variant变异 | Epigenome表观基因组 | Disease-susceptible gene 疾病易感基因

Posted 2021-11-26 leezx

Genotype-Tissue Expression Project (GTEx)

Roadmap Epigenomics Project

这个研究的思路是什么？鉴定出有功能调控作用的变异。

 

 

对于复杂性状，通常会由很多遗传因素来控制，从而影响到表型。GWAS鉴定出了很多SNP，但是却只能解释部分heritability。

怎么鉴定带有一定effect size的causal的变异来解释缺失的heritability是现在的研究热点。大白话就是现在的GWAS只关注 pvalue < 5x10^-8 的SNP，但这些SNP只能解释很小一部分的遗传性，现在普遍认为缺失的那部分就是pvalue略小的SNP中。

这些SNP大部分都坐落在非编码区，覆盖了大量的基因调控元件，说明这些causal SNPs是通过影响基因表达来影响表型的。

Identifying causal variants with moderate effect size underlying the missing heritability is currently one of the biggest challenges 

The majority of GWAS risk loci, as well as loci with subgenome-wide significance (P values between 1 × 10−5 and 5 × 10−8), localize to non-coding genomic regions with many gene regulatory signals [3], suggesting that most trait/disease causal SNPs exert their phenotypic effects by altering gene expression

另一个证据就是这些SNPs会富集在eQTL和开放染色质区域。

This is further supported by GWAS risk loci being enriched in genomic regions with many expression quantitative trait loci (eQTLs) and open chromatins

基因调控具有高度的tissues and celltypes特异性。