SNP rs7549881, near SGIP1 at 1p31.3, is significantly associated with digestive disorders and Parkinsonism in women

BackgroundA recent study identified a mutation in the SH3GL Interacting Endocytic Adaptor 1 (SGIP1) gene, located at 1p31.3, linked to early-onset Parkinsonism in 2 sisters in an Arab family with a history of young-onset Parkinson symptoms. SGIP1 had not been previously associated with Parkinsonism, a group of disorders including Parkinsons disease (PD), characterized by motor dysfunction and cognitive decline. SGIP1 plays a role in endocytosis, particularly clathrin-mediated synaptic vesicle recycling, essential for synaptic proteostasis. In a fruit fly model, SGIP1 deletion resulted in synaptic dysfunction, impaired protein recycling, and brain cell degeneration, which mirrors Parkinsonism. We aimed to explore the genetic association of SGIP1 in Parkinsons disease using data from the UK Biobank, specifically examining the nearby common intron variant rs7549881 at 1p31.3. MethodsThis study utilized data from the UK Biobank, a large biomedical database with genetic and health information from approximately 500,000 participants. We analyzed the association between rs7549881 and PD. The study included all participants with self-reported or ICD-diagnosed PD and restricted analysis to those with at least seven years of education. Genetic association analysis was performed using PLINK and SPSS, with logistic regression adjusting for covariates such as age, sex, and smoking. Additionally, a Phenome-Wide Association Study (PheWAS) was conducted to examine rs7549881 across a wide range of phenotypes. ResultsThe study analyzed data from 385,629 subjects, with PD patients having a mean age of 63 {+/-} 5 years. Among females, 26% of those homozygous for the rs7549881 GG allele had PD, compared to 22.2% who did not have PD (p = 0.004). This effect was not significant in males. Logistic regression revealed that male sex (OR 1.828, p < 0.001), age (OR 1.141 per year, p < 0.001), and constipation (OR 4.726, p = 0.001) increased PD risk, while cigarette smoking decreased it (OR 0.748, p < 0.001). The GG genotype was associated with increased PD risk when compared to the AA phenotype (OR 1.208, p = 0.015). PheWAS identified significant associations of rs7549881 with digestive disorders, including functional digestive disorders and non-infectious gastroenteritis. ConclusionThe study demonstrated an association between the rs7549881 variant and PD in females, highlighting the potential role of SGIP1 in neurodegeneration. Additionally, the PheWAS findings link this variant to gastrointestinal disorders, supporting the emerging concept of a gut-brain axis in PD. The results suggest that SGIP1 may influence both neuronal and gastrointestinal functions, providing a new avenue for understanding the genetic mechanisms underlying Parkinsons disease and its non-motor symptoms.