Identification of de novo mutations in prenatal neurodevelopment-associated genes in schizophrenia in two Han Chinese patient-sibling family-based cohorts.
Journal
Translational psychiatry
ISSN: 2158-3188
Titre abrégé: Transl Psychiatry
Pays: United States
ID NLM: 101562664
Informations de publication
Date de publication:
01 09 2020
01 09 2020
Historique:
received:
17
03
2020
accepted:
10
08
2020
revised:
01
08
2020
entrez:
3
9
2020
pubmed:
3
9
2020
medline:
22
6
2021
Statut:
epublish
Résumé
Schizophrenia (SCZ) is a severe psychiatric disorder with a strong genetic component. High heritability of SCZ suggests a major role for transmitted genetic variants. Furthermore, SCZ is also associated with a marked reduction in fecundity, leading to the hypothesis that alleles with large effects on risk might often occur de novo. In this study, we conducted whole-genome sequencing for 23 families from two cohorts with unaffected siblings and parents. Two nonsense de novo mutations (DNMs) in GJC1 and HIST1H2AD were identified in SCZ patients. Ten genes (DPYSL2, NBPF1, SDK1, ZNF595, ZNF718, GCNT2, SNX9, AACS, KCNQ1, and MSI2) were found to carry more DNMs in SCZ patients than their unaffected siblings by burden test. Expression analyses indicated that these DNM implicated genes showed significantly higher expression in prefrontal cortex in prenatal stage. The DNM in the GJC1 gene is highly likely a loss function mutation (pLI = 0.94), leading to the dysregulation of ion channel in the glutamatergic excitatory neurons. Analysis of rare variants in independent exome sequencing dataset indicates that GJC1 has significantly more rare variants in SCZ patients than in unaffected controls. Data from genome-wide association studies suggested that common variants in the GJC1 gene may be associated with SCZ and SCZ-related traits. Genes co-expressed with GJC1 are involved in SCZ, SCZ-associated pathways, and drug targets. These evidences suggest that GJC1 may be a risk gene for SCZ and its function may be involved in prenatal and early neurodevelopment, a vulnerable period for developmental disorders such as SCZ.
Identifiants
pubmed: 32873781
doi: 10.1038/s41398-020-00987-z
pii: 10.1038/s41398-020-00987-z
pmc: PMC7463022
doi:
Substances chimiques
Connexins
0
connexin 45
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Retracted Publication
Langues
eng
Sous-ensembles de citation
IM
Pagination
307Subventions
Organisme : NLM NIH HHS
ID : R01 LM012806
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH085560
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH101054
Pays : United States
Commentaires et corrections
Type : RetractionIn
Références
Schizophrenia Working Group of the Psychiatric Genomics C. Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421–427 (2014).
doi: 10.1038/nature13595
Sekar, A. et al. Schizophrenia risk from complex variation of complement component 4. Nature 530, 177–183 (2016).
pmcid: 4752392
doi: 10.1038/nature16549
pubmed: 26814963
Marshall, C. R. et al. Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects. Nat. Genet. 49, 27–35 (2017).
doi: 10.1038/ng.3725
pubmed: 27869829
pmcid: 27869829
Iossifov, I. et al. The contribution of de novo coding mutations to autism spectrum disorder. Nature 515, 216–221 (2014).
pmcid: 4313871
doi: 10.1038/nature13908
pubmed: 25363768
Kim, D. S. et al. Sequencing of sporadic Attention-Deficit Hyperactivity Disorder (ADHD) identifies novel and potentially pathogenic de novo variants and excludes overlap with genes associated with autism spectrum disorder. Am. J. Med. Genet. B Neuropsychiatr. Genet. 174, 381–389 (2017).
pmcid: 5467442
doi: 10.1002/ajmg.b.32527
pubmed: 28332277
Epi, K. C. De novo mutations in SLC1A2 and CACNA1A are important causes of epileptic encephalopathies. Am. J. Hum. Genet. 99, 287–298 (2016).
doi: 10.1016/j.ajhg.2016.06.003
Xu, B. et al. Exome sequencing supports a de novo mutational paradigm for schizophrenia. Nat. Genet. 43, 864–868 (2011).
pmcid: 3196550
doi: 10.1038/ng.902
pubmed: 21822266
Girard, S. L. et al. Increased exonic de novo mutation rate in individuals with schizophrenia. Nat. Genet. 43, 860–863 (2011).
doi: 10.1038/ng.886
pubmed: 21743468
pmcid: 21743468
Fromer, M. et al. De novo mutations in schizophrenia implicate synaptic networks. Nature 506, 179–184 (2014).
