rs2506030 is a Single Nucleotide Polymorphism in gene RET. Its ancestral/non-risk allele is A and derived allele G. RET (ret proto-oncogene) is a cadherin family member and encodes a receptor tyrosine kinases. Functionally, it is involved in neural crest development. Its located on the plus strand at 10q11.2 of the human genome spanning over 50K bp. There are 21 exons in the gene and 2 isoforms. Other than Hirschsprung disease, mutations in this gene is also associated with Multiple Endocrine Neoplasia And Medullary Thyroid Carcinoma.
Hirschsprung disease (HSCR) or congenital aganglionosis is a developmental defect characterized by the absence of neuronal ganglia in the myenteric and submucosal plexuses. Patients can be classified into 3 sub categories based on the length of the colon: short segment, long segment, or total colonic aganglionosis (TCA). The incidence is roughly 15/100,000 in population of European descent and twice as high for Asians. HSCR is a non-Mendelian disease. Mutations in a few genes have been identified to be associated with HSCR: RET, GDNF, NRTN, SOX10, EDNRB, EDN3, ECE1, ZEB2, PHOX2B, KIAA1279, TCF4, and L1CAM.
rs2506030 was first identified by Charkravartis group in a family-based GWAS study published in 2015. A total of 220 European American trios with short-segment HSCR were recruited and their DNA genotyped using Affymetrix platform, resulting in 500,000 SNPs. Association was tested using case pseudo-control and rs2506030 is statistically significantly different in the two groups (p value 2.78*10^-15). Furthermore, the statistical significance was confirmed in a replication study of 429 more HSCR trios of all segment lengths (p value 2.02*10^-4, combined p value 4.44*10-15, odds ratio = 2.0). Note that rs2506030 is independent of another common RET SNP rs2435357, which is common in HSCR patients based on previous studies. They hypothesize that rs2506030 affects a RET enhancer. [PMID 25839327]
Another study by the same group further studied rs2506030 in HSCR patients. This study includes a population case control comparison as well as family based association testing. Comparing the allele frequencies in cases and controls, there was a significant difference between allele frequencies in rs2506030 (p value 4.7*10^-10). Similarly, there is significant statistical evidence (p value = 5.3*10^9) of higher frequency of risk allele homozygotes in cases. OR was estimated to be 1.8. In addition, TDT was performed in 254 trios and 72 duos and the risk allele is over transmitted to probands (p = 9.5*10^-6). [PMID 25666438]
[PMID 25839327] Functional loss of semaphorin 3C and/or semaphorin 3D and their epistatic interaction with ret are critical to Hirschsprung disease liability.
[PMID 25666438] Population variation in total genetic risk of Hirschsprung disease from common RET, SEMA3 and NRG1 susceptibility polymorphisms.