Rare loss-of-function variants in SETD1A are associated with schizophrenia and developmental disorders
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Abstract
By analyzing the whole-exome sequences of 4,264 schizophrenia cases, 9,343 controls and 1,077 trios, we identified a genome-wide significant association between rare loss-of-function (LoF) variants in SETD1A and risk for schizophrenia (P = 3.3 × 10(-9)). We found only two heterozygous LoF variants in 45,376 exomes from individuals without a neuropsychiatric diagnosis, indicating that SETD1A is substantially depleted of LoF variants in the general population. Seven of the ten individuals with schizophrenia carrying SETD1A LoF variants also had learning difficulties. We further identified four SETD1A LoF carriers among 4,281 children with severe developmental disorders and two more carriers in an independent sample of 5,720 Finnish exomes, both with notable neuropsychiatric phenotypes. Together, our observations indicate that LoF variants in SETD1A cause a range of neurodevelopmental disorders, including schizophrenia. Combining these data with previous common variant evidence, we suggest that epigenetic dysregulation, specifically in the histone H3K4 methylation pathway, is an important mechanism in the pathogenesis of schizophrenia.
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110 schizophrenia risk genes with elevated burden of rare variation at FDR < 0.3 were obtained from Singh et al., 2016.
“Schizophrenia risk genes with elevated burden of rare variation were obtained from Singh et al., 201666 (110 genes with FDR<0.3).”
From A computational tool (H-MAGMA) for improved prediction of brain-disorder risk genes by incorporating brain chromatin interaction profiles (2020) · cites this paper as [66]
Whole-exome sequencing has identified only two genes for schizophrenia at sample sizes that produced dozens of associations for autism spectrum disorder.
“WES has implicated only two genes for SCZ (Singh et al., 2016; Steinberg et al., 2017) at sample sizes that yielded dozens of associations for ASD.”
From Defining the genetic, genomic, cellular, and diagnostic architectures of psychiatric disorders (2019) · cites this paper as Singh et al., 2016
Resequencing in autism spectrum disorder yields substantially more findings than in other psychiatric disorders.
“The yield of resequencing in ASD is markedly higher than for other psychiatric disorders.”
From Defining the genetic, genomic, cellular, and diagnostic architectures of psychiatric disorders (2019) · cites this paper as Singh et al., 2016
Analysis of URVs has had limited success in delivering individual gene discovery in schizophrenia because of power limitations, with only a single gene, SETD1A, identified as robustly associated.
“However, the analysis of URVs has had limited success in delivering individual gene discovery in schizophrenia because of power limitations, with only a single gene, SETD1A, identified as robustly associated 13,18 .”
From Exome sequencing identifies rare coding variants in 10 genes which confer substantial risk for schizophrenia (2020) · cites this paper as [18]
SETD1A had a significant de novo PTV signal in DD/ID (Xobs = 8, Xexp = 0.41; P = 1.3 x 10 -8 ), supporting an earlier report that described SETD1A as a gene associated with both schizophrenia and broader neurodevelopmental disorders.
“SETD1A had a significant de novo PTV signal in DD/ID (Xobs = 8, Xexp = 0.41; P = 1.3 x 10 -8 ), supporting an earlier report that described SETD1A as a gene associated with both schizophrenia and broader neurodevelopmental disorders 18 .”
From Exome sequencing identifies rare coding variants in 10 genes which confer substantial risk for schizophrenia (2020) · cites this paper as [18]
Earlier sequencing studies established that ultra-rare and de novo mutations contribute to schizophrenia risk and found enrichment in neuronal genes and synaptic processes.
“Earlier schizophrenia sequencing studies have established that ultra-rare and de novo mutations contribute to risk as a category, and have prioritized disease-relevant tissues and processes, specifically observing an enrichment in neuronal genes and synaptic processes9,11,19–23.”
From Rare coding variants in ten genes confer substantial risk for schizophrenia (2022) · cites this paper as [20]
Among genes previously reported to have potential connections between rare variants and schizophrenia, the authors identified an ultra-rare splice donor variant in TAF13, an ultra-rare nonsense variant in SETD1A, and a single ultra-rare nonsense variant in NRXN1.
“we identified an ultra-rare splice donor variant in TAF1312, an ultra-rare nonsense variant in SETD1A16,17, and a single ultra-rare nonsense variant in NRXN1, a gene in which exonic deletions associate with schizophrenia18.”
From Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia (2016) · cites this paper as [17]
The enrichment in ID/DD genes is compatible with observations of the role of intellectual disability genes in some cases of autism and schizophrenia, though penetrance for schizophrenia may be much less than for intellectual disability and may reside primarily in syndromic cases.
