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Downloads/ (Accessed on 17 January 2020) cells Review Novel Approaches for Identifying the Molecular Background of Schizophrenia Arkadiy K. Golov 1,2,*, Nikolay V. Kondratyev 1 , George P. Kostyuk 3 and Vera E. Golimbet 1 1 Mental Health Research Center, 34 Kashirskoye shosse, 115522 Moscow, Russian; [email protected] (N.V.K.); [email protected] (V.E.G.) 2 Institute of Gene Biology, Russian Academy of Sciences, 34/5 Vavilova Street, 119334 Moscow, Russian 3 Alekseev Psychiatric Clinical Hospital No. 1, 2 Zagorodnoye shosse, 115191 Moscow, Russian; [email protected] * Correspondence: [email protected] Received: 5 November 2019; Accepted: 16 January 2020; Published: 18 January 2020 Abstract: Recent advances in psychiatric genetics have led to the discovery of dozens of genomic loci associated with schizophrenia. However, a gap exists between the detection of genetic associations and understanding the underlying molecular mechanisms. This review describes the basic approaches used in the so-called post-GWAS studies to generate biological interpretation of the existing population genetic data, including both molecular (creation and analysis of knockout animals, exploration of the transcriptional effects of common variants in human brain cells) and computational (fine-mapping of causal variability, gene set enrichment analysis, partitioned heritability analysis) methods. The results of the crucial studies, in which these approaches were used to uncover the molecular and neurobiological basis of the disease, are also reported. Keywords: schizophrenia; GWAS; causal genetic variants; enhancers; brain epigenomics; genome/epigenome editing 1. Introduction Schizophrenia is a severe mental illness that affects between 0.5% and 0.7% of the human population [1]. Both environmental and genetic factors are thought to be involved in its pathogenesis, with genetic factors playing a key role in disease risk, as the heritability of schizophrenia is estimated to be 70–85% [2,3]. According to a current polygenic model of schizophrenia, hundreds of common variants (polymorphisms) are responsible for the bulk of a population’s genetic predisposition [4–6]. The additive effect of this common variability can explain up to half of the heritability of schizophrenia measured in twin studies [7,8]. Genome-wide association studies (GWASs) that aim to identify common genetic variants associated with schizophrenia have become key sources of new information regarding the molecular mechanisms that underlie schizophrenia. Many recent studies have been inspired by the idea that the molecular and pathophysiological mechanisms of schizophrenia can be reconstructed based on genetic data [6,9]. However, several obstacles exist between identifying significant genetic associations and understanding the biology of this disease. A recent meta-analysis of several GWASs identified more than 150 polymorphisms associated with schizophrenia (Figure1A) [ 10,11]. However, each association detected by GWAS, in fact is not an individual polymorphism, but instead represents a group of polymorphisms from the same genomic region. This phenomenon is a reflection of linkage disequilibrium (LD), which describes the co-inheritance of polymorphisms located between two hot spots of meiotic recombination. As a result, these linked polymorphisms could be co-associated with the studied phenotypes [12]. Therefore, each independent association should more accurately be referred Cells 2020, 9, 246; doi:10.3390/cells9010246 www.mdpi.com/journal/cells Cells 2020, 9, 246 2 of 33 Cells 2020, 9, x FOR PEER REVIEW 2 of 30 referredto as a genomic to as a genomic locus or locus region or associated region associated with schizophrenia with schizophrenia (hereafter (hereafter referred referred to as GWAS to as region).GWAS region).The median The lengthmedian of length GWAS of regions GWAS in regions the meta-analysis in the meta-analysis performed performed by the Psychiatric by the Psychiatric Genomics GenomicsConsortium Consortium (PGC) is approximately (PGC) is approximately 130 kb, and 130 they kb, can and contain they can several contain dozens several of genes dozens [11 of]. Likely,genes [11].only oneLikely, or aonly few ofone the or polymorphisms a few of the polymorphisms in each region in are each associated region withare associated the disease with through the disease a direct throughcausal link a [direct13,14]. causal GWAS link results [13, do14]. not GWAS facilitate results the direct do not identification facilitate the of schizophrenia-associateddirect identification of schizophrenia-associatedgenes; however, a number ofgenes; approaches however, can a be number used to of identify approaches the most can plausible be used targetto identify genes the of causal most plausiblevariability. target Another