Independent Associated SNPs at SORCS3 and Its Protein Interactors for Multiple Brain-Related Disorders and Traits

Sortilin-related vacuolar protein sorting 10 (VPS10) domain containing receptor 3 (SORCS3) is a neuron-specific transmembrane protein involved in the trafficking of proteins between intracellular vesicles and the plasma membrane. Genetic variation at SORCS3 is associated with multiple neuropsychiatric disorders and behavioural phenotypes. Here, we undertake a systematic search of published genome-wide association studies to identify and catalogue associations between SORCS3 and brain-related disorders and traits. We also generate a SORCS3 gene-set based on protein-protein interactions and investigate the contribution of this gene-set to the heritability of these phenotypes and its overlap with synaptic biology. Analysis of association signals at SORSC3 showed individual SNPs to be associated with multiple neuropsychiatric and neurodevelopmental brain-related disorders and traits that have an impact on the experience of feeling, emotion or mood or cognitive function, while multiple LD-independent SNPs were associated with the same phenotypes. Across these SNPs, alleles associated with the more favourable outcomes for each phenotype (e.g., decreased risk of neuropsychiatric illness) were associated with increased expression of the SORCS3 gene. The SORCS3 gene-set was enriched for heritability contributing to schizophrenia (SCZ), bipolar disorder (BPD), intelligence (IQ) and education attainment (EA). Eleven genes from the SORCS3 gene-set were associated with more than one of these phenotypes at the genome-wide level, with RBFOX1 associated with SCZ, IQ and EA. Functional annotation revealed that the SORCS3 gene-set is enriched for multiple ontologies related to the structure and function of synapses. Overall, we find many independent association signals at SORCS3 with brain-related disorders and traits, with the effect possibly mediated by reduced gene expression, resulting in a negative impact on synaptic function.