“This enrichment is compatible with observations of the role of intellectual disability genes in some cases of autism38–40 and schizophrenia17, though the penetrance of such mutations for schizophrenia may be much less than their penetrance for intellectual disability, and they may reside primarily in syndromic cases in which schizophrenia is preceded by other developmental disorders17.”
From Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia (2016) · cites this paper as [17]
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Cites
Fast and accurate short read alignment with Burrows-Wheeler transform
Li, H., & Durbin, R. (2009) · Bioinformatics · doi:10.1093/bioinformatics/btp324 · Cited by 58,607 · see citing works
PLINK: a tool set for whole-genome association and population-based linkage analyses.
Purcell, S., Neale, B., Todd-Brown, K., Thomas, L., Ferreira, M. A. R., Bender, D., Maller, J., Sklar, P., de Bakker, P. I. W., Daly, M. J., et al. (2007) · The American Journal of Human Genetics · doi:10.1086/519795 · Cited by 34,089 · see citing works
Self-citationThe Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data
McKenna, A., Hanna, M., Banks, E., Sivachenko, A., Cibulskis, K., Kernytsky, A., Garimella, K., Altshuler, D., Gabriel, S., Daly, M., et al. (2010) · Genome Research · doi:10.1101/gr.107524.110 · Cited by 27,895 · see citing works
Self-citationA framework for variation discovery and genotyping using next-generation DNA sequencing data
DePristo, M. A., Banks, E., Poplin, R. E., Garimella, K. V., Maguire, J., Hartl, C., Philippakis, A., del Angel, G., Rivas, M. A., Hanna, M., et al. (2011) · Nature Genetics · doi:10.1038/ng.806 · Cited by 11,216 · see citing works
Self-citationAnalysis of protein-coding genetic variation in 60,706 humans
Exome Aggregation Consortium, Lek, M., Karczewski, K. J., Minikel, E. V., Samocha, K. E., Banks, E., Fennell, T., O’Donnell-Luria, A. H., Ware, J. S., Hill, A. J., et al. (2016) · Nature · doi:10.1038/nature19057 · Cited by 9,587 · see citing works
Self-citationBiological insights from 108 schizophrenia-associated genetic loci
Schizophrenia Working Group of the Psychiatric Genomics Consortium (2014) · Nature · doi:10.1038/nature13595 · Cited by 7,577 · see citing works
Van der Auwera, G. A., Carneiro, M. O., Hartl, C., Poplin, R., del Angel, G., Levy‐Moonshine, A., Jordan, T., Shakir, K., Roazen, D., Thibault, J., et al. (2013) · Current Protocols in Bioinformatics · doi:10.1002/0471250953.bi1110s43 · Cited by 6,687 · see citing works
A general framework for estimating the relative pathogenicity of human genetic variants
Kircher, M., Witten, D. M., Jain, P., O'Roak, B. J., Cooper, G. M., & Shendure, J. (2014) · Nature Genetics · doi:10.1038/ng.2892 · Cited by 6,183 · see citing works
UniProt: a hub for protein information
The UniProt Consortium (2015) · Nucleic Acids Research · doi:10.1093/nar/gku989 · Cited by 5,106 · see citing works
GENCODE: The reference human genome annotation for The ENCODE Project
Harrow, J., Frankish, A., Gonzalez, J. M., Tapanari, E., Diekhans, M., Kokocinski, F., Aken, B. L., Barrell, D., Zadissa, A., Searle, S., et al. (2012) · Genome Research · doi:10.1101/gr.135350.111 · Cited by 4,585 · see citing works
Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence
Genovese, G., Kähler, A. K., Handsaker, R. E., Lindberg, J., Rose, S. A., Bakhoum, S. F., Chambert, K., Mick, E., Neale, B. M., Fromer, M., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1409405 · Cited by 3,531 · see citing works
Self-citationSynaptic, transcriptional and chromatin genes disrupted in autism
Study, T. D., De Rubeis, S., Autism, H. M. C. F., UK10K Consortium, The Autism Sequencing Consortium, He, X., Goldberg, A. P., Poultney, C. S., Samocha, K., Ercument Cicek, A., et al. (2014) · Nature · doi:10.1038/nature13772 · Cited by 2,746 · see citing works
Self-citationThe contribution of de novo coding mutations to autism spectrum disorder