pmcid: 4237002
doi: 10.1038/nature12929
pubmed: 24463507
Francioli, L. C. et al. Genome-wide patterns and properties of de novo mutations in humans. Nat. Genet. 47, 822–826 (2015).
pmcid: 4485564
doi: 10.1038/ng.3292
pubmed: 25985141
Wang, G. S. & Cooper, T. A. Splicing in disease: disruption of the splicing code and the decoding machinery. Nat. Rev. Genet. 8, 749–761 (2007).
doi: 10.1038/nrg2164
pubmed: 17726481
pmcid: 17726481
Takata, A., Matsumoto, N. & Kato, T. Genome-wide identification of splicing QTLs in the human brain and their enrichment among schizophrenia-associated loci. Nat. Commun. 8, 14519 (2017).
pmcid: 5333373
doi: 10.1038/ncomms14519
pubmed: 28240266
Takata, A., Ionita-Laza, I., Gogos, J. A., Xu, B. & Karayiorgou, M. De novo synonymous mutations in regulatory elements contribute to the genetic etiology of autism and schizophrenia. Neuron 89, 940–947 (2016).
pmcid: 4793939
doi: 10.1016/j.neuron.2016.02.024
pubmed: 26938441
Hwu, H. G. et al. Taiwan schizophrenia linkage study: the field study. Am. J. Med. Genet. B Neuropsychiatr. Genet. 134B, 30–36 (2005).
doi: 10.1002/ajmg.b.30139
pubmed: 15685625
pmcid: 15685625
Faraone, S. V. et al. Genome scan of Han Chinese schizophrenia families from Taiwan: confirmation of linkage to 10q22.3. Am. J. Psychiatry 163, 1760–1766 (2006).
doi: 10.1176/ajp.2006.163.10.1760
pubmed: 17012687
pmcid: 17012687
Chen, W. J., Hsiao, C. K., Hsiao, L. L. & Hwu, H. G. Performance of the Continuous Performance Test among community samples. Schizophr. Bull. 24, 163–174 (1998).
doi: 10.1093/oxfordjournals.schbul.a033308
pubmed: 9502554
pmcid: 9502554
Chen, J. et al. A frameshift variant in the CHST9 gene identified by family-based whole genome sequencing is associated with schizophrenia in Chinese population. Sci. Rep. 9, 12717 (2019).
pmcid: 6722128
doi: 10.1038/s41598-019-49052-w
pubmed: 31481703
Van der Auwera, G. A. et al. From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline. Curr. Protoc. Bioinforma. 43, 11–33 (2013). 11 10.
doi: 10.1002/0471250953.bi1110s43
Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754–1760 (2009).
pmcid: 19451168
doi: 10.1093/bioinformatics/btp324
pubmed: 19451168
Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).
pmcid: 1950838
doi: 10.1086/519795
pubmed: 1950838
Francioli, L. C. et al. A framework for the detection of de novo mutations in family-based sequencing data. Eur. J. Hum. Genet. 25, 227–233 (2017).
doi: 10.1038/ejhg.2016.147
Wei, Q. et al. A Bayesian framework for de novo mutation calling in parents-offspring trios. Bioinformatics 31, 1375–1381 (2015).
doi: 10.1093/bioinformatics/btu839
Ramu, A. et al. DeNovoGear: de novo indel and point mutation discovery and phasing. Nat. Methods 10, 985–987 (2013).
pmcid: 4003501
doi: 10.1038/nmeth.2611
pubmed: 23975140
Wang, K., Li, M. & Hakonarson, H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 38, e164 (2010).
pmcid: 2938201
doi: 10.1093/nar/gkq603
pubmed: 20601685
Untergasser, A. et al. Primer3Plus, an enhanced web interface to Primer3. Nucleic Acids Res. 35, W71–W74 (2007).
pmcid: 1933133
doi: 10.1093/nar/gkm306
pubmed: 17485472
Ware, J. S., Samocha, K. E., Homsy, J. & Daly, M. J. Interpreting de novo variation in human disease using denovolyzeR. Curr. Protoc. Hum. Genet. 87, 21–15 (2015). 7 25.
