[Identifying genetic etiology of ischemic stroke based on pleiotropy of obesity related genes: A sibling study].

Objective: To identify genetic etiology of ischemic stroke (IS) based on pleiotropy of obesity related genes.

Methods: A discordant sib-pair study was designed based on the Fangshan family cohort in Beijing. Body mass index (BMI) polygenic risk score (PRS) was first constructed under different P values. Using the polygenic transmission disequilibrium test (pTDT), we then compared the actual BMI genetic risk of siblings with IS to their expected risk, to analyze whether higher BMI was over-transmitted to siblings with IS. The single nucleotide polymorphism (SNP) that comprised the PRS over-transmitted with IS and that corresponded to the highest heritability of IS were identified as a pleiotropy SNPs set between BMI and IS. This set was then utilized as a candidate set to identify and verify risk SNPs asso-ciated IS by transmission disequilibrium test. Finally, we identified independent genomic risk loci and mapped to genes, we then explored the biological function of the identified risk loci and genes by functional annotation and pathway enrichment.

Results: A total of 541 participants were enrolled, with an average age of (58.4±8.1) years, including 326 discordant sib pairs of ischemic stroke. Compared with non-IS participants, IS participants with males, education level below junior high school, hypertension and hyperlipidemia accounted for a higher proportion (P < 0.05). For all the BMI PRS, we found that the actual genetic risk of BMI in siblings with IS was higher than their expectation, suggesting that genetic risk associated with high BMI was over-transmitted with IS. Compared with other SNP sets, the set (P < 5×10^-4) corresponded to the best analytical statistics of pTDT and the highest heritability of IS and was identified as the pleiotropy SNP set between BMI and IS. Within this set, there were 45 SNPs having linkage and association with IS, which were located in 43 independent genomic risk loci and mapped to 40 genes. These genes were significantly enriched in the lipid metabolism pathway. The rs2232852 corrected by multiple tests was mapped to CYB5R1 and ADIPOR1, which were related to lipid metabolism and the ferroptosis pathway.

Conclusion: Pleiotropy between BMI-related genes and IS was observed. Forty-five SNPs were found with linkage and association with IS in the pleiotropy gene set and mapped to 40 genes, which were functionally enriched in lipid metabolic pathways. The rs2232852 corrected by multiple tests during association analysis validation was mapped to CYB5R1 and ADIPOR1, which were related to lipid metabolism and the ferroptosis pathway, suggesting that lipid metabolism and ferroptosis played an important role in the development of IS.