Loss-of-function variants in schizophrenia risk and SETD1A as a candidate susceptibility gene

Neuron
Atsushi TakataMaria Karayiorgou

Abstract

Loss-of-function (LOF) (i.e., nonsense, splice site, and frameshift) variants that lead to disruption of gene function are likely to contribute to the etiology of neuropsychiatric disorders. Here, we perform a systematic investigation of the role of both de novo and inherited LOF variants in schizophrenia using exome sequencing data from 231 case and 34 control trios. We identify two de novo LOF variants in the SETD1A gene, which encodes a subunit of histone methyltransferase, a finding unlikely to have occurred by chance, and provide evidence for a more general role of chromatin regulators in schizophrenia risk. Transmission pattern analyses reveal that LOF variants are more likely to be transmitted to affected individuals than controls. This is especially true for private LOF variants in genes intolerant to functional genetic variation. These findings highlight the contribution of LOF mutations to the genetic architecture of schizophrenia and provide important insights into disease pathogenesis.

References

Aug 15, 1995·Proceedings of the National Academy of Sciences of the United States of America·M KarayiorgouV K Lasseter
Mar 27, 2001·Nature Reviews. Genetics·J F Crow
Nov 1, 2001·Proceedings of the National Academy of Sciences of the United States of America·T MillerA Shilatifard
Mar 19, 2005·The EMBO Journal·Alisha Schlichter, Bradley R Cairns
Oct 18, 2005·Nature Cell Biology·Christopher WynderRamin Shiekhattar
Dec 17, 2005·The Journal of Biological Chemistry·Tanju G NacakJens Kroll
Aug 22, 2006·The Journal of Biological Chemistry·Pierre-Marie DehéVincent Géli
Oct 19, 2007·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Hsien-Sung HuangSchahram Akbarian
May 31, 2008·Nature Genetics·Bin XuMaria Karayiorgou
Mar 12, 2010·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Swati GuptaFarah D Lubin
Apr 1, 2010·Nature Methods·Ivan A AdzhubeiShamil R Sunyaev
May 4, 2010·Human Genetics·Giuseppe MerlaCarmela Fusco
Sep 17, 2010·Nature Reviews. Cancer·Man MohanAli Shilatifard
Oct 29, 2010·Genome Research·Cornelis A AlbersRichard Durbin
Jan 12, 2011·Nature Biotechnology·James T RobinsonJill P Mesirov
Apr 5, 2011·American Journal of Human Genetics·Qianqian ZhuDavid B Goldstein
Jul 12, 2011·Nature Genetics·Simon L GirardGuy A Rouleau
Aug 9, 2011·Nature Genetics·Bin XuMaria Karayiorgou
Nov 1, 2011·Annual Review of Medicine·Laura Rodriguez-MurilloMaria Karayiorgou
Dec 27, 2011·Neuron·Dheeraj MalhotraJonathan Sebat
Feb 22, 2012·Science·Daniel G MacArthurChris Tyler-Smith
Mar 20, 2012·Cell·Dheeraj Malhotra, Jonathan Sebat
May 1, 2012·Neuron·Ivan IossifovMichael Wigler
May 26, 2012·Nature Neuroscience·Maria KarayiorgouUNKNOWN Genetic and Neural Complexity in Psychiatry 2011 Working Group
Jul 19, 2012·Nature Reviews. Genetics·Joris A Veltman, Han G Brunner
Oct 5, 2012·The New England Journal of Medicine·Joep de LigtLisenka E L M Vissers
Jan 29, 2013·Neuron·Timothy W YuChristopher A Walsh
Apr 10, 2013·Nature Reviews. Genetics·Jehnna L RonanGerald R Crabtree
Aug 27, 2013·Nature Genetics·Stephan RipkePatrick F Sullivan
Aug 31, 2013·PLoS Genetics·Slavé PetrovskiDavid B Goldstein
Dec 18, 2013·Proceedings of the National Academy of Sciences of the United States of America·Iuliana Ionita-LazaMaria Karayiorgou