Singh, T. et al. Rare loss-of-function variants in SETD1A are associated with schizophrenia and developmental disorders. Nat. Neurosci. 19, 571–577 (2016).
pmcid: 6689268
doi: 10.1038/nn.4267
pubmed: 26974950
Ionita-Laza, I., Lee, S., Makarov, V., Buxbaum, J. D. & Lin, X. Sequence kernel association tests for the combined effect of rare and common variants. Am. J. Hum. Genet. 92, 841–853 (2013).
pmcid: 3675243
doi: 10.1016/j.ajhg.2013.04.015
pubmed: 23684009
Wang D. et al. Comprehensive functional genomic resource and integrative model for the human brain. Science 362, eaat8464 (2018).
Dreos, R., Ambrosini, G., Perier, R. C. & Bucher, P. The Eukaryotic Promoter Database: expansion of EPDnew and new promoter analysis tools. Nucleic Acids Res. 43, D92–D96 (2015).
doi: 10.1093/nar/gku1111
pubmed: 25378343
pmcid: 25378343
Khandaker, G. M., Zimbron, J., Lewis, G. & Jones, P. B. Prenatal maternal infection, neurodevelopment and adult schizophrenia: a systematic review of population-based studies. Psychol. Med. 43, 239–257 (2013).
doi: 10.1017/S0033291712000736
pubmed: 22717193
pmcid: 22717193
Susser, E., St Clair, D. & He, L. Latent effects of prenatal malnutrition on adult health: the example of schizophrenia. Ann. N.Y. Acad. Sci. 1136, 185–192 (2008).
doi: 10.1196/annals.1425.024
pubmed: 18579882
pmcid: 18579882
Khashan, A. S. et al. Higher risk of offspring schizophrenia following antenatal maternal exposure to severe adverse life events. Arch. Gen. Psychiatry 65, 146–152 (2008).
doi: 10.1001/archgenpsychiatry.2007.20
Birnbaum, R. & Weinberger, D. R. Genetic insights into the neurodevelopmental origins of schizophrenia. Nat. Rev. Neurosci. 18, 727–740 (2017).
doi: 10.1038/nrn.2017.125
Colantuoni, C. et al. Temporal dynamics and genetic control of transcription in the human prefrontal cortex. Nature 478, 519–523 (2011).
pmcid: 3510670
doi: 10.1038/nature10524
pubmed: 3510670
Miller, J. A. et al. Transcriptional landscape of the prenatal human brain. Nature 508, 199–206 (2014).
pmcid: 4105188
doi: 10.1038/nature13185
pubmed: 4105188
Grote, S., Prufer, K., Kelso, J. & Dannemann, M. ABAEnrichment: an R package to test for gene set expression enrichment in the adult and developing human brain. Bioinformatics 32, 3201–3203 (2016).
pmcid: 5048072
doi: 10.1093/bioinformatics/btw392
pubmed: 5048072
Fertuzinhos, S. et al. Laminar and temporal expression dynamics of coding and noncoding RNAs in the mouse neocortex. Cell. Rep. 6, 938–950 (2014).
pmcid: 3999901
doi: 10.1016/j.celrep.2014.01.036
pubmed: 24561256
Bakken, T. E. et al. A comprehensive transcriptional map of primate brain development. Nature 535, 367–375 (2016).
pmcid: 5325728
doi: 10.1038/nature18637
pubmed: 27409810
Autism Spectrum Disorders Working Group of The Psychiatric Genomics C. Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia. Mol. Autism 8, 21 (2017).
doi: 10.1186/s13229-017-0137-9
Demontis, D. et al. Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder. Nat. Genet. 51, 63–75 (2019).
doi: 10.1038/s41588-018-0269-7
pubmed: 30478444
pmcid: 30478444
Stahl, E. A. et al. Genome-wide association study identifies 30 loci associated with bipolar disorder. Nat. Genet. 51, 793–803 (2019).
pmcid: 6956732
doi: 10.1038/s41588-019-0397-8
pubmed: 31043756
Wray, N. R. et al. Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression. Nat. Genet. 50, 668–681 (2018).
pmcid: 5934326
doi: 10.1038/s41588-018-0090-3
pubmed: 29700475
Savage, J. E. et al. Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence. Nat. Genet. 50, 912–919 (2018).
pmcid: 6411041
doi: 10.1038/s41588-018-0152-6
pubmed: 29942086
Lee, J. J. et al. Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals. Nat. Genet. 50, 1112–1121 (2018).
pmcid: 6393768
doi: 10.1038/s41588-018-0147-3
pubmed: 30038396
Liu, M. et al. Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use. Nat. Genet. 51, 237–244 (2019).
pmcid: 6358542
doi: 10.1038/s41588-018-0307-5
pubmed: 30643251
Wang, J., Vasaikar, S., Shi, Z., Greer, M. & Zhang, B. WebGestalt 2017: a more comprehensive, powerful, flexible and interactive gene set enrichment analysis toolkit. Nucleic Acids Res. 45, W130–W137 (2017).
pmcid: 5570149
doi: 10.1093/nar/gkx356
pubmed: 28472511
Benjamini, Y. & Hochberg, Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. R. Stat. Soc.: Ser. B (Methodol.) 57, 289–300 (1995).
