The contribution of rare variants to risk of schizophrenia in individuals with and without intellectual disability

Nature Genetics

Volumn 49, Issue 8, 2017, Pages 1167-1173

  Singh, Tarjinder ^a   Walters, James T R ^b   Johnstone, Mandy ^c   Curtis, David ^d,e   Suvisaari, Jaana ^f   Torniainen, Minna ^f   Rees, Elliott ^b   Iyegbe, Conrad ^g   Blackwood, Douglas ^c   McIntosh, Andrew M ^c   Kirov, Georg ^b   Geschwind, Daniel ^h   Murray, Robin M ^g   Di Forti, Marta ^g   Bramon, Elvira ^d   Gandal, Michael ^h   Hultman, Christina M ⁱ   Sklar, Pamela ^j   Palotie, Aarno ^k,l   Sullivan, Patrick F ^i,m   O'Donovan, Michael C ^b   Owen, Michael J ^b   Barrett, Jeffrey C ^a   more..

^a WELLCOME TRUST SANGER INSTITUTE   (United Kingdom)

^b CARDIFF UNIVERSITY   (United Kingdom)

^c UNIVERSITY OF EDINBURGH   (United Kingdom)

^d UNIVERSITY COLLEGE LONDON   (United Kingdom)

^e QUEEN MARY UNIVERSITY OF LONDON   (United Kingdom)

^f NATIONAL PUBLIC HEALTH INSTITUTE   (Finland)

^g KING'S COLLEGE LONDON   (United Kingdom)

^h UNIVERSITY OF CALIFORNIA   (United States)

ⁱ KAROLINSKA INSTITUTE   (Sweden)

^j MOUNT SINAI SCHOOL OF MEDICINE   (United States)

^k UNIVERSITY OF HELSINKI   (Finland)

^l BROAD INSTITUTE OF MIT AND HARVARD   (United States)

^m UNIVERSITY OF NORTH CAROLINA SCHOOL OF MEDICINE   (United States)

more..

Author keywords

[No Author keywords available]

Indexed keywords

ARTICLE; CONTROLLED STUDY; GENE MUTATION; GENETIC RISK; GENETIC VARIABILITY; HUMAN; INTELLECTUAL IMPAIRMENT; MAJOR CLINICAL STUDY; MENTAL DISEASE; PRIORITY JOURNAL; SCHIZOPHRENIA; CASE CONTROL STUDY; DNA SEQUENCE; EXOME; GENETIC PREDISPOSITION; GENETIC VARIATION; GENETICS; GENOTYPING TECHNIQUE; META ANALYSIS; MUTATION; PATHOPHYSIOLOGY; SINGLE NUCLEOTIDE POLYMORPHISM;

CASE-CONTROL STUDIES; EXOME; GENETIC PREDISPOSITION TO DISEASE; GENETIC VARIATION; GENOTYPING TECHNIQUES; HUMANS; INTELLECTUAL DISABILITY; MUTATION; NEURODEVELOPMENTAL DISORDERS; POLYMORPHISM, SINGLE NUCLEOTIDE; SCHIZOPHRENIA; SEQUENCE ANALYSIS, DNA;

EID: 85026373110     PISSN: 10614036     EISSN: 15461718     Source Type: Journal    
DOI: 10.1038/ng.3903     Document Type: Article

References (53)