Iossifov, I., O’Roak, B. J., Sanders, S. J., Ronemus, M., Krumm, N., Levy, D., Stessman, H. A., Witherspoon, K. T., Vives, L., Patterson, K. E., et al. (2014) · Nature · doi:10.1038/nature13908 · Cited by 2,585 · see citing works
Schizophrenia as a Complex Trait: Evidence From a Meta-analysis of Twin Studies
Sullivan, P. F., Kendler, K. S., & Neale, M. C. (2003) · Archives of General Psychiatry · doi:10.1001/archpsyc.60.12.1187 · Cited by 2,356 · see citing works
Self-citationRare-Variant Association Testing for Sequencing Data with the Sequence Kernel Association Test
Wu, M. C., Lee, S., Cai, T., Li, Y., Boehnke, M., & Lin, X. (2011) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2011.05.029 · Cited by 2,317 · see citing works
Lichtenstein, P., Yip, B. H., Björk, C., Pawitan, Y., Cannon, T. D., Sullivan, P. F., & Hultman, C. M. (2009) · The Lancet · doi:10.1016/s0140-6736(09)60072-6 · Cited by 2,125 · see citing works
Self-citationDe novo mutations revealed by whole-exome sequencing are strongly associated with autism
Sanders, S. J., Murtha, M. T., Gupta, A. R., Murdoch, J. D., Raubeson, M. J., Willsey, A. J., Ercan-Sencicek, A. G., DiLullo, N. M., Parikshak, N. N., Stein, J. L., et al. (2012) · Nature · doi:10.1038/nature10945 · Cited by 2,084 · see citing works
Self-citationSaha, S., Chant, D., & McGrath, J. (2007) · Archives of General Psychiatry · doi:10.1001/archpsyc.64.10.1123 · Cited by 2,065 · see citing works
DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources
Firth, H. V., Richards, S. M., Bevan, A. P., Clayton, S., Corpas, M., Rajan, D., Vooren, S. V., Moreau, Y., Pettett, R. M., & Carter, N. P. (2009) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2009.03.010 · Cited by 1,990 · see citing works
van Os, J., & Kapur, S. (2009) · The Lancet · doi:10.1016/s0140-6736(09)60995-8 · Cited by 1,971 · see citing works
Burnside, R. D. (2015) · Cytogenetic and Genome Research · doi:10.1159/000438708 · Cited by 1,958 · see citing works
De novo mutations in schizophrenia implicate synaptic networks
Fromer, M., Pocklington, A. J., Kavanagh, D. H., Williams, H. J., Dwyer, S., Gormley, P., Georgieva, L., Rees, E., Palta, P., Ruderfer, D. M., et al. (2014) · Nature · doi:10.1038/nature12929 · Cited by 1,617 · see citing works
Self-citationDeriving the consequences of genomic variants with the Ensembl API and SNP Effect Predictor
McLaren, W. M., Yates, B., Ríos, D., Chen, Y., Flicek, P., & Cunningham, F. M. (2010) · Bioinformatics · doi:10.1093/bioinformatics/btq330 · Cited by 1,586 · see citing works
Diagnostic exome sequencing in persons with severe intellectual disability
de Ligt, J., Willemsen, M. H., van Bon, B. W. M., Kleefstra, T., Yntema, H. G., Kroes, T., Vulto-van Silfhout, A. T., Koolen, D. A., de Vries, P., Gilissen, C., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1206524 · Cited by 1,546 · see citing works
Lifetime Prevalence of Psychotic and Bipolar I Disorders in a General Population
Perälä, J., Suvisaari, J., Saarni, S. I., Kuoppasalmi, K. I., Isometsä, E. T., Pirkola, S. P., Partonen, T., Tuulio‐Henriksson, A., Hintikka, J., Kieseppä, T., et al. (2007) · Archives of General Psychiatry · doi:10.1001/archpsyc.64.1.19 · Cited by 1,523 · see citing works
Self-citationRare chromosomal deletions and duplications increase risk of schizophrenia
The International Schizophrenia Consortium (2008) · Nature · doi:10.1038/nature07239 · Cited by 1,475 · see citing works
Insights into autism spectrum disorder genomic architecture and biology from 71 risk loci
Sanders, S. J., He, X., Willsey, A. J., Ercan-Sencicek, A. G., Samocha, K. E., Cicek, A. E., Murtha, M. T., Bal, V. H., Bishop, S. L., Dong, S., et al. (2015) · Neuron · doi:10.1016/j.neuron.2015.09.016 · Cited by 1,430 · see citing works
Self-citationA polygenic burden of rare disruptive mutations in schizophrenia
Purcell, S. M., Moran, J. L., Fromer, M., Ruderfer, D., Solovieff, N., Roussos, P., O’Dushlaine, C., Chambert, K., Bergen, S. E., Kähler, A., et al. (2014) · Nature · doi:10.1038/nature12975 · Cited by 1,385 · see citing works
