The topology of brain functional networks has small-world properties, promoting efficient information transfer at low wiring cost. Several studies have demonstrated altered small world features in neuropsychiatric conditions such as schizophrenia, autism or epilepsy. While previous studies have shown small-worldness properties to be heritable (Smit, 2008), the neurogenetic basis of brain small world properties has not yet been characterized.
Gene sets enrichment analysis (GSEA) was used to investigate genetic contributions to human brain network topology. Resting-state fMRI was acquired from a whole-genome genotyped sample of 273 healthy subjects (mean age =33.7 ± 9.88, 132 males), and networks constructed as previously described (Braun, 2012). Association with SNPs was obtained in Plink and the LDsnpR package was used to map SNPs to gene bins and to derive a single gene score using the modified sidak test (Ersland, 2012). GSEA analysis was then run using the Broad Institute GSEA java tool and gene ontology categories from the MSig-database (Subramanian, 2005). Gene sets with 15-200 genes were analyzed. Stringent multiple comparison control was performed using FDR (q=0.05).
GSEA analysis revealed significant enrichment of genes belonging to the ‘Response to Hypoxia’ GO category (FDR q=0.02, FWER=0.02). This category is involved in control of oxygen homeostasis in the brain and includes genes implicated in the pathophysiology of schizophrenia such as the nicotinic acetylcholine receptors and the angiotensin gene (Leonard, 2002; Kucukali, 2009).
Given the prior evidence for disease-related heritability of the small-world phenotype we employed, our results identify a category of genes whose risk may be mediated through brain wiring efficiency and cost. Experiments in non-human vertebrates have linked hypoxia response genes to axon guidance and neuronal development processes (Stevenson, 2012). In addition, we speculate that this category could also contribute to gene-environment interactions (GxE), since hypoxia under birth is an established, but nonspecific risk factor for mental disorders such as schizophrenia and has been linked to decreased hippocampal and cortical gray matter volumes as well as increased functional connectivity during resting state fMRI (Wang, 2013). Genetic variation in hypoxia-regulated genes has been associated with schizophrenia risk in GxE interaction studies (Nicodemus, 2008). Future work is necessary to show the presence of altered small-world network properties in subjects with obstetric complications and possible GxE effects related to this phenotype.