1. van Os, J. &Kapur, S. Schizophrenia. Lancet 374, 635-645 (2009).
2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM-5) (American Psychiatric Publishing, 2013).
3. Tandon, R. et al. Definition and description of schizophrenia in the DSM-5. Schizophr. Res. 150, 3-10 (2013).
4. Owen, M.J. New approaches to psychiatric diagnostic classification. Neuron 84, 564-571 (2014).
5. Owen, M.J., Sawa, A. &Mortensen, P.B. Schizophrenia. Lancet 388, 86-97 (2016).
6. Howes, O.D. &Kapur, S. The dopamine hypothesis of schizophrenia: version III\-The final common pathway. Schizophr. Bull. 35, 549-562 (2009).
7. Pocklington, A.J. et al. Novel findings from CNVs implicate inhibitory and excitatory signaling complexes in schizophrenia. Neuron 86, 1203-1214 (2015).
8. Sekar, A. et al. Schizophrenia risk from complex variation of complement component 4. Nature 530, 177-183 (2016).
9. Owen, M.J., O'Donovan, M.C., Thapar, A. &Craddock, N. Neurodevelopmental hypothesis of schizophrenia. Br. J. Psychiatry 198, 173-175 (2011).
10. Rapoport, J.L., Giedd, J.N. &Gogtay, N. Neurodevelopmental model of schizophrenia: update 2012. Mol. Psychiatry 17, 1228-1238 (2012).
11. Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421-427 (2014).
12. Loh, P.-R. et al. Contrasting genetic architectures of schizophrenia and other complex diseases using fast variance-components analysis. Nat. Genet. 47, 1385-1392 (2015).
13. Fromer, M. et al. De novo mutations in schizophrenia implicate synaptic networks. Nature 506, 179-184 (2014).
14. Kirov, G. et al. De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia. Mol. Psychiatry 17, 142-153 (2012).
15. International Schizophrenia Consortium. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 455, 237-241 (2008).
16. Rees, E. et al. Analysis of copy number variations at 15 schizophrenia-associated loci. Br. J. Psychiatry 204, 108-114 (2014).
17. Zhu, X., Need, A.C., Petrovski, S. &Goldstein, D.B. One gene, many neuropsychiatric disorders: lessons from Mendelian diseases. Nat. Neurosci. 17, 773-781 (2014).
18. Singh, T. et al. Rare loss-of-function variants in SETD1A are associated with schizophrenia and developmental disorders. Nat. Neurosci. 19, 571-577 (2016).
19. Szatkiewicz, J.P. et al. Copy number variation in schizophrenia in Sweden. Mol. Psychiatry 19, 762-773 (2014).
20. Network and Pathway Analysis Subgroup of Psychiatric Genomics Consortium. Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways. Nat. Neurosci. 18, 199-209 (2015).
21. Lee, S.H. et al. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nat. Genet. 45, 984-994 (2013).
22. Robinson, E.B. et al. Genetic risk for autism spectrum disorders and neuropsychiatric variation in the general population. Nat. Genet. 48, 552-555 (2016).
23. Sanders, S.J. et al. Insights into autism spectrum disorder genomic architecture and biology from 71 risk loci. Neuron 87, 1215-1233 (2015).
24. Samocha, K.E. et al. A framework for the interpretation of de novo mutation in human disease. Nat. Genet. 46, 944-950 (2014).
25. Lek, M. et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature 536, 285-291 (2016).
26. Genovese, G. et al. Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia. Nat. Neurosci. 19, 1433-1441 (2016).
27. Kirov, G. et al. The penetrance of copy number variations for schizophrenia and developmental delay. Biol. Psychiatry 75, 378-385 (2014).
28. Iossifov, I. et al. The contribution of de novo coding mutations to autism spectrum disorder. Nature 515, 216-221 (2014).
29. Rees, E. et al. CNV analysis in a large schizophrenia sample implicates deletions at 16p12.1 and SLC1A1 and duplications at 1p36.33 and CGNL1. Hum. Mol. Genet. 23, 1669-1676 (2014).
30. Price, A.L. et al. Pooled association tests for rare variants in exon-resequencing studies. Am. J. Hum. Genet. 86, 832-838 (2010).
31. Raychaudhuri, S. et al. Accurately assessing the risk of schizophrenia conferred by rare copy-number variation affecting genes with brain function. PLoS Genet. 6, e1001097 (2010).
32. De Rubeis, S. et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature 515, 209-215 (2014).
33. Firth, H.V. et al. DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources. Am. J. Hum. Genet. 84, 524-533 (2009).
34. Deciphering Developmental Disorders Study. Prevalence and architecture of de novo mutations in developmental disorders. Nature 542, 433-438 (2017).
35. Purcell, S.M. et al. A polygenic burden of rare disruptive mutations in schizophrenia. Nature 506, 185-190 (2014).
36. Cotney, J. et al. The autism-associated chromatin modifier CHD8 regulates other autism risk genes during human neurodevelopment. Nat. Commun. 6, 6404 (2015).
37. Weyn-Vanhentenryck, S.M. et al. HITS-CLIP and integrative modeling define the Rbfox splicing-regulatory network linked to brain development and autism. Cell Rep. 6, 1139-1152 (2014).
38. Darnell, J.C. et al. FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell 146, 247-261 (2011).
39. Ascano, M. Jr. et al. FMRP targets distinct mRNA sequence elements to regulate protein expression. Nature 492, 382-386 (2012).
40. Ganna, A. et al. Ultra-rare disruptive and damaging mutations influence educational attainment in the general population. Nat. Neurosci. 19, 1563-1565 (2016).
41. Deciphering Developmental Disorders Study. Large-scale discovery of novel genetic causes of developmental disorders. Nature 519, 223-228 (2015).
42. Pardiñas, A.F. et al. Common schizophrenia alleles are enriched in mutation-intolerant genes and maintained by background selection. Preprint at bioRxiv http://dx.doi.org/10.1101/068593 (2016).
43. Ben-Shachar, S. et al. 22q11.2 distal deletion: a recurrent genomic disorder distinct from DiGeorge syndrome and velocardiofacial syndrome. Am. J. Hum. Genet. 82, 214-221 (2008).
44. Michaelovsky, E. et al. Genotype-phenotype correlation in 22q11.2 deletion syndrome. BMC Med. Genet. 13, 122 (2012).
45. Guipponi, M. et al. Exome sequencing in 53 sporadic cases of schizophrenia identifies 18 putative candidate genes. PLoS One 9, e112745 (2014).
46. Girard, S.L. et al. Increased exonic de novo mutation rate in individuals with schizophrenia. Nat. Genet. 43, 860-863 (2011).
47. McCarthy, S.E. et al. De novo mutations in schizophrenia implicate chromatin remodeling and support a genetic overlap with autism and intellectual disability. Mol. Psychiatry 19, 652-658 (2014).
48. Takata, A. et al. Loss-of-function variants in schizophrenia risk and SETD1A as a candidate susceptibility gene. Neuron 82, 773-780 (2014).
49. Xu, B. et al. Exome sequencing supports a de novo mutational paradigm for schizophrenia. Nat. Genet. 43, 864-868 (2011).
50. Xu, B. et al. De novo gene mutations highlight patterns of genetic and neural complexity in schizophrenia. Nat. Genet. 44, 1365-1369 (2012).
51. Do, R. et al. Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. Nature 518, 102-106 (2015).
52. Kircher, M. et al. A general framework for estimating the relative pathogenicity of human genetic variants. Nat. Genet. 46, 310-315 (2014).
53. Doody, G.A., Johnstone, E.C., Sanderson, T.L., Owens, D.G. &Muir, W.J. 'Pfropfschizophrenie' revisited. Schizophrenia in people with mild learning disability. Br. J. Psychiatry 173, 145-153 (1998).