Overlap in the Genetic Architecture of Stroke Risk, Early Neurological Changes, and Cardiovascular Risk Factors

Abstract

Background and Purpose: The genetic relationships between stroke risk, stroke severity, and early neurological changes are complex and not completely understood. Genetic studies have identified 32 all stroke risk loci. Polygenic Risk Scores (PRS) can be used to compare the genetic architecture of related traits. In this study, we compare the genetic architecture of stroke risk, stroke severity, and early neurological changes with that of two stroke risk factors: Type 2 Diabetes Mellitus (T2DM) and Hypertension (HTN). Methods: We assessed the degree of overlap in the genetic architecture of stroke risk, T2DM, HTN, and two acute stroke phenotypes based on the NIH Stroke Scale (NIHSS), which ranges from 0 for no stroke symptoms to 21-42 for a severe stroke: baseline (within 6h after onset) and change in NIHSS (ΔNIHSS=NIHSS at baseline minus NIHSS at 24h). This was done by: 1) SNP by SNP comparison, 2) weighted PRS with sentinel variants and 3) whole genome PRS using multiple p-values thresholds. Results: We found evidence of genetic architecture overlap between stroke risk and T2DM (p=2.53×10 −169), HTN (p=3.93×10 −04) and baseline NIHSS (p=0.03). However, there was no evidence of overlap between ΔNIHSS and stroke risk, T2DM or HTN.

Genomic and multi-tissue proteomic integration for understanding the biology of disease and other complex traits

“…In plasma, we replicated the known pleiotropy of the ABO locus for seven different proteins including E-Selectin ( Fig. 2f, Extended Fig.6b, Table S11), which was implicated in stroke risk by recent studies using Mendelian Randomization approaches 22 . Further studies are needed to establish how these, and other genetic variants are associated with more than one protein.…”

Genomic and multi-tissue proteomic integration for understanding the biology of disease and other complex traits

“…In plasma, we replicated the known pleiotropy of the ABO locus for seven different proteins including E-Selectin ( Fig. 2f, Extended Fig.5b, Table S12), which was implicated in stroke risk by recent studies using Mendelian Randomization approaches 23 . Further studies are needed to establish how these, and other genetic variants are associated with more than one protein.…”

“…These findings also highlight the power of pQTL to help in determining the causal gene in a multi-loci genomic region associated with disease risk. E-Selectin protein is a known stroke biomarker 23 , and our MR analyses indicate that this protein is not only a biomarker but also is part of the cascade of pathogenic events that leads to disease (Table S28). Some proteins were inferred to be functional across more than one neurodegenerative disease within each tissue (Table S28) Our study and those like it are not only useful for identifying pQTL that will help to resolve GWAS locus, but also for identifying novel biomarkers and causal pathways using MR analyses.…”

Identification of Susceptibility Loci for Cardiovascular Disease in Adults With Hypertension, Diabetes and Dyslipidemia 

“…[29] Interestingly, CARD14 and SLC26A11 in the region of 17q25.3 were located within 400 kb of the lead SNP for CCD in DM (17q25.3/RPTOR rs139293840) as well. HTN and DM share common risk factors and frequently co-occur; [30] additionally, CVD is the most common long-term complication of both. [6] The overlapping association of SNPs and genetic loci between HTN and DM support the existence of shared points of regulation for these phenotypes.…”

“…[6] The overlapping association of SNPs and genetic loci between HTN and DM support the existence of shared points of regulation for these phenotypes. [30] RPTOR, RNF213, CARD14, and SLC26A11 all bear the potential to be the mechanism behind DM-CCD risk loci 17q25.3 [RPTOR]. RNF213 plays important roles in vascular development, and mutant RNF213 has been shown to reduce angiogenesis and induce endothelial dysfunction.…”