❮ Previous
Next ❯

Citations

Aug 20, 2014·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·Erica ShenSchahram Akbarian
Aug 13, 2015·Neuroscience·T KatoK Nakajima
Mar 30, 2016·Nature Neuroscience·Jonathan Flint
Oct 17, 2014·Psychiatry and Clinical Neurosciences·Tadafumi Kato
Aug 19, 2015·Frontiers in Psychiatry·Berit Kerner
Jun 17, 2015·Epigenomics·Christina N Vallianatos, Shigeki Iwase
May 23, 2015·Nature Reviews. Cancer·Rajesh C Rao, Yali Dou
Apr 8, 2015·PloS One·Erica Y ShenSchahram Akbarian
Aug 3, 2016·The British Journal of Psychiatry : the Journal of Mental Science·David Curtis
Nov 5, 2016·The Journal of Experimental Medicine·Zhenhua YangHao Jiang
Oct 21, 2016·American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics : the Official Publication of the International Society of Psychiatric Genetics·Laura WhittonDerek W Morris
Jul 1, 2017·International Journal of Molecular Sciences·Jeong-Hoon KimKyoung Sang Cho
Oct 10, 2015·The Neuroscientist : a Review Journal Bringing Neurobiology, Neurology and Psychiatry·Eric J NestlerSchahram Akbarian
Mar 21, 2017·Journal of Medical Genetics·Xiaoming LiuJiao Chen
Apr 15, 2018·NPJ Schizophrenia·Masaki NishiokaKazuya Iwamoto
Nov 11, 2017·The International Journal of Neuropsychopharmacology·Hiroki KimuraNorio Ozaki
Jun 21, 2018·Annals of Human Genetics·Leda Coelewij, David Curtis
Jan 19, 2019·The Neuroscientist : a Review Journal Bringing Neurobiology, Neurology and Psychiatry·Anastasia Diamantopoulou, Joseph A Gogos
Apr 29, 2018·American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics : the Official Publication of the International Society of Psychiatric Genetics·Yannis J TrakadisAnkur Krishnan
Oct 5, 2019·Nature Structural & Molecular Biology·Dylan Husmann, Or Gozani
Jul 12, 2019·Nature Communications·Jacob L TaylorElise B Robinson
Aug 29, 2019·Nature Neuroscience·Michael S BreenUNKNOWN CommonMind Consortium
Oct 8, 2018·Psychiatry and Clinical Neurosciences·Atsushi Takata
May 11, 2020·Journal of Neural Transmission·Yoshiro MorimotoHiroki Ozawa
May 10, 2020·Human Genetics·Yong WuYong-Gang Yao
Aug 9, 2018·Molecular Psychiatry·Masaki NishiokaTadafumi Kato
Jun 15, 2019·Neuroscience Bulletin·Xiuya YuWenhao Zhou
Jul 13, 2017·American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics : the Official Publication of the International Society of Psychiatric Genetics·Behnam JavidfarSchahram Akbarian

❮ Previous
Next ❯

Related Concepts

Related Feeds

Brain developing: Influences & Outcomes

This feed focuses on influences that affect the developing brain including genetics, fetal development, prenatal care, and gene-environment interactions. Here is the latest research in this field.

Antipsychotic Drugs

Antipsychotic drugs are a class of medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizophrenia and bipolar disorder. Discover the latest research on antipsychotic drugs here

Autism: Treatment Targets

The absence of effective treatments for autism are due to the high clinical and genetic heterogeneity between affected individuals, restricted knowledge of the underlying pathophysiological mechanisms, and the lack of reliable diagnostic biomarkers. Identification of more homogenous biological subgroups is therefore essential for the development of novel treatments based on the molecular mechanisms underpinning autism and autism spectrum disorders. Find the latest research on autism treatment targets here.

Alternative splicing

Alternative splicing a regulated gene expression process that allows a single genetic sequence to code for multiple proteins. Here is that latest research.

Autism

Autism spectrum disorder is associated with challenges with social skills, repetitive behaviors, and often accompanied by sensory sensitivities and medical issues. Here is the latest research on autism.