Lake, B. B. et al. Integrative single-cell analysis of transcriptional and epigenetic states in the human adult brain. Nat. Biotechnol. 36, 70–80 (2018).
doi: 10.1038/nbt.4038
pubmed: 29227469
pmcid: 29227469
Butler, A., Hoffman, P., Smibert, P., Papalexi, E. & Satija, R. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat. Biotechnol. 36, 411–420 (2018).
pmcid: 29608179
doi: 10.1038/nbt.4096
pubmed: 29608179
Xu, B. et al. De novo gene mutations highlight patterns of genetic and neural complexity in schizophrenia. Nat. Genet. 44, 1365–1369 (2012).
pmcid: 3556813
doi: 10.1038/ng.2446
pubmed: 23042115
Samocha, K. E. et al. A framework for the interpretation of de novo mutation in human disease. Nat. Genet. 46, 944–950 (2014).
pmcid: 4222185
doi: 10.1038/ng.3050
pubmed: 25086666
O’Roak, B. J. et al. Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science 338, 1619–1622 (2012).
pmcid: 3528801
doi: 10.1126/science.1227764
pubmed: 23160955
Kircher, M. et al. A general framework for estimating the relative pathogenicity of human genetic variants. Nat. Genet. 46, 310–315 (2014).
pmcid: 3992975
doi: 10.1038/ng.2892
pubmed: 24487276
Lek, M. et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature 536, 285–291 (2016).
pmcid: 5018207
doi: 10.1038/nature19057
pubmed: 5018207
Gilman, S. R. et al. Diverse types of genetic variation converge on functional gene networks involved in schizophrenia. Nat. Neurosci. 15, 1723–1728 (2012).
pmcid: 3689007
doi: 10.1038/nn.3261
pubmed: 23143521
Leung, D. S., Unsicker, K. & Reuss, B. Expression and developmental regulation of gap junction connexins cx26, cx32, cx43 and cx45 in the rat midbrain-floor. Int. J. Dev. Neurosci. 20, 63–75 (2002).
doi: 10.1016/S0736-5748(01)00056-9
pubmed: 12008076
pmcid: 12008076
Aukes, M. F. et al. Genetic overlap among intelligence and other candidate endophenotypes for schizophrenia. Biol. Psychiatry 65, 527–534 (2009).
doi: 10.1016/j.biopsych.2008.09.020
pubmed: 19013556
pmcid: 19013556
Le Hellard, S. et al. Identification of gene loci that overlap between schizophrenia and educational attainment. Schizophr. Bull. 43, 654–664 (2017).
pubmed: 27338279
pmcid: 27338279
Liddle, P. F. Schizophrenic syndromes, cognitive performance and neurological dysfunction. Psychol. Med. 17, 49–57 (1987).
doi: 10.1017/S0033291700012976
Nielsen, S. M., Toftdahl, N. G., Nordentoft, M. & Hjorthoj, C. Association between alcohol, cannabis, and other illicit substance abuse and risk of developing schizophrenia: a nationwide population based register study. Psychol. Med. 47, 1668–1677 (2017).
doi: 10.1017/S0033291717000162
Olney, J. W. & Farber, N. B. Glutamate receptor dysfunction and schizophrenia. Arch. Gen. Psychiatry 52, 998–1007 (1995).
doi: 10.1001/archpsyc.1995.03950240016004
Yamasaki, R. J. C. & Neuroimmunology, E. Connexins in health and disease.Cin. Exp. Neuroimmunol. 9, 30–36 (2018).
doi: 10.1111/cen3.12433
Hug, N., Longman, D. & Caceres, J. F. Mechanism and regulation of the nonsense-mediated decay pathway. Nucleic Acids Res. 44, 1483–1495 (2016).
pmcid: 4770240
doi: 10.1093/nar/gkw010
pubmed: 4770240
Kruger, O. et al. Defective vascular development in connexin 45-deficient mice. Development 127, 4179–4193 (2000).
Kumai, M. et al. Loss of connexin45 causes a cushion defect in early cardiogenesis. Development 127, 3501–3512 (2000).
