THE DISTRIBUTION OF AMINO ACID CHANGES FROM CODING VARIANTS IS ALTERED IN SCHIZOPHRENIA

Background Schizophrenia is a highly heritable polygenic disorder with a neurodevelopmental component. Despite the recent success of genome-wide association studies in identifying common risk loci, as well as the discovery of a role for rare and coding variants in disease risk, together, these variants explain only a portion of heritability. Here, we investigate the hypothesis that coding variants disproportionately affect specific amino acid changes in schizophrenia. In particular, we hypothesize that schizophrenia patients have an increased burden of coding variants that result in a higher need for specific essential amino acids, i.e., amino acids that can only be obtained from food intake. Methods In a case-control cohort of 5,090 Swedish samples (2,546 cases and 2,544 controls) for which whole exome sequencing data are publically available, we tested this hypothesis by comparing case/control distributions of the number of coding variants for each possible amino acid change. Results Interestingly, we observe two significant amino acid changes affected by common variants that survive correction for multiple testing: threonine → proline (TP: mean(sd)=69.2 (7.0) in controls, 68.3(7.0) in cases, P=2.44 ×10-5) and threonine → lysine (TK: 26.7(3.4) in controls, 26.3(3.4) in cases, P=1.20×10-4). This result is not driven by outliers in the cohort. Both changes were observed less frequently in cases than controls. We do not observe significant changes in overall common coding variants, variants altering essential versus non-essential amino acids, or rare variants. The genes that harbor these common coding variants are relatively tolerant to variation and ubiquitously expressed. Moreover, preliminary gene set analysis highlight a glycosylation cluster as the most enriched cluster for both TP and TK changes (Enrichment score z=6.8, P=2.1 ×10-10 for TP, and z=2.3, P=1.2 ×10-3 for TK using DAVID 6.8 with standard settings). Interestingly, glycans (the carbohydrate that attaches to proteins during glycosylation) do attach to threonine, but not to proline and lysine. Discussion Threonine is an essential amino acid, and the decreased number of variants away from threonine, as observed in schizophrenia cases, results in a higher need for its intake. Threonine is transformed to glycine, which works in the brain to reduce unwanted muscle contractions and has been used for treatment of ALS and multiple sclerosis. Recent evidence suggests that it also has antipsychotic effects. Given the hypothesized neurodevelopmental component of schizophrenia, it is noteworthy that reduced maternal supply of threonine during development has been linked to limited fetal protein accretion and fetal growth. Our results highlight an imbalance in amino-acid coding variants in schizophrenia patients, resulting in a potential increased need for threonine (and glycine). While preliminary in nature, these findings could potentially lead to a better understanding of disease etiology and inform treatment plans. However, these results need to be replicated in an independent cohort, and further scrutiny and additional analyses are needed to determine the biological significance of our findings: we are currently performing these follow up analyses.