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Massively parallel reporter assays investigate shared genetic variants of eight psychiatric disorders

ABSTRACT: A meta-genome-wide association study encompassing eight psychiatric disorders has shed light on the genetic architecture of pleiotropy. However, mechanisms underlying pleiotropic effects of these variants remain to be investigated. We conducted a massively parallel reporter assay to decipher the regulatory logic of variants with disease-specific and pleiotropic effects. Pleiotropic variants differ from disease-specific variants by manifesting chromatin accessibility that extends across diverse cell types in the neuronal lineage, and altering motifs for transcription factors with higher connectivity in protein-protein interaction (PPI) networks. Next, we mapped pleiotropic and disease-specific variants to putative target genes, which may offer insights into potential mechanisms of pleiotropy. Compared with disease-specific genes, pleiotropic genes demonstrate associations with generic biological pathways, widespread temporal dynamics during neuronal lineage, and higher connectivity in PPI networks. Collectively, variants exert pleiotropic effects by regulating genes involved in global biological functions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE244011 | GEO | 2025/01/29

REPOSITORIES: GEO

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Project description:Pleiotropy is an important biological phenomenon with complicated genetic architectures for multiple traits. To date, pleiotropy was mainly identified by multi-trait GWAS, but GWAS method has its disadvantages, and new developments for pleiotropy detection methods are needed. Here we defined a novel metric, self-product, and based on it, we developed a transcriptome method to identify candidate pleiotropic genes and revealed the genetic architectures of immune and growth trait pairs in pigs. In statistics, the well-known covariance is used to quantify the co-variation between two variables. Suppose that X and Y represent two traits with individual records of xi and yi and corresponding means of μx and μy. We defined the individual-level product (xi − μx)(yi − μy) as self-product. Obviously, self-product is an individual-level measurement for the co-variation between two traits of the ith individual, and the covariance Cov(X , Y) is the mean of the self-product (xi − μx)(yi − μy). The self-product-based transcriptome method was tested using immune and growth trait pairs in pigs.We identify candidate pleiotropic genes using the Affymetrix Porcine Genechip. Result:Comparative transcriptome analyses identified dozens of candidate pleiotropic genes related to 8 trait pairs from two tails of self-product distribution. GO enrichment analysis indicated that most of identified pleiotropic genes were involved in both immune- and growth-related biological processes. We established pleiotropic genes interaction network to exhibit core genes shared by 8 trait pairs, of which CCL5 and IL-10 genes were hub genes. Genetic association analyses showed that SmaI-polymorphisms of CCL5 and IL-10 genes had significant associations with phenotypic co-variations of multiple trait pairs, indicating that the variants in pleiotropic genes were also pleiotropic variants. Conclusions:The validity of our proposed method was preliminarily verified, and our findings provide new insights into the genetic basis of pleiotropic architectures of immune and growth trait pairs in pigs.

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Massively parallel reporter assays investigate shared genetic variants of eight psychiatric disorders

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