Abstract
The complexity of schizophrenia (SZ) and bipolar disorder (BD) has slowed down progress in understanding their genetic roots. Alternative genomic approaches are needed to bypass these difficulties. We attempted a multimodal approach to follow-up on reported linkage findings in SZ and BD from the Eastern Quebec kindreds in chromosomes 3q21, 4p34, 6p22, 8p21, 8p11, 13q11-q14, 15q13, 16p12, and 18q21. First, in 498 subjects, we measured RNA expression (47 K Illumina chips) in SZ and BD patients that we compared with their non-affected relatives (NARs) to identify, for each chromosomal region, genes showing the most significant differences in expression. Second, we performed SNP genotyping (700 K Illumina chips) and cis-eQTN analysis. Third, we measured DNA methylation on genes with RNA expression differences or eQTNs. We found a significant overexpression of the gene ITGB5 at 3q25 in SZ and BD after multiple testing p value adjustment. SPCS3 gene at 4q34, and FZD3 gene at 8p21, contained significant eQTNs after multiple testing corrections, while ITGB5 provided suggestive results. Methylation in associated genes did not explain the expression differences between patients and NARs. Our multimodal approach involving RNA expression, dense SNP genotyping and eQTN analyses, restricted to chromosomal regions having shown linkage, lowered the multiple testing burden and allowed for a deeper examination of candidate genes in SZ or BD.
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References
Sekar A, Bialas AR, de Rivera H, Davis A, Hammond TR, Kamitaki N, et al. Schizophrenia risk from complex variation of complement component 4. Nature. 2016;530:177–83.
Paccalet T, Gilbert E, Berthelot N, Marquet P, Jomphe V, Lussier D, et al. Liability indicators aggregate many years before transition to illness in offspring descending from kindreds affected by schizophrenia or bipolar disorder. Schizophrenia Res. 2016;175:186–92.
Cannon TD, Chung Y, He G, Sun D, Jacobson A, van Erp TG, et al. Progressive reduction in cortical thickness as psychosis develops: a multisite longitudinal neuroimaging study of youth at elevated clinical risk. Biol Psychiatry. 2015;77:147–57.
Glausier JR, Lewis DA. Dendritic spine pathology in schizophrenia. Neuroscience. 2013;251:90–107.
Kendler KS. What psychiatric genetics has taught us about the nature of psychiatric illness and what is left to learn. Mol Psychiatry. 2013;18:1058–66.
Keshavan MS. Development, disease and degeneration in schizophrenia: a unitary pathophysiological model. J Psychiatry Res. 1999;33:513–21.
Maziade M, Paccalet T. A protective-compensatory model may reconcile the genetic and the developmental findings in schizophrenia. Schizophrenia Res. 2013;144:9–15.
Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511:421–7.
Kim S, Cho H, Lee D, Webster MJ. Association between SNPs and gene expression in multiple regions of the human brain. Transl Psychiatry. 2012;2:e113.
Glatt SJ, Everall IP, Kremen WS, Corbeil J, Sasik R, Khanlou N, et al. Comparative gene expression analysis of blood and brain provides concurrent validation of SELENBP1 up-regulation in schizophrenia. PNAS. 2005;102:15533–8.
Sullivan PF, Fan C, Perou CM. Evaluating the comparability of gene expression in blood and brain. Am J Med Genet Part B, Neuropsychiatr Genet. 2006;141B:261–8.
Chagnon YC, Roy MA, Bureau A, Merette C, Maziade M. Differential RNA expression between schizophrenic patients and controls of the dystrobrevin binding protein 1 and neuregulin 1 genes in immortalized lymphocytes. Schizophrenia Res. 2008;100:281–90.
Cattane N, Minelli A, Milanesi E, Maj C, Bignotti S, Bortolomasi M, et al. Altered gene expression in schizophrenia: findings from transcriptional signatures in fibroblasts and blood. PLoS ONE. 2015;10:e0116686.
Lee J, Goh LK, Chen G, Verma S, Tan CH, Lee TS. Analysis of blood-based gene expression signature in first-episode psychosis. Psychiatry Res. 2012;200:52–4.
Maschietto M, Silva AR, Puga RD, Lima L, Pereira CB, Nakano EY, et al. Gene expression of peripheral blood lymphocytes may discriminate patients with schizophrenia from controls. Psychiatry Res. 2012;200:1018–21.
Takahashi M, Hayashi H, Watanabe Y, Sawamura K, Fukui N, Watanabe J, et al. Diagnostic classification of schizophrenia by neural network analysis of blood-based gene expression signatures. Schizophrenia Res. 2010;119:210–8.
Clelland CL, Read LL, Panek LJ, Nadrich RH, Bancroft C, Clelland JD. Utilization of never-medicated bipolar disorder patients towards development and validation of a peripheral biomarker profile. PLoS ONE. 2013;8:e69082.
Kato T, Hayashi-Takagi A, Toyota T, Yoshikawa T, Iwamoto K. Gene expression analysis in lymphoblastoid cells as a potential biomarker of bipolar disorder. J Hum Genet. 2011;56:779–83.
Fromer M, Roussos P, Sieberts SK, Johnson JS, Kavanagh DH, Perumal TM, et al. Gene expression elucidates functional impact of polygenic risk for schizophrenia. Nat Neurosci. 2016;19:1442–53.
Lopez de Lara C, Jaitovich-Groisman I, Cruceanu C, Mamdani F, Lebel V, Yerko V, et al. Implication of synapse-related genes in bipolar disorder by linkage and gene expression analyses. Int J Neuropsychopharmacol. 2010;13:1397–410.
Kinoshita M, Numata S, Tajima A, Shimodera S, Ono S, Imamura A, et al. DNA methylation signatures of peripheral leukocytes in schizophrenia. Neuromolecular Med. 2013;15:95–101.