Nishii, K. et al. Mice lacking connexin45 conditionally in cardiac myocytes display embryonic lethality similar to that of germline knockout mice without endocardial cushion defect. Cell Commun. Adhes. 10, 365–369 (2003).
doi: 10.1080/cac.10.4-6.365.369
pubmed: 14681043
pmcid: 14681043
Homsy, J. et al. De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies. Science 350, 1262–1266 (2015).
pmcid: 4890146
doi: 10.1126/science.aac9396
pubmed: 26785492
Miyake, A. et al. Disruption of the ether-a-go-go K+ channel gene BEC1/KCNH3 enhances cognitive function. J. Neurosci. 29, 14637–14645 (2009).
pmcid: 6665833
doi: 10.1523/JNEUROSCI.0901-09.2009
pubmed: 19923296
Ghelardini, C., Galeotti, N. & Bartolini, A. Influence of potassium channel modulators on cognitive processes in mice. Br. J. Pharmacol. 123, 1079–1084 (1998).
pmcid: 1565263
doi: 10.1038/sj.bjp.0701709
pubmed: 1565263
Mitterauer, B. Loss of function of glial gap junctions may cause severe cognitive impairments in schizophrenia. Med. Hypotheses 73, 393–397 (2009).
doi: 10.1016/j.mehy.2009.04.003
pubmed: 19435655
pmcid: 19435655
Lewis, D. A., Hashimoto, T. & Volk, D. W. Cortical inhibitory neurons and schizophrenia. Nat. Rev. Neurosci. 6, 312–324 (2005).
doi: 10.1038/nrn1648
Guidotti, A. et al. GABAergic dysfunction in schizophrenia: new treatment strategies on the horizon. Psychopharmacology 180, 191–205 (2005).
doi: 10.1007/s00213-005-2212-8
pubmed: 15864560
pmcid: 15864560
Hasan, A., Mitchell, A., Schneider, A., Halene, T. & Akbarian, S. Epigenetic dysregulation in schizophrenia: molecular and clinical aspects of histone deacetylase inhibitors. Eur. Arch. Psychiatry Clin. Neurosci. 263, 273–284 (2013).
doi: 10.1007/s00406-013-0395-2
Luan, Z., Lu, T., Ruan, Y., Yue, W. & Zhang, D. The human MSI2 gene is associated with schizophrenia in the Chinese Han population. Neurosci. Bull. 32, 239–245 (2016).
pmcid: 5563770
doi: 10.1007/s12264-016-0026-9
pubmed: 5563770
Lee, H. et al. Changes in Dpysl2 expression are associated with prenatally stressed rat offspring and susceptibility to schizophrenia in humans. Int. J. Mol. Med. 35, 1574–1586 (2015).
pmcid: 4432923
doi: 10.3892/ijmm.2015.2161
pubmed: 4432923
Bruce, H. A. et al. Potassium channel gene associations with joint processing speed and white matter impairments in schizophrenia. Genes Brain Behav. 16, 515–521 (2017).
pmcid: 5457349
doi: 10.1111/gbb.12372
pubmed: 5457349
Geschwind M. et al. Neuropsychological profiles of voltage-gated potassium channel complex and other autoimmune encephalopathies; more than memory impairment (S18. 005). AAN Enterprises (2014).
Meyer-Lindenberg, A. S. et al. Regionally specific disturbance of dorsolateral prefrontal-hippocampal functional connectivity in schizophrenia. Arch. Gen. Psychiatry 62, 379–386 (2005).
doi: 10.1001/archpsyc.62.4.379
Peltola, M. A. et al. AMIGO-Kv2.1 potassium channel complex is associated with schizophrenia-related phenotypes. Schizophr. Bull. 42, 191–201 (2016).
pubmed: 26240432
pmcid: 26240432
Pers, T. H. et al. Comprehensive analysis of schizophrenia-associated loci highlights ion channel pathways and biologically plausible candidate causal genes. Hum. Mol. Genet. 25, 1247–1254 (2016).
pmcid: 4764200
doi: 10.1093/hmg/ddw007
pubmed: 26755824
Gmitrowicz, A. & Kucharska, A. Developmental disorders in the fourth edition of the American classification: diagnostic and statistical manual of mental disorders (DSM IV-optional book). Psychiatr. Pol. 28, 509 (1994).
pubmed: 7527563
pmcid: 7527563
Lam, M. et al. Comparative genetic architectures of schizophrenia in East Asian and European populations. Nat. Genet. 51, 1670–1678 (2019).
pmcid: 6885121
doi: 10.1038/s41588-019-0512-x
pubmed: 31740837