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

GRP Investigators, Rees, E., Han, J., Morgan, J., Carrera, N., Escott-Price, V., Pocklington, A. J., Duffield, M., Hall, L. S., Legge, S. E., Pardinas, A. F., Richards, A. L., Roth, J., Lezheiko, T., Kondratyev, N., Kaleda, V., Golimbet, V., Parellada, M., Gonzalez-Penas, J. & Arango, C., Feb-2020, In : Nature neuroscience. 23, 2, p. 179-184 11 p.

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

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  • GRP Investigators
  • Elliott Rees
  • Jun Han
  • Joanne Morgan
  • Noa Carrera
  • Valentina Escott-Price
  • Andrew J. Pocklington
  • Madeleine Duffield
  • Lynsey S. Hall
  • Sophie E. Legge
  • Antonio F. Pardinas
  • Alexander L. Richards
  • Julian Roth
  • Tatyana Lezheiko
  • Nikolay Kondratyev
  • Vasilii Kaleda
  • Vera Golimbet
  • Mara Parellada
  • Javier Gonzalez-Penas
  • Celso Arango

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.

Original languageEnglish
Pages (from-to)179-184
Number of pages11
JournalNature neuroscience
Issue number2
Publication statusPublished - Feb-2020



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