TY - JOUR
T1 - De novo mutations identified by exome sequencing implicate rare missense variants in SLC6A1 in schizophrenia
AU - Rees, Elliott
AU - Han, Jun
AU - Morgan, Joanne
AU - Carrera, Noa
AU - Escott-Price, Valentina
AU - Pocklington, Andrew J.
AU - Duffield, Madeleine
AU - Hall, Lynsey S.
AU - Legge, Sophie E.
AU - Pardiñas, Antonio F.
AU - Richards, Alexander L.
AU - Roth, Julian
AU - Lezheiko, Tatyana
AU - Kondratyev, Nikolay
AU - Kaleda, Vasilii
AU - Golimbet, Vera
AU - Parellada, Mara
AU - González-Peñas, Javier
AU - Arango, Celso
AU - Alizadeh, Behrooz Z.
AU - van Amelsvoort, Therese
AU - Bruggeman, Richard
AU - Cahn, Wiepke
AU - de Haan, Lieuwe
AU - Luykx, Jurjen J.
AU - Rutten, Bart P. F.
AU - van Os, Jim
AU - van Winkel, Ruud
AU - Gawlik, Micha
AU - Kirov, George
AU - Walters, James T. R.
AU - Holmans, Peter
AU - O’Donovan, Michael C.
AU - Owen, Michael J.
AU - GROUP investigators
AU - Alizadeh, Behrooz Z.
AU - van Amelsvoort, Therese
AU - Bruggeman, Richard
AU - Cahn, Wiepke
AU - de Haan, Lieuwe
AU - Luykx, Jurjen J.
AU - Rutten, Bart P. F.
AU - van Os, Jim
AU - van Winkel, Ruud
PY - 2020/2/1
Y1 - 2020/2/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85077979127&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41593-019-0565-2
DO - https://doi.org/10.1038/s41593-019-0565-2
M3 - Article
C2 - 31932766
SN - 1097-6256
VL - 23
SP - 179
EP - 184
JO - Nature neuroscience
JF - Nature neuroscience
IS - 2
ER -