Protein-interaction-network-based analysis for genome-wide association analysis of schizophrenia in Han Chinese population.

Schizophrenia is a severe neuropsychiatric disorder with a strong and complex genetic background. Recent genome-wide association studies (GWAS) have successfully identified several susceptibility loci of schizophrenia. In order to interpret the functional role of the genetic variants and detect the combined effects of some of these genes on schizophrenia, protein-interaction-network-based analysis (PINBA) has emerged as an effective approach. In the current study, we conducted a PINBA of our previous GWAS data taken from the Han Chinese population. In order to do so, we used dense module search (DMS), a method that locates densely connected modules for complex diseases by integrating the association signal from GWAS datasets into the human protein-protein interaction (PPI) network. As a result, we identified one gene set with a joint effect significantly associated with schizophrenia and gene expression profiling analysis suggested that they were mainly neuro- and immune-related genes, such as glutamatergic gene (GRM5), GABAergic genes (GABRB1, GABARAP) and genes located in the MHC region (HLA-C, TAP2, HIST1H1B). Further pathway enrichment analysis suggested that these genes are involved in processes related to neuronal and immune systems, such as the Adherens junction pathway, the Neurotrophin signaling pathway and the Toll-like receptor signaling pathway. In our study, we identified a set of susceptibility genes that had been missed in single-marker GWAS, and our findings could promote the study of the genetic mechanisms in schizophrenia.

[1]  Peter Uetz,et al.  Exhaustive benchmarking of the yeast two-hybrid system , 2010, Nature Methods.

[2]  Kai Wang,et al.  Pathway-based approaches for analysis of genomewide association studies. , 2007, American journal of human genetics.

[3]  M. Cairns,et al.  Increased inflammatory markers identified in the dorsolateral prefrontal cortex of individuals with schizophrenia , 2013, Molecular Psychiatry.

[4]  Judy H. Cho,et al.  Finding the missing heritability of complex diseases , 2009, Nature.

[5]  Susumu Goto,et al.  KEGG for representation and analysis of molecular networks involving diseases and drugs , 2009, Nucleic Acids Res..

[6]  A. Craig,et al.  Induction of GABAergic postsynaptic differentiation by alpha-neurexins. , 2008, The Journal of biological chemistry.

[7]  Jason H. Moore,et al.  Missing heritability and strategies for finding the underlying causes of complex disease , 2010, Nature Reviews Genetics.

[8]  Ramnik J. Xavier,et al.  Gene enrichment profiles reveal T-cell development, differentiation, and lineage-specific transcription factors including ZBTB25 as a novel NF-AT repressor. , 2010, Blood.

[9]  A. Barabasi,et al.  Network medicine : a network-based approach to human disease , 2010 .

[10]  M. Stoll,et al.  A genome-wide association study identifies a gene network of ADAMTS genes in the predisposition to pediatric stroke. , 2012, Blood.

[11]  C. Spencer,et al.  Identification of loci associated with schizophrenia by genome-wide association and follow-up , 2008, Nature Genetics.

[12]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[13]  Jianxin Shi,et al.  Common variants on chromosome 6p22.1 are associated with schizophrenia , 2009, Nature.

[14]  Pall I. Olason,et al.  Common variants conferring risk of schizophrenia , 2009, Nature.

[15]  G. Thaker,et al.  Advances in schizophrenia , 2001, Nature Medicine.

[16]  Bing Liu,et al.  Gene expression analysis reveals schizophrenia-associated dysregulation of immune pathways in peripheral blood mononuclear cells , 2012, Journal of Psychiatric Research.

[17]  Tyrone D. Cannon,et al.  Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study , 2009, The Lancet.

[18]  F. Collins,et al.  Potential etiologic and functional implications of genome-wide association loci for human diseases and traits , 2009, Proceedings of the National Academy of Sciences.

[19]  P. Matthews,et al.  Pathway and network-based analysis of genome-wide association studies in multiple sclerosis , 2009, Human molecular genetics.

[20]  Wei Zheng,et al.  dmGWAS: dense module searching for genome-wide association studies in protein-protein interaction networks , 2011, Bioinform..

[21]  Benno Schwikowski,et al.  Discovering regulatory and signalling circuits in molecular interaction networks , 2002, ISMB.

[22]  Aiden Corvin,et al.  Network-assisted investigation of combined causal signals from genome-wide association studies in schizophrenia. , 2012 .

[23]  H. Hakonarson,et al.  Analysing biological pathways in genome-wide association studies , 2010, Nature Reviews Genetics.

[24]  Daniel L. Koller,et al.  Convergent functional genomics of schizophrenia: from comprehensive understanding to genetic risk prediction , 2012, Molecular Psychiatry.

[25]  Yan V. Sun,et al.  Integration of biological networks and pathways with genetic association studies , 2012, Human Genetics.

[26]  R. Handsaker,et al.  Genome-wide association study in a Swedish population yields support for greater CNV and MHC involvement in schizophrenia compared with bipolar disorder , 2012, Molecular Psychiatry.

[27]  B. Millet,et al.  Association of Disrupted in Schizophrenia 1 (DISC1) missense variants with ultra-resistant schizophrenia , 2011, The Pharmacogenomics Journal.

[28]  Brad T. Sherman,et al.  Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources , 2008, Nature Protocols.

[29]  Anders D. Børglum,et al.  Genome-wide association study identifies five new schizophrenia loci , 2011, Nature Genetics.

[30]  A. Craig,et al.  Induction of GABAergic Postsynaptic Differentiation by α-Neurexins* , 2008, Journal of Biological Chemistry.

[31]  P. Visscher,et al.  Common polygenic variation contributes to risk of schizophrenia and bipolar disorder , 2009, Nature.

[32]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[33]  E. Lambe,et al.  Schizophrenia susceptibility pathway neuregulin 1–ErbB4 suppresses Src upregulation of NMDA receptors , 2011, Nature Medicine.

[34]  Robert J. Elshire,et al.  Switchgrass Genomic Diversity, Ploidy, and Evolution: Novel Insights from a Network-Based SNP Discovery Protocol , 2013, PLoS genetics.

[35]  M. Gill,et al.  Molecular pathways involved in neuronal cell adhesion and membrane scaffolding contribute to schizophrenia and bipolar disorder susceptibility , 2011, Molecular Psychiatry.

[36]  Yi Wang,et al.  Genome-wide association study identifies a susceptibility locus for schizophrenia in Han Chinese at 11p11.2 , 2011, Nature Genetics.

[37]  Hai-Gwo Hwu,et al.  Genome-Wide Association Study of Treatment Refractory Schizophrenia in Han Chinese , 2012, PloS one.

[38]  David Curtis,et al.  Case–case genome-wide association analysis shows markers differentially associated with schizophrenia and bipolar disorder and implicates calcium channel genes , 2011, Psychiatric genetics.

[39]  H. Stefánsson,et al.  Common variants at VRK2 and TCF4 conferring risk of schizophrenia. , 2011, Human molecular genetics.

[40]  Y. Liou,et al.  Association Analysis of the Genetic Variants of the N-Methyl D-Aspartate Receptor Subunit 2b (NR2b) and Treatment-Refractory Schizophrenia in the Chinese , 2003, Neuropsychobiology.