Pathway-wide association study identifies five shared pathways associated with schizophrenia in three ancestral
C Liu1, C A Bousman1,2,3,4, C Pantelis1,2,5,6
1Department of Psychiatry, Melbourne Neuropsychiatry Centre, The University of Melbourne and Melbourne Health, Carlton South, VIC, Australia.
Translational Psychiatry
|February 22, 2017
Summary
Schizophrenia is a complex polygenic disorder. This study reveals it is also a poly-pathway disorder, with distinct genetic pathways contributing to schizophrenia risk across diverse populations.
Area of Science:
- Genetics
- Neuroscience
- Psychiatry
Background:
- Genome-wide association studies (GWAS) indicate schizophrenia is polygenic, involving numerous alleles.
- Low generalizability of individual allelic markers suggests a pathway-based model for schizophrenia.
Purpose of the Study:
- To empirically test the pathway disorder hypothesis of schizophrenia.
- To identify specific biological pathways associated with schizophrenia liability across diverse ethnic groups.
Main Methods:
- Conducted a pathway-wide association study (PWAS) using 255 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways.
- Analyzed data from 5033 schizophrenia patients and 5332 healthy controls across European-American (EA), African-American (AA), and Han Chinese (CH) populations.
Main Results:
- Identified 103, 74, and 87 pathways associated with schizophrenia liability in EA, CH, and AA populations, respectively.
- Found significant pathway heterogeneity, with about half unique to each population.
- Discovered five shared pathways (serotonergic synapse, ubiquitin mediated proteolysis, hedgehog signaling, adipocytokine signaling, renin secretion) across all populations, enriched for regulatory single-nucleotide polymorphisms.
Conclusions:
- Provides empirical support for schizophrenia as a pathway disorder.
- Suggests schizophrenia is a poly-pathway disorder with substantial genetic and pathway heterogeneity across populations.
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