Self-citationRyan, A. K., Goodship, J. A., Wilson, D. I., Philip, N., Levy, A., Seidel, H., Schuffenhauer, S., Oechsler, H., Belohradsky, B. H., Prieur, M., et al. (1997) · Journal of Medical Genetics · doi:10.1136/jmg.34.10.798 · Cited by 1,192 · see citing works
Large-scale discovery of novel genetic causes of developmental disorders
Study, T. D. D. D. (2015) · Nature · doi:10.1038/nature14135 · Cited by 1,124 · see citing works
Rauch, A., Wieczorek, D., Graf, E., Wieland, T., Endele, S., Schwarzmayr, T., Albrecht, B., Bartholdi, D., Beygo, J., Di Donato, N., et al. (2012) · The Lancet · doi:10.1016/s0140-6736(12)61480-9 · Cited by 1,041 · see citing works
A framework for the interpretation of de novo mutation in human disease
Samocha, K. E., Robinson, E. B., Sanders, S. J., Stevens, C., Sabo, A., McGrath, L. M., Kosmicki, J. A., Rehnström, K., Mallick, S., Kirby, A., et al. (2014) · Nature Genetics · doi:10.1038/ng.3050 · Cited by 979 · see citing works
Self-citationToward better understanding of artifacts in variant calling from high-coverage samples
Li, H. (2014) · Bioinformatics · doi:10.1093/bioinformatics/btu356 · Cited by 896 · see citing works
CNVs: Harbingers of a Rare Variant Revolution in Psychiatric Genetics
Malhotra, D., & Sebat, J. (2012) · Cell · doi:10.1016/j.cell.2012.02.039 · Cited by 854 · see citing works
Kirov, G., Pocklington, A. J., Holmans, P., Ivanov, D., Ikeda, M., Ruderfer, D., Moran, J., Chambert, K., Toncheva, D., Georgieva, L., et al. (2012) · Molecular Psychiatry · doi:10.1038/mp.2011.154 · Cited by 844 · see citing works
Self-citationThe Human Phenotype Ontology project: linking molecular biology and disease through phenotype data
Köhler, S., Doelken, S., Mungall, C. J., Bauer, S., Firth, H., Bailleul-Forestier, I., Black, G., Brown, D. L., Brudno, M., Campbell, J., et al. (2013) · Nucleic Acids Res. · doi:10.1093/nar/gkt1026 · Cited by 840 · see citing works
Self-citationPsychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways
The Network and Pathway Analysis Subgroup of the Psychiatric Genomics Consortium (2015) · Nature Neuroscience · doi:10.1038/nn.3922 · Cited by 755 · see citing works
Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction
Do, R., Stitziel, N. O., Won, H.-H., Jørgensen, A. B., Duga, S., Angelica Merlini, P., Kiezun, A., Farrall, M., Goel, A., Zuk, O., et al. (2015) · Nature · doi:10.1038/nature13917 · Cited by 650 · see citing works
Self-citationGulsuner, S., Walsh, T., Watts, A. C., Lee, M. K., Thornton, A. M., Casadei, S., Rippey, C., Shahin, H., Braff, D., Cadenhead, K. S., et al. (2013) · Cell · doi:10.1016/j.cell.2013.06.049 · Cited by 536 · see citing works
Jun, G., Flickinger, M., Hetrick, K. N., Romm, J. M., Doheny, K. F., Abecasis, G. R., Boehnke, M., & Kang, H. M. (2012) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2012.09.004 · Cited by 484 · see citing works
Clinical features of 78 adults with 22q11 deletion syndrome
Bassett, A. S., Chow, E. W. C., Husted, J., Weksberg, R., Caluseriu, O., Webb, G. D., & Gatzoulis, M. Α. (2005) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.30984 · Cited by 476 · see citing works
Analysis of copy number variations at 15 schizophrenia-associated loci
Rees, E., Walters, J. T. R., Georgieva, L., Isles, A. R., Chambert, K. D., Richards, A. L., Mahoney-Davies, G., Legge, S. E., Moran, J. L., McCarroll, S. A., et al. (2014) · British Journal of Psychiatry · doi:10.1192/bjp.bp.113.131052 · Cited by 443 · see citing works
Self-citationDe novo gene mutations highlight patterns of genetic and neural complexity in schizophrenia
Xu, B., Ionita-Laza, I., Roos, J. L., Boone, B., Woodrick, S., Sun, Y., Levy, S., Gogos, J. A., & Karayiorgou, M. (2012) · Nature Genetics · doi:10.1038/ng.2446 · Cited by 442 · see citing works
Increased exonic de novo mutation rate in individuals with schizophrenia
Girard, S. L., Gauthier, J., Noreau, A., Xiong, L., Zhou, S., Jouan, L., Dionne-Laporte, A., Spiegelman, D., Henrion, E., Diallo, O., et al. (2011) · Nature Genetics · doi:10.1038/ng.886 · Cited by 438 · see citing works