Nishioka M, Bundo M, Koike S, Takizawa R, Kakiuchi C, Araki T, et al. Comprehensive DNA methylation analysis of peripheral blood cells derived from patients with first-episode schizophrenia. J Hum Genet. 2013;58:91–7.
Kumar G, Clark SL, McClay JL, Shabalin AA, Adkins DE, Xie L, et al. Refinement of schizophrenia GWAS loci using methylome-wide association data. Hum Genet. 2015;134:77–87.
Hannon E, Dempster E, Viana J, Burrage J, Smith AR, Macdonald R, et al. An integrated genetic-epigenetic analysis of schizophrenia: evidence for co-localization of genetic associations and differential DNA methylation. Genome Biol. 2016;17:176.
van Eijk KR, de Jong S, Strengman E, Buizer-Voskamp JE, Kahn RS, Boks MP, et al. Identification of schizophrenia-associated loci by combining DNA methylation and gene expression data from whole blood. Eur J Hum Genet. 2015;23:1106–10.
Maziade M, Roy MA, Chagnon YC, Cliche D, Fournier JP, Montgrain N, et al. Shared and specific susceptibility loci for schizophrenia and bipolar disorder: a dense genome scan in Eastern Quebec families. Mol Psychiatry. 2005;10:486–99.
Merette C, Roy MA, Bureau A, Fournier A, Emond C, Cliche D, et al. Replication of linkage with bipolar disorder on chromosome 16p in the Eastern Quebec population. Am J Med Genet Part B, Neuropsychiatr Genet. 2008;147B:737–44.
Maziade M, Chagnon YC, Roy MA, Bureau A, Fournier A, Merette C. Chromosome 13q13-q14 locus overlaps mood and psychotic disorders: the relevance for redefining phenotype. Eur J Hum Genet. 2009;17:1034–42.
Maziade M, Roy MA, Fournier JP, Cliche D, Merette C, Caron C, et al. Reliability of best-estimate diagnosis in genetic linkage studies of major psychoses: results from the Quebec pedigree studies. Am J Psychiatry. 1992;149:1674–86.
Maziade M, Roy MA, Martinez M, Cliche D, Fournier JP, Garneau Y, et al. Negative, psychoticism, and disorganized dimensions in patients with familial schizophrenia or bipolar disorder: continuity and discontinuity between the major psychoses. Am J Psychiatry. 1995;152:1458–63.
Roy MA, Lanctot G, Merette C, Cliche D, Fournier JP, Boutin P, et al. Clinical and methodological factors related to reliability of the best-estimate diagnostic procedure. Am J Psychiatry. 1997;154:1726–33.
Li LC, Dahiya R. MethPrimer: designing primers for methylation PCRs. Bioinformatics. 2002;18:1427–31.
Gagnon-Bartsch JA, Speed TP. Using control genes to correct for unwanted variation in microarray data. Biostatistics. 2012;13:539–52.
Zhao SD, Cai TT, Li H. More powerful genetic association testing via a new statistical framework for integrative genomics. Biometrics. 2014;70:881–90.
Karege F, Schwald M, El Kouaissi R. Drug-induced decrease of protein kinase a activity reveals alteration in BDNF expression of bipolar affective disorder. Neuropsychopharmacol. 29:805–12.
Bureau A, Chagnon YC, Croteau J, Fournier A, Roy MA, Paccalet T, et al. Follow-up of a major psychosis linkage site in 13q13-q14 reveals significant association in both case-control and family samples. Biol Psychiatry. 2013;74:444–50.
Kang C, Zhou L, Liu H, Yang J. Association study of the frizzled 3 gene with Chinese Va schizophrenia. Neurosci Lett. 2011;505:196–9.
Yang J, Si T, Ling Y, Ruan Y, Han Y, Wang X, et al. Association study of the human FZD3 locus with schizophrenia. Biol Psychiatry. 2003;54:1298–301.
Pantavou KG, Braliou GG, Kontou PI, Dimou NL, Bagos PG. A meta-analysis of FZD3 gene polymorphisms and their association with schizophrenia. Psychiatr Genet. 2016;26:272–80.
Tabares-Seisdedos R, Rubenstein JL. Chromosome 8p as a potential hub for developmental neuropsychiatric disorders: implications for schizophrenia, autism and cancer. Mol Psychiatry. 2009;14:563–89.
Acknowledgements
We are grateful to our professional research assistants: Louise Bélanger, Marie-Claude Boisvert, Linda René, Lisette Gagnon, Claudie Poirier, Nicole Leclerc, Julie Lamarche, Pierrette Boutin, Lise St-Germain, Mélanie Mercier, Isabel Moreau (Centre de recherche CERVO), and to the family members, adults and children, who participated in this study. We thank Dr Aurélie Labbe (HEC Montréal) for her statistical advices on gene expression data and Dr Chantal Mérette (Centre de recherche CERVO) for her input on data analysis.
Funding
This work was supported by the Canadian Institutes of Health research (CIHR, grants MOP-74430, MOP-119408 and MOP-114988) and by a Canada Research Chair (# 950–200810) in the genetics of neuropsychiatric disorders of which M. Maziade was the Chair. The data management system was supported by the Canada Foundation for Innovation Leadership Opportunity Fund (grant 27592).
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Chagnon, Y.C., Maziade, M., Paccalet, T. et al. A multimodal attempt to follow-up linkage regions using RNA expression, SNPs and CpG methylation in schizophrenia and bipolar disorder kindreds. Eur J Hum Genet 28, 499–507 (2020). https://doi.org/10.1038/s41431-019-0526-y
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DOI: https://doi.org/10.1038/s41431-019-0526-y
