User:Euclides Mendonca/sandbox

= Expression-based Polygenic Score - ePRS = Not to be confused with European Parliamentary Research Service or the EPRS gene.

An Expression-based Polygenic Score (ePRS) is an approach to genomic profiling informed by biological function. It characterizes gene networks based on the levels of co-expression with a determined gene in a specific tissue, thus the relevant biological unit of influence is a gene network, and not a single gene like candidate gene studies.

ePRS x PRS
Genome-wide association studies (GWAS) of epidemiological data allowed large scale analyses of common markers for specific disorders and different traits. The use of methods of genomic risk profiling is consistent with the idea that the genetic contribution to a certain condition is derived from a combination of small effects from many genetic variants. To take into account the effects of many SNP s, the concept of polygenic risk score (PRS) was introduced. PRS summarizes an individual's genetic risk for a specific condition. A polygenic risk score is calculated for each subject in the target sample as a sum of the risk alleles count, weighted by the effect size described in a discovery GWAS. Dr. Patricia Silveira, Dr Michael Meaney and Dr Kieran O’Donell from McGill University argue that one problem of the GWAS and consequentially the PRS technology is that it identifies statistically significant associations between scattered SNPs and a certain condition or trait, not acknowledging the fact that genes operate in networks and code for precise biological functions in specific tissues. The ePRS approach circumvents this limitation by integrating information from molecular neurobiology with GWAS technology to develop a biologically-informed polygenic score based on gene co-expression data usually from specific brain regions.

ePRS Calculation
In an ePRS, a set of genetic markers (SNPs) is genotyped, than the genes co-expressed with a gene of interest, or a set of genes identified using WGCNA, in animal tissue are selected – at the co-expression selection, an absolute value of the co-expression correlation r ≥ |0.5| is considered. BrainSpan is used to find their homologous human genes, and identify SNPs for these genes in humans (NCBI Variation Viewer). Other round of SNP selection is performed considering the equivalent autosomal transcripts differentially expressed in the tissue of interest at ≥ 1.5 fold during fetal and early infant development as compared to adults. Linkage disequilibrium clumping removes highly correlated SNPs (r2 > 0.2) across 500 kb regions, with aim of maintain independent functional SNPs. At the final step, a count function is used to determine the number of alleles at a given SNP weighted by the slope coefficient from a regression model predicting gene expression by SNPs, and each weighted SNP is summed to obtain an individual ePRS score.

ePRS Applicability
Recently ePRS methodology have been associated with a variety of research questions. The insulin receptor ePRS considering mesocorticolimbic and hippocampal brain tissue was predictive of impulsivity, risk for addiction, cognitive performance and presence of Alzheimer's disease. The ePRS methodology have also contributed to studies of GxE interactions. For example, the ePRS of the serotonin transporter solute carrier family C6, member 4 (SLC6A4) gene interacts with prenatal environment adversity predicting a broad range of neurodevelopmental outcomes. Also the prefrontal cortex dopamine transporter gene ePRS moderated the effect of perinatal hypoxic-ischemic conditions on cognitive flexibility and brain gray matter density of children in two ethnically distinct cohorts.

Criticism
One of the limitations of the ePRS is the use of GTEX as method of co-expression gene selection. GTex data is based on a Caucasian sample of which is thus not representative of human genetic diversity.

Another limitation is that the ePRS does not consider intron regions of the DNA. These regions, although do not encode protein products, are integral to gene expression regulation.