Published on Sun May 09 2021

Whole exome sequencing in the UK Biobank reveals risk gene SLC2A1 and biological insights for major depressive disorder

Tian, R., Ge, T., Liu, J. Z., Lam, M., Biogen Biobank team, , Levey, D. F., Gelernter, J., Stein, M. B., Tsai, E. A., Huang, H., Lencz, T., Runz, H., Chen, C.-Y.

Exome analysis of depression based on 320,356 UK Biobank participants. SLC2A1, a blood-brain barrier glucose transporter underlying GLUT1 deficiency syndrome, reached exome-wide significance. The burden of rare disruptive coding variants for depression overlapped with that of developmental disorder

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Abstract

Nearly two hundred common-variant depression risk loci have been identified by genome-wide association studies (GWAS)1-4. However, the impact of rare coding variants on depression remains poorly understood. Here, we present the largest to date exome analysis of depression based on 320,356 UK Biobank participants. We show that the burden of rare disruptive coding variants in loss-of-function intolerant genes is significantly associated with depression risk. Among 30 genes with false discovery rate (FDR) <0.1, SLC2A1, a blood-brain barrier glucose transporter underlying GLUT1 deficiency syndrome5-7, reached exome-wide significance (P=2.96e-7). Gene-set enrichment supports neuron projection development and muscle activities2, 3 as implicated in depression. Integrating exomes with polygenic risk revealed additive contributions from common and rare variants to depression risk. The burden of rare disruptive coding variants for depression overlapped with that of developmental disorder, autism and schizophrenia. Our study provides novel insight into the contribution of rare coding variants on depression and genetic relationships across developmental and psychiatric disorders.