pleiotropy and genetic architecture

======

- [A global overview of pleiotropy and genetic architecture in complex traits](https://www.nature.com/articles/s41588-019-0481-0)
- Materials: /Users/zxli/Dropbox/Projects/CPloci/Materials
- Supplementary Note and Supplementary Figs. 1–12
- Supplementary Tables 1–26
- website: [https://atlas.ctglab.nl/](https://atlas.ctglab.nl/)

## Study design

pleiotropy loci in human genome

Characteristic of the loci

Genome-wide summary statistic data and UKBB

## Results

### Catalog of 4,155 GWAS summary statistics

Q：“3,555 sets of GWAS summary statistics from 294 studies”，什么是study，什么是GWAS set？为什么一个study有这么多sets？还有“In total, we collected 4,155 GWASs from 295 unique studies covering 2,965 unique traits (Supplementary Table 3)”。PMID：28240269这篇paper有1124个GWAS set，是啥意思？

A：一个paper是一个study。把paper ID放到Linux下计算一下，就会发现大部分都是一个，28240269有1124个是因为他们是pGWAS，一个蛋白就是一个trait。

Q：“by selecting nonbinary traits with >50,000 European individuals with nonmissing phenotypes, and binary traits for which the number of available cases and controls were both >10,000 and total sample size was >50,000”，为什么nonbinary traits对样本分布无要求？在binary traits中，cases and controls数量失衡会怎么样？我们是否要去掉在这方面做一下QC？

Q：打开“Supplementary Tables 1 and 2”，看看UKBB里面是些什么data？

A：UKB里都是很抽象的表型（UKB里既没有height 也没有BMI），如“Frequency of friend/family visits”，这些也被做了GWAS，算在他们的Pleiotropic genomic loci。

Q：“Traits were classified into 27 domains”，domains、chapter和subchapter的分类依据是什么？

Q：网站里的”phenome-wide plots“是什么？

Q：”resulting in 558 GWASs for 558 unique traits across 24 trait domains (479 GWASs based on UKB2, Supplementary Table 3).“ 最终大部分数据都是UKB2的。为什么设置这么严格的过滤标准，那么多数据都不用了？

### Extent of pleiotropy

Q：”Our definition thus refers to ‘statistical pleiotropy’, and includes situations of true pleiotropy (for example, one SNP directly influences multiple traits, or different causal variants are present for two traits, but these are in high linkage disequilibrium (LD)), and situations where **statistical associations to multiple traits are induced** via causal effects of one trait on another, via phenotypic correlations between traits or via a third common factor“，”statistical associations to multiple traits are induced“是什么意思，属于哪一种情况？

Q：”The level of pleiotropy was grouped into three categories: multidomain (associated with traits from multiple domains), domain specific (associated with multiple traits from a single domain) and trait specific (associated with a single trait; see Methods).“，”trait specific“是什么意思？trait是不最小单位吗？一个trait就没有pleiotropy了啊？

Q：locus和SNP有什么区别，这种排序结构是什么意思？这篇文章一开始就讨论Pleiotropic genomic loci，他们的Pleiotropic genomic loci是什么意思啊？不应该先讨论最小的单位Pleiotropic SNPs吗

#### Pleiotropic genomic loci

Q：”The 558 GWASs yielded 41,533 trait-associated loci (from 470 traits; 88 traits did not yield any genome-wide significant associations; see Methods).“，这里的”trait-associated loci“是啥，不就是SNP吗？

A：see ”Methods: Definition of lead SNPs and trait-associated loci“ and ”Supp: Fig. 3. Definition of grouped loci based on physical overlap and colocalization.“

Q：go into the method，因为用的数据不同我们和他们对初始loci的定义不一样。

#### Pleiotropic genes

#### Pleiotropic SNPs

#### Pleiotropic gene sets

#### Genetic correlations across traits

### Nature of trait-associated variants

#### Distribution of MAF and effect sizes of lead SNPs

#### Characterization of trait-associated loci and lead SNPs

#### Characterization of a credible set of SNPs based on fine mapping

### Nature of the genetic architecture of complex traits

#### SNP heritability

#### Polygenicity and discoverability of complex traits

参考：

1. [Beyond SNP heritability: Polygenicity and discoverability of phenotypes estimated with a univariate Gaussian mixture model](https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1008612) - 什么是Polygenicity and discoverability？
2. [Connecting genetic risk to disease end points through the human blood plasma proteome](http://metabolomics.helmholtz-muenchen.de/pgwas/index.php) - 另类GWAS，什么是pGWAS？
3. [Statistical Colocalization of Genetic Risk Variants for Related Autoimmune Diseases in the Context of Common Controls](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4754941/) - 什么是Colocalization？sharing the same causal SNP.