duanyang 1 ; Zhang, Hao 1 ; Li, Jiaqi 1 ; Zhang, Zhe 1 ;
作者机构： 1.South China Agr Univ, Coll Anim Sci, Guangdong Prov Key Lab Agroanim Genom & Mol Breed, Guangzhou 510642, Peoples R China
关键词： heritability enrichment; genetic architecture; LD; livestock; complex trait
期刊名称：GENES （ 影响因子：4.141； 五年影响因子：4.474 ）
ISSN：
年卷期： 2022 年 13 卷 9 期
页码：
收录情况： SCI
摘要： Heritability enrichment analysis is an important means of exploring the genetic architecture of complex traits in human genetics. Heritability enrichment is typically defined as the proportion of an SNP subset explained heritability, divided by the proportion of SNPs. Heritability enrichment enables better study of underlying complex traits, such as functional variant/gene subsets, biological networks and metabolic pathways detected through integrating explosively increased omics data. This would be beneficial for genomic prediction of disease risk in humans and genetic values estimation of important economical traits in livestock and plant species. However, in livestock, factors affecting the heritability enrichment estimation of complex traits have not been examined. Previous studies on humans reported that the frequencies, effect sizes, and levels of linkage disequilibrium (LD) of underlying causal variants (CVs) would affect the heritability enrichment estimation. Therefore, the distribution of heritability across the genome should be fully considered to obtain the unbiased estimation of heritability enrichment. To explore the performance of different heritability enrichment models in livestock populations, we used the VanRaden, GCTA and alpha models, assuming different alpha values, and the LDAK model, considering LD weight. We simulated three types of phenotypes, with CVs from various minor allele frequency (MAF) ranges: genome-wide (0.005 <= MAF <= 0.5), common (0.05 <= MAF <= 0.5), and uncommon (0.01 <= MAF < 0.05). The performances of the models with two different subsets (one of which contained known CVs and the other consisting of randomly selected markers) were compared to verify the accuracy of heritability enrichment estimation of functional variant sets. Our results showed that models with known CV subsets provided more robust enrichment estimation. Models with different alpha values tended to provide stable and accurate estimates for common and genome-wide CVs (relative deviation 0.5-2.2%), while tending to underestimate the enrichment of uncommon CVs. As the alpha value increased, enrichments from 15.73% higher than true value (i.e., 3.00) to 48.93% lower than true value for uncommon CVs were observed. In addition, the long-range LD windows (e.g., 5000 kb) led to large bias of the enrichment estimations for both common and uncommon CVs. Overall, heritability enrichment estimations were sensitive for the alpha value assumption and LD weight consideration of different models. Accuracy would be greatly improved by using a suitable model. This study would be helpful in understanding the genetic architecture of complex traits and provides a reference for genetic analysis in the livestock population.
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