title: Pathway-wide association study identifies five shared pathways associated with schizophrenia in three ancestral distinct populations.
abstract: Genome-wide association studies have confirmed the polygenic nature of schizophrenia and suggest that there are hundreds or thousands of alleles associated with increased liability for the disorder. However, the generalizability of any one allelic marker of liability is remarkably low and has bred the notion that schizophrenia may be better conceptualized as a pathway(s) disorder. Here, we empirically tested this notion by conducting a pathway-wide association study (PWAS) encompassing 255 experimentally validated Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways among 5033 individuals diagnosed with schizophrenia and 5332 unrelated healthy controls across three distinct ethnic populations; European-American (EA), African-American (AA) and Han Chinese (CH). We identified 103, 74 and 87 pathways associated with schizophrenia liability in the EA, CH and AA populations, respectively. About half of these pathways were uniquely associated with schizophrenia liability in each of the three populations. Five pathways (serotonergic synapse, ubiquitin mediated proteolysis, hedgehog signaling, adipocytokine signaling and renin secretion) were shared across all three populations and the single-nucleotide polymorphism sets representing these five pathways were enriched for single-nucleotide polymorphisms with regulatory function. Our findings provide empirical support for schizophrenia as a pathway disorder and suggest schizophrenia is not only a polygenic but likely also a poly-pathway disorder characterized by both genetic and pathway heterogeneity.
authors.affiliation: Department of Psychiatry, Melbourne Neuropsychiatry Centre, The University of Melbourne and Melbourne Health, Carlton South, VIC, Australia.
authors.forename: C
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Psychiatry, Melbourne Neuropsychiatry Centre, The University of Melbourne and Melbourne Health, Carlton South, VIC, Australia.|Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia.|Department of General Practice, The University of Melbourne, Parkville, VIC, Australia.|Centre for Human Psychopharmacology, Swinburne University of Technology, Hawthorn, VIC, Australia.
authors.forename: C A
authors.initials: CA
authors.lastname: Bousman
authors.affiliation: Department of Psychiatry, Melbourne Neuropsychiatry Centre, The University of Melbourne and Melbourne Health, Carlton South, VIC, Australia.|Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia.|Department of Electrical and Electronic Engineering, Centre for Neural Engineering (CfNE), University of Melbourne, Carlton South, VIC, Australia.|NorthWestern Mental Health, Melbourne, VIC, Australia.
authors.forename: C
authors.identifier: 0000-0002-9565-0238
authors.initials: C
authors.lastname: Pantelis
authors.affiliation: Department of Psychiatry, Melbourne Neuropsychiatry Centre, The University of Melbourne and Melbourne Health, Carlton South, VIC, Australia.|Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia.|Department of Electrical and Electronic Engineering, Centre for Neural Engineering (CfNE), University of Melbourne, Carlton South, VIC, Australia.
authors.forename: E
authors.identifier: 0000-0003-4263-9972
authors.initials: E
authors.lastname: Skafidas
authors.affiliation: Institute of Mental Health, The Sixth Hospital, Peking University, Beijing, China.|Key Laboratory of Mental Health, Ministry of Health & National Clinical Research Center for Mental Disorders (Peking University), Beijing, China.|Peking-Tsinghua Joint Center for Life Sciences/PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, China.
authors.forename: D
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Institute of Mental Health, The Sixth Hospital, Peking University, Beijing, China.|Key Laboratory of Mental Health, Ministry of Health & National Clinical Research Center for Mental Disorders (Peking University), Beijing, China.
authors.forename: W
authors.initials: W
authors.lastname: Yue
authors.affiliation: Department of Psychiatry, Melbourne Neuropsychiatry Centre, The University of Melbourne and Melbourne Health, Carlton South, VIC, Australia.|Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia.|Department of Electrical and Electronic Engineering, Centre for Neural Engineering (CfNE), University of Melbourne, Carlton South, VIC, Australia.|NorthWestern Mental Health, Melbourne, VIC, Australia.
authors.forename: I P
authors.initials: IP
authors.lastname: Everall
mesh_terms: D054392:Adipokines / Q000378:metabolism; D000328:Adult; D001741:Black or African American / Q000235:genetics*; D000483:Alleles; D044466:Asian People / Q000235:genetics*; D016022:Case-Control Studies; D002681:China; D005260:Female; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D020412:Multifactorial Inheritance; D020641:Polymorphism, Single Nucleotide; D059748:Proteolysis; D012083:Renin / Q000378:metabolism; D012559:Schizophrenia / Q000235:genetics*; D059326:Serotonergic Neurons / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014452:Ubiquitins / Q000378:metabolism; D044465:White People / Q000235:genetics*
chemical_list: D054392:Adipokines; D053823:Hedgehog Proteins; D014452:Ubiquitins; D012083:Renin