genes key of obstacle causal preventingvariability. the Another translation key fromobstacle identifying preventing genetically-associated the translation from loci identifyingto understanding genetically-associated schizophrenia pathophysiology loci to understanding is the transition schizophrenia from genes pathophysiology to the molecular is andthe transitioncellular systems from genes in which to the the molecular products and of these cellular genes systems are active. in which Important the products tools in of this these step genes include are active.the study Important of brain celltools diversity, in this usingstep single-cellinclude the transcriptomics, study of brain and cell analytical diversity, approaches using single-cell that have transcriptomics,been developed inand the analytical field of systems approaches biology. that Ahave new been area developed of research, in post-GWAS the field of studies,systems hasbiology. been Aestablished new area of to research, address these post-GWAS issues [ 15studies,]. In this has review, been established we describe to theaddress basic these approaches issues [15]. that In could this review,be utilised we todescribe identify the schizophrenia basic approaches genes that and coul to understandd be utilised schizophrenia to identify schizophrenia pathophysiology, genes and topresent understand the key schizophrenia results of these path studiesophysiology, (the concise and description present ofthe the key most results widely of appliedthese studies methods (the is conciseset out indescription Table1). of the most widely applied methods is set out in Table 1). Figure 1. Cont. Cells 2020, 9, 246 3 of 33 Cells 2020, 9, x FOR PEER REVIEW 3 of 30 FigureFigure 1. ResultsResults of of recent recent schizophrenia schizophrenia genome-wide genome-wide association association studies studies (GWASs) (GWASs) and and basic basic methodsmethods for for identification identification of schizophrenia genes. (A (A) )Manhattan Manhattan plot plot for for recent recent schizophrenia schizophrenia GWASGWAS meta-analysis [11]. [11]. Many Many GWAS GWAS regions regions cover cover several several genes. genes. However, However, some some of of them them are are locatedlocated in in intergenic intergenic DNA. DNA. Two Two representative representative GWAS GWAS regions regions are are zoomed zoomed in: in: significantly significantly associated associated polymorphismspolymorphisms are depicted as vertical bars. ( (BB)) Statistical Statistical fine-mapping fine-mapping of of genetic genetic associations. associations. Each Each polymorphism’spolymorphism’s probability probability to to be be causal causal is assessed in this type of analysis. Additional epigenetic informationinformation can can improve improve prediction prediction accuracy. accuracy. Idealized Idealized fine-mapping fine-mapping of of GWAS GWAS region region is is depicted. depicted. OnlyOnly one one of of 10 10 genome-wide genome-wide significant significant polymorphism polymorphismss (highlighted (highlighted in in dashed dashed rectangle) rectangle) appears appears to to bebe credible credible causal variant. ( C) Trans-ethnic GWAS.GWAS. Trans-ethnic Trans-ethnic study study including including human human populations populations of ofthree three di differentfferent ancestries ancestries is is represented. represented. Picture Picture shows shows oneone ofof 1010 variants from an idealized idealized GWAS GWAS regionregion as as consistently consistently (non-heterog (non-heterogeneously)eneously) associated associated with with the thephen phenotype.otype. It is assumed It is assumed that such that variantssuch variants are likely are likely to be to causal. be causal. (D) (DStudy) Study of ofhighly highly penetrant penetrant mutations mutations with with brain-related brain-related phenotypes.phenotypes. Genes, Genes, identified identified using using three three different different approaches approaches of of this this class class as as being being schizophrenia genes,genes, are are represented. Whole-ex Whole-exomeome sequencing sequencing (WES) (WES) studies studies indicated indicated that that rare rare mutations mutations in in SLC6A1SLC6A1 causecause schizophrenia schizophrenia [16]. [16]. This This stro stronglyngly suggests suggests that that expression expression of of SLC6A1SLC6A1 isis regulated regulated by by schizophrenia-associatedschizophrenia-associated common common variants variants as as one one of ofGW GWASAS regions regions is located is located in close in close vicinity vicinity to this to genethis gene(200 kb (200 upstream). kb upstream). Rare Mendelian Rare Mendelian syndrome syndrome with psychiatric with psychiatric symptoms symptoms confirms confirms role of TCF4 role inof schizophreniaTCF4 in schizophrenia
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