De novo mutations identified by exome sequencing implicate rare missense variants in SLC6A1 in schizophrenia

• Published in: Nature neuroscience Vol. 23; no. 2; pp. 179 - 184
• Main Authors: Rees, Elliott, Han, Jun, Morgan, Joanne, Carrera, Noa, Escott-Price, Valentina, Pocklington, Andrew J., Duffield, Madeleine, Hall, Lynsey S., Legge, Sophie E., Pardiñas, Antonio F., Richards, Alexander L., Roth, Julian, Lezheiko, Tatyana, Kondratyev, Nikolay, Kaleda, Vasilii, Golimbet, Vera, Parellada, Mara, González-Peñas, Javier, Arango, Celso, Gawlik, Micha, Kirov, George, Walters, James T. R., Holmans, Peter, O’Donovan, Michael C., Owen, Michael J.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.02.2020; Nature Publishing Group
• Subjects: 45; 45/23; 631/208/205/2138; 631/208/514; 692/699/476/1799; Adult; Animal Genetics and Genomics; Behavioral Sciences; Biological evolution; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Bipolar disorder; Disorders; Exome Sequencing; Female; GABA Plasma Membrane Transport Proteins - genetics; Genes; Genetic aspects; Genetic Predisposition to Disease - genetics; Genomes; Health aspects; Humans; Identification and classification; Liability; Male; Mental disorders; Mutation; Mutation, Missense; Neurobiology; Neurodevelopmental disorders; Neurosciences; Risk analysis; Risk factors; Schizophrenia; Schizophrenia - genetics; Single nucleotide polymorphisms; γ-Aminobutyric acid; United States
• ISSN: 1097-6256; 1546-1726; 1546-1726
• DOI: 10.1038/s41593-019-0565-2

Schizophrenia is a highly polygenic disorder with important contributions from both common and rare risk alleles. We analyzed exome sequencing data for de novo variants (DNVs) in a new sample of 613 schizophrenia trios and combined this with published data to give a total of 3,444 trios. In this new data, loss-of-function (LoF) DNVs were significantly enriched among 3,471 LoF-intolerant genes, which supports previous findings. In the full dataset, genes associated with neurodevelopmental disorders ( n  = 159) were significantly enriched for LoF DNVs. Within these neurodevelopmental disorder genes, SLC6A1 , which encodes a γ-aminobutyric acid transporter, was associated with missense-damaging DNVs. In 1,122 trios for which genome-wide common variant data were available, schizophrenia and bipolar disorder polygenic risk were significantly overtransmitted to probands. Probands carrying LoF or deletion DNVs in LoF-intolerant or neurodevelopmental disorder genes had significantly less overtransmission of schizophrenia polygenic risk than did non-carriers, which provides a second robust line of evidence that these DNVs increase liability to schizophrenia. Rees et al. show that de novo mutations in the gene SLC6A1 , and more broadly across evolutionary constrained genes and genes implicated in neurodevelopmental disorders, increase the risk for developing schizophrenia.