Rare Loss-of-function Variants in SETD1A Are Associated with Schizophrenia and Developmental Disorders

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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References

Guipponi M, Santoni F, Setola V, Gehrig C, Rotharmel M, Cuenca M . Exome sequencing in 53 sporadic cases of schizophrenia identifies 18 putative candidate genes. PLoS One. 2014; 9(11):e112745. PMC: 4242613. DOI: 10.1371/journal.pone.0112745. View

Malhotra D, Sebat J . CNVs: harbingers of a rare variant revolution in psychiatric genetics. Cell. 2012; 148(6):1223-41. PMC: 3351385. DOI: 10.1016/j.cell.2012.02.039. View

. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature. 2008; 455(7210):237-41. PMC: 3912847. DOI: 10.1038/nature07239. View

Kirov G, Pocklington A, Holmans P, Ivanov D, Ikeda M, Ruderfer D . De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia. Mol Psychiatry. 2011; 17(2):142-53. PMC: 3603134. DOI: 10.1038/mp.2011.154. View

Lee J, Skalnik D . Wdr82 is a C-terminal domain-binding protein that recruits the Setd1A Histone H3-Lys4 methyltransferase complex to transcription start sites of transcribed human genes. Mol Cell Biol. 2007; 28(2):609-18. PMC: 2223426. DOI: 10.1128/MCB.01356-07. View

Sanders S, Murtha M, Gupta A, Murdoch J, Raubeson M, Willsey A . De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature. 2012; 485(7397):237-41. PMC: 3667984. DOI: 10.1038/nature10945. View

Moore C, Sambrook J, Walker M, Tolkien Z, Kaptoge S, Allen D . The INTERVAL trial to determine whether intervals between blood donations can be safely and acceptably decreased to optimise blood supply: study protocol for a randomised controlled trial. Trials. 2014; 15:363. PMC: 4177700. DOI: 10.1186/1745-6215-15-363. View

Genovese G, Kahler A, Handsaker R, Lindberg J, Rose S, Bakhoum S . Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med. 2014; 371(26):2477-87. PMC: 4290021. DOI: 10.1056/NEJMoa1409405. View

. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014; 511(7510):421-7. PMC: 4112379. DOI: 10.1038/nature13595. View

10.

Sanders S, He X, Willsey A, Ercan-Sencicek A, Samocha K, Cicek A . Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci. Neuron. 2015; 87(6):1215-1233. PMC: 4624267. DOI: 10.1016/j.neuron.2015.09.016. View

11.

Samocha K, Robinson E, Sanders S, Stevens C, Sabo A, McGrath L . A framework for the interpretation of de novo mutation in human disease. Nat Genet. 2014; 46(9):944-50. PMC: 4222185. DOI: 10.1038/ng.3050. View

12.

Jun G, Flickinger M, Hetrick K, Romm J, Doheny K, Abecasis G . Detecting and estimating contamination of human DNA samples in sequencing and array-based genotype data. Am J Hum Genet. 2012; 91(5):839-48. PMC: 3487130. DOI: 10.1016/j.ajhg.2012.09.004. View

13.

Rauch A, Wieczorek D, Graf E, Wieland T, Endele S, Schwarzmayr T . Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet. 2012; 380(9854):1674-82. DOI: 10.1016/S0140-6736(12)61480-9. View

14.

Li H . Toward better understanding of artifacts in variant calling from high-coverage samples. Bioinformatics. 2014; 30(20):2843-51. PMC: 4271055. DOI: 10.1093/bioinformatics/btu356. View

15.

Rajji T, Ismail Z, Mulsant B . Age at onset and cognition in schizophrenia: meta-analysis. Br J Psychiatry. 2009; 195(4):286-93. DOI: 10.1192/bjp.bp.108.060723. View

16.

Lichtenstein P, Yip B, Bjork C, Pawitan Y, Cannon T, Sullivan P . Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet. 2009; 373(9659):234-9. PMC: 3879718. DOI: 10.1016/S0140-6736(09)60072-6. View

17.

He X, Sanders S, Liu L, De Rubeis S, Lim E, Sutcliffe J . Integrated model of de novo and inherited genetic variants yields greater power to identify risk genes. PLoS Genet. 2013; 9(8):e1003671. PMC: 3744441. DOI: 10.1371/journal.pgen.1003671. View

18.

Firth H, Richards S, Bevan A, Clayton S, Corpas M, Rajan D . DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources. Am J Hum Genet. 2009; 84(4):524-33. PMC: 2667985. DOI: 10.1016/j.ajhg.2009.03.010. View

19.

Van der Auwera G, Carneiro M, Hartl C, Poplin R, Del Angel G, Levy-Moonshine A . From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline. Curr Protoc Bioinformatics. 2014; 43:11.10.1-11.10.33. PMC: 4243306. DOI: 10.1002/0471250953.bi1110s43. View

20.

Iossifov I, ORoak B, Sanders S, Ronemus M, Krumm N, Levy D . The contribution of de novo coding mutations to autism spectrum disorder. Nature. 2014; 515(7526):216-21. PMC: 4313871. DOI: 10.1038/nature13908. View