Age at onset and cognition in schizophrenia: meta-analysis
Rajji, T. K., Ismail, Z., & Mulsant, B. H. (2009) · The British Journal of Psychiatry · doi:10.1192/bjp.bp.108.060723 · Cited by 395 · see citing works
The Penetrance of Copy Number Variations for Schizophrenia and Developmental Delay
Kirov, G., Rees, E., Walters, J. T. R., Escott-Price, V., Georgieva, L., Richards, A. L., Chambert, K. D., Davies, G., Legge, S. E., Moran, J. L., et al. (2014) · Biological Psychiatry · doi:10.1016/j.biopsych.2013.07.022 · Cited by 368 · see citing works
Self-citationMcCarthy, S. E., Gillis, J., Kramer, M., Lihm, J., Yoon, S. C., Berstein, Y., Mistry, M., Pavlidis, P., Solomon, R., Ghiban, E., et al. (2014) · Molecular Psychiatry · doi:10.1038/mp.2014.29 · Cited by 332 · see citing works
He, X., Sanders, S. J., Liu, L., De Rubeis, S., Lim, E. T., Sutcliffe, J. S., Schellenberg, G. D., Gibbs, R. A., Daly, M. J., Buxbaum, J. D., et al. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003671 · Cited by 304 · see citing works
Self-citationIdentification and Characterization of the Human Set1B Histone H3-Lys4 Methyltransferase Complex
Lee, J., Tate, C. M., You, J., & Skalnik, D. G. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m609809200 · Cited by 266 · see citing works
Kleefstra, T., van Zelst-Stams, W. A., Nillesen, W. M., Cormier-Daire, V, Houge, G., Foulds, N., van Dooren, M., Willemsen, M. H., Pfundt, R., Turner, A., et al. (2009) · Journal of Medical Genetics · doi:10.1136/jmg.2008.062950 · Cited by 252 · see citing works
Lee, J., & Skalnik, D. G. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.01356-07 · Cited by 218 · see citing works
Estimating Kinship in Admixed Populations
Thornton, T. A., Tang, H., Hoffmann, T. J., Ochs‐Balcom, H. M., Caan, B. J., & RISCH, N. J. (2012) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2012.05.024 · Cited by 206 · see citing works
Loss-of-Function Variants in Schizophrenia Risk and SETD1A as a Candidate Susceptibility Gene
Takata, A., Xu, B., Ionita-Laza, I., Roos, J. L., Gogos, J. A., & Karayiorgou, M. (2014) · Neuron · doi:10.1016/j.neuron.2014.04.043 · Cited by 204 · see citing works
Mendelian Disorders of the Epigenetic Machinery: Tipping the Balance of Chromatin States
Fahrner, J. A., & Bjornsson, H. T. (2014) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-090613-094245 · Cited by 161 · see citing works
Moore, C. S., Sambrook, J., Walker, M. R., Tolkien, Z., Kaptoge, S. K., Allen, D., Mehenny, S., Mant, J., Angelantonio, E. D., Thompson, S. G., et al. (2014) · Trials · doi:10.1186/1745-6215-15-363 · Cited by 145 · see citing works
Self-citationAnalysis of protein-coding genetic variation in 60,706 humansPreprint
Lek, M., Karczewski, K. J., Minikel, E. V., et al. (2015) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/030338 · Cited by 144 · see citing works
Functional outcomes of adults with 22q11.2 deletion syndrome
Butcher, N. J., Chow, E. W. C., Costain, G., Karas, D. J., Ho, A., & Bassett, A. S. (2012) · Genetics in Medicine · doi:10.1038/gim.2012.66 · Cited by 90 · see citing works
Exome Sequencing in 53 Sporadic Cases of Schizophrenia Identifies 18 Putative Candidate Genes
Guipponi, M., Santoni, F. A., Setola, V., Gehrig, C., Rothärmel, M., Cuenca, M., Guillin, O., Dikeos, D. G., Georgantopoulos, G., Papadimitriou, G. N., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0112745 · Cited by 89 · see citing works
Dincer, A., Gavin, D. P., Xu, K., Zhang, B., Dudley, J. T., Schadt, E. E., & Akbarian, S. (2015) · Translational Psychiatry · doi:10.1038/tp.2015.169 · Cited by 65 · see citing works
Dushlaine, C. O., Rossin, L., Ph, L., Duncan, L. E., Parikshak, N., Newhouse, S., Ripke, S., Neale, B. M., Purcell, S., Danielle Posthuma, B., et al. (2015) · Cited by 43 · see citing works
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GERAD1 Consortium, Pardiñas, A. F., CRESTAR Consortium, Holmans, P., Pocklington, A. J., Escott-Price, V., Ripke, S., Carrera, N., Legge, S. E., Bishop, S., et al. (2018) · Nature Genetics · doi:10.1038/s41588-018-0059-2 · Cited by 1,552 · see citing works
Self-citationComprehensive functional genomic resource and integrative model for the human brain
Wang, D., Liu, S., Warrell, J., Won, H., Shi, X., Navarro, F. C. P., Clarke, D., Gu, M., Emani, P., Yang, Y. T., et al. (2018) · Science · doi:10.1126/science.aat8464 · Cited by 965 · see citing works
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Self-citationExpansion of the Human Phenotype Ontology (HPO) knowledge base and resources
Köhler, S., Carmody, L., Vasilevsky, N., Jacobsen, J. O. B., Danis, D., Gourdine, J.-P., Gargano, M., Harris, N. L., Matentzoglu, N., McMurry, J. A., et al. (2019) · Nucleic Acids Research · doi:10.1093/nar/gky1105 · Cited by 677 · see citing works
Genetic identification of brain cell types underlying schizophrenia
Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Skene, N. G., Bryois, J., Bakken, T. E., Breen, G., Crowley, J. J., Gaspar, H. A., Giusti-Rodriguez, P., Hodge, R. D., Miller, J. A., et al. (2018) · Nature Genetics · doi:10.1038/s41588-018-0129-5 · Cited by 651 · see citing works
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Self-citationDefining the genetic, genomic, cellular, and diagnostic architectures of psychiatric disorders
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Niemi, M. E. K., Martin, H. C., Rice, D. L., Gallone, G., Gordon, S., Kelemen, M., McAloney, K., McRae, J., Radford, E. J., Yu, S., et al. (2018) · Nature · doi:10.1038/s41586-018-0566-4 · Cited by 340 · see citing works
Self-citationSey, N. Y. A., Hu, B., Mah, W., Fauni, H., McAfee, J. C., Rajarajan, P., Brennand, K. J., Akbarian, S., & Won, H. (2020) · Nature Neuroscience · doi:10.1038/s41593-020-0603-0 · Cited by 297 · see citing works
Singh, T., Walters, J. T. R., Johnstone, M., Curtis, D., Suvisaari, J., Torniainen, M., Rees, E., Iyegbe, C., Blackwood, D., McIntosh, A. M., et al. (2017) · Nature Genetics · doi:10.1038/ng.3903 · Cited by 231 · see citing works
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Gandal, M. J., Leppa, V., Won, H., Parikshak, N. N., & Geschwind, D. H. (2016) · Nature Neuroscience · doi:10.1038/nn.4409 · Cited by 223 · see citing works
Self-citationQuantifying the contribution of recessive coding variation to developmental disorders
Martin, H. C., Jones, W. D., McIntyre, R., Sanchez-Andrade, G., Sanderson, M., Stephenson, J. D., Jones, C. P., Handsaker, J., Gallone, G., Bruntraeger, M., et al. (2018) · Science · doi:10.1126/science.aar6731 · Cited by 201 · see citing works
Self-citationEvaluation of chromatin accessibility in prefrontal cortex of individuals with schizophrenia
Bryois, J., Garrett, M. E., Song, L., Safi, A., Giusti-Rodriguez, P., Johnson, G. D., Shieh, A. W., Buil, A., Fullard, J. F., Roussos, P., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-05379-y · Cited by 167 · see citing works
Self-citationHowrigan, D. P., Rose, S. A., Samocha, K. E., Fromer, M., Cerrato, F., Chen, W. J., Churchhouse, C., Chambert, K., Chandler, S. D., Daly, M. J., et al. (2020) · Nature Neuroscience · doi:10.1038/s41593-019-0564-3 · Cited by 168 · see citing works
Self-citationLuo, Y., de Lange, K. M., Jostins, L., Moutsianas, L., Randall, J., Kennedy, N. A., Lamb, C. A., McCarthy, S., Ahmad, T., Edwards, C., et al. (2017) · Nature Genetics · doi:10.1038/ng.3761 · Cited by 162 · see citing works
Self-citationThe implications of the shared genetics of psychiatric disorders
O'Donovan, M. C., & Owen, M. J. (2016) · Nature Medicine · doi:10.1038/nm.4196 · Cited by 157 · see citing works
Self-citationSingh, T., Neale, B. M., & Daly, M. J. (2020) · doi:10.1101/2020.09.18.20192815 · Cited by 980 · see citing works
“Paralogs of this gene, including KMT2A (Wiedemann-Steiner syndrome), KMT2B , KMT2C , and KMT2D (Kabuki syndrome), have been associated with severe neurodevelopmental disorders 18,43 .”
BackgroundResultInfluentialSelf-citationRecurrent de novo mutations in neurodevelopmental disorders: properties and clinical implications
Wilfert, A. B., Sulovari, A., Turner, T. N., Coe, B. P., & Eichler, E. E. (2017) · Genome Medicine · doi:10.1186/s13073-017-0498-x · Cited by 144 · see citing works
GROUP Investigators, Rees, E., Han, J., Morgan, J., Carrera, N., Escott-Price, V., Pocklington, A. J., Duffield, M., Hall, L. S., Legge, S. E., et al. (2020) · Nature Neuroscience · doi:10.1038/s41593-019-0565-2 · Cited by 129 · see citing works
Self-citationGenetics of schizophrenia in the South African Xhosa
Gulsuner, S., Stein, D. J., Susser, E. S., Sibeko, G., Pretorius, A., Walsh, T., Majara, L., Mndini, M. M., Mqulwana, S. G., Ntola, O. A., et al. (2020) · Science · doi:10.1126/science.aay8833 · Cited by 118 · see citing works
De novo variants in SETD1B are associated with intellectual disability, epilepsy and autism
Hiraide, T., Nakashima, M., Yamoto, K., Fukuda, T., Kato, M., Ikeda, H., Sugie, Y., Aoto, K., Kaname, T., Nakabayashi, K., et al. (2018) · Human Genetics · doi:10.1007/s00439-017-1863-y · Cited by 75 · see citing works
Truncating mutations in RBM12 are associated with psychosis
Steinberg, S., Gudmundsdottir, S., Sveinbjornsson, G., Suvisaari, J., Paunio, T., Torniainen-Holm, M., Frigge, M. L., Jonsdottir, G. A., Huttenlocher, J., Arnarsdottir, S., et al. (2017) · Nature Genetics · doi:10.1038/ng.3894 · Cited by 70 · see citing works
Self-citationMechanisms Underlying Circuit Dysfunction in Neurodevelopmental Disorders
Exposito-Alonso, D., & Rico, B. (2022) · Annual Review of Genetics · doi:10.1146/annurev-genet-072820-023642 · Cited by 49 · see citing works
Mah, W., & Won, H. (2020) · Schizophrenia Research · doi:10.1016/j.schres.2019.03.007 · Cited by 38 · see citing works
Tyagi, P., Tasleem, M., Prakash, S., & Chouhan, G. (2020) · Food Research International · doi:10.1016/j.foodres.2020.109489 · Cited by 42 · see citing works
Sokolowski, M., Wasserman, J., & Wasserman, D. (2018) · American Journal of Medical Genetics Part B: Neuropsychiatric Genetics · doi:10.1002/ajmg.b.32694 · Cited by 30 · see citing works
Rare variants are common in schizophrenia
Gratten, J. (2016) · Nature Neuroscience · doi:10.1038/nn.4422 · Cited by 12 · see citing works
Evaluation of chromatin accessibility in prefrontal cortex of schizophrenia cases and controls
Bryois, J., Garrett, M. E., Song, L., Safi, A., Giusti-Rodriguez, P., Johnson, G. D., Demur, A. B., Fullard, J. F., Roussos, P., Sklar, P., et al. (2017) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/141986 · Cited by 7 · see citing works
Self-citation
- Authors
- Study, S. S., Singh, T., Study, I., Study, D., UK10 K Consortium, Kurki, M. I., Curtis, D., Purcell, S. M., Crooks, L., McRae, J., Suvisaari, J., Chheda, H., Blackwood, D., Breen, G., Pietiläinen, O., Gerety, S. S., Ayub, M., Blyth, M., Cole, T., Collier, D., Coomber, E. L., Craddock, N., Daly, M. J., Danesh, J., DiForti, M., Foster, A., Freimer, N. B., Geschwind, D., Johnstone, M., Joss, S., Kirov, G., Körkkö, J., Kuismin, O., Holmans, P., Hultman, C. M., Iyegbe, C., Lönnqvist, J., Männikkö, M., McCarroll, S. A., McGuffin, P., McIntosh, A. M., McQuillin, A., Moilanen, J. S., Moore, C., Murray, R. M., Newbury-Ecob, R., Ouwehand, W., Paunio, T., Prigmore, E., Rees, E., Roberts, D., Sambrook, J., Sklar, P., Clair, D. S., Veijola, J., Walters, J. T. R., Williams, H., Sullivan, P. F., Hurles, M. E., O'Donovan, M. C., Palotie, A., Owen, M. J., & Barrett, J. C.
- Affiliations
- Wellcome Sanger Institute (GB)
- Broad Institute (US)
- University College London (GB)
- Icahn School of Medicine at Mount Sinai (US)
- Finnish Institute for Health and Welfare (FI)
- University of Helsinki (FI)
- Royal Edinburgh Hospital (GB)
- King's College London (GB)
- Chapel Allerton Hospital (GB)
- Birmingham Women's Hospital (GB)
- University of California, Los Angeles (US)
- Oulu University Hospital (FI)
- Karolinska Institutet (SE)
- University of Cambridge (GB)
- University Hospitals Bristol NHS Foundation Trust (GB)
- NHS Blood and Transplant (GB)
- Cardiff University (GB)
- University of Aberdeen (GB)
- Corresponding author
- Barrett, Jeffrey C
- ORCID
- Singh, Tarjinder
- Kurki, Mitja I
- Curtis, David
- Purcell, Shaun M
- Crooks, Lucy
- McRae, Jeremy
- Suvisaari, Jaana
- Blackwood, Douglas
- Breen, Gerome
- Pietiläinen, Olli
- Gerety, Sebastian S
- Ayub, Muhammad
- Blyth, Moira
- Collier, David
- Coomber, Eve L
- Craddock, Nick
- Daly, Mark J
- Danesh, John
- Foster, Alison
- Freimer, Nelson B
- Geschwind, Daniel
- Johnstone, Mandy
- Joss, Shelagh
- Kuismin, Outi
- Holmans, Peter
- Iyegbe, Conrad
- Lönnqvist, Jouko
- Männikkö, Minna
- McGuffin, Peter
- McIntosh, Andrew M
- McQuillin, Andrew
- Moilanen, Jukka S
- Moore, Carmel
- Murray, Robin M
- Newbury-Ecob, Ruth
- Ouwehand, Willem
- Paunio, Tiina
- Prigmore, Elena
- Rees, Elliott
- Roberts, David
- Sklar, Pamela
- Clair, David St
- Veijola, Juha
- Walters, James T R
- Williams, Hywel
- Sullivan, Patrick F
- Hurles, Matthew E
- O'Donovan, Michael C
- Palotie, Aarno
- Owen, Michael J
- Barrett, Jeffrey C
- Venue
- Nature Neuroscience
- Published
- 2016-03-14
- Volume
- 19
- Issue
- 4
- Pages
- 571-577
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC6689268
- OpenAlex
- W2277462866
- Cited by
- 452
- References
- 60
- Citations by year
- 2026: 23 · 2025: 27 · 2024: 34 · 2023: 33 · 2022: 45 · 2021: 46 · 2020: 56 · 2019: 65 · 2018: 51 · 2017: 42 · 2016: 30
- FWCI
- 55.67
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by-nd
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- SHURA (Sheffield Hallam University Research Archive) (Sheffield Hallam University) (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Bristol Research (University of Bristol) (submittedVersion)
- STM:n Hallinnonalan avoin julkaisuarkisto (Julkari) (submittedVersion)
- Funders
- Williams College
- Wellcome Trust (UK10K, WT 098051, 100135, 104036, WT091310)
- National Institute for Health and Care Research (NF-SI-0510-10214, RP-PG-0310-1002, NF-SI-0512-10110, RP-PG-0606-1049, NF-SI-0513-10151)
- British Heart Foundation (SP/09/002, RG/09/012/28096)
- Cardiff University (G0800509)
- Sydäntutkimussäätiö
- Saastamoisen säätiö
- National Institutes of Health
- U.S. Public Health Service (NIMH U01MH105666)
- NIHR BioResource
- Medical Research Council (MR/K004867/1, G0801418, MR/P005748/1, MR/K013807/1, MR/K026992/1, MR/L010305/1, G0800509)
- National Institute of Mental Health (R01MH077139, U01MH105666, NIH R01 MH077139, MH077139)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- SETD1A, loss-of-function mutations, schizophrenia, developmental disorders, neurodevelopmental disorders, histone H3 lysine 4 methylation, epigenetic dysregulation, learning difficulties, genetic risk, exome sequencing
- MeSH terms
- Female, Finland, Humans, Male, Histone-Lysine N-Methyltransferase, Schizophrenia, Genetic Variation, Cohort Studies, Case-Control Studies, Genetic Predisposition to Disease, Genetic Association Studies, Neurodevelopmental Disorders
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