Genetic determinants of cognition are poorly characterized, and their relationship to genes that confer risk for neurodevelopmental disease is unclear. Here we performed a systems-level analysis of genome-wide gene expression data to infer gene-regulatory networks conserved across species and brain regions. Two of these networks, M1 and M3, showed replicable enrichment for common genetic variants underlying healthy human cognitive abilities, including memory. Using exome sequence data from 6,871 trios, we found that M3 genes were also enriched for mutations ascertained from patients with neurodevelopmental disease generally, and intellectual disability and epileptic encephalopathy in particular. M3 consists of 150 genes whose expression is tightly developmentally regulated, but which are collectively poorly annotated for known functional pathways. These results illustrate how systems-level analyses can reveal previously unappreciated relationships between neurodevelopmental disease–associated genes in the developed human brain, and provide empirical support for a convergent gene-regulatory network influencing cognition and neurodevelopmental disease.
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We acknowledge funding from UK Imperial National Institute for Health Research Biomedical Research Centre (M.R.J.), the UK Medical Research Council (M.R.J., E.P. and D.S.), The National Genome Research Network (NGFNplus: EMINet, grant 01GS08122; A.J.B.), EuroEpinomics (A.J.B.), UCB Pharma (M.R.J. and E.P.) and the Singapore Ministry of Health (E.P.). We thank the Lothian Birth Cohort 1936 research team for data collection and collation. The Lothian Birth Cohort 1936 is supported by Age UK (Disconnected Mind project). The work at The University of Edinburgh was undertaken by The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (MR/K026992/1). We acknowledge funding from the Biotechnology and Biological Sciences Research Council and MRC. Generation Scotland received core funding from the Chief Scientist Office of the Scottish Government Health Directorate CZD/16/6 and the Scottish Funding Council HR03006. Genotyping of the GS:SFHS samples was carried out by staff at the Genetics Core Laboratory at the Wellcome Trust Clinical Research Facility, Edinburgh, Scotland and was funded by the UK's Medical Research Council. We thank all the families who took part, the general practitioners and the Scottish School of Primary Care for their help in recruiting them, and the whole Generation Scotland team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, healthcare assistants and nurses. A.D.-D. was supported by a Marie Curie Intra European Fellowship within the 7th European Community Framework Programme.
The authors declare no competing financial interests.
Integrated supplementary information
We hypothesized that gene regulatory networks starting from the human hippocampus could be informative for genes and pathways relevant to diverse cognitive abilities and neurodevelopmental disease. Hippocampus gene-regulatory networks were inferred a priori, without reference to cognitive phenotypes using fresh-frozen hippocampus samