Rs35518360

rs35518360 is a SNP that has been found to be associated with Schizophrenia. Schizophrenia is a mental disorder and complex trait, with a lifetime risk of around 1%, characterized by abnormal behavior, false beliefs, confused thinking, auditory hallucinations, and lack of motivation. Besides environment, heritability studies of Schizophrenia have found a significant genetic component to the disease that has yet to be thoroughly understood. From a univariate heritability analysis researchers found that there heritability estimate (h^2) is approximately 0.23, however this number is significantly lower than an h^2 of 0.81 which was what estimated from twin/family studies [1].

Our SNP of interest was identified by the authors of a multi-stage Schizophrenia GWAS with 36,989 case and 113,075 control individuals from a multi-ethnic population, which consisted mostly of Europeans [www.nature.com/articles/nature13595]. The research team aggregated data from 5 mega studies in an attempt to increase their power to discover associated loci, and analyzed approximately 9 million SNPs (after imputation to 1KG). They found 108 conservatively defined independent loci meeting genome-wide significance.

The SNP rs35518360 is located on the 4th chromosome at the q arm on the 2nd region of the 4th band at base position 102225733 (using the GRCh38 reference assembly). The major allele is an A and the minor allele is a T, which has a minor allele frequency of 0.0274. The odds-ratio of the association to Schizophrenia was 0.857, and the p-value was 1.98e-15. According to the NHGRI GWAS catalog this variant is also significantly associated with blood pressure, body mass index, diastolic blood pressure, HDL cholesterol, and systolic blood pressure.

This loci is 25kb upstream of the gene SLC39A8 [2], which is a member of the SLC39 family of solute carrier genes. This gene has structural characteristics of zinc transporters and tends to be located in the plasma membrane and the mitochondrial membrane. Studies show that it functions as a zinc importer during periods of inflammation [3].

Drugs exist for treating schizophrenia however, they have low efficacy. Mechanistically, most of these drugs work by blocking the type 2 dopaminergic receptor, and no new mechanisms of treatment have been successfully translated into a therapeutic target. Using GWAS approaches to further understand schizophrenia disease architecture potentially leading to novel therapeutic targets would greatly help the approximately 24 million afflicted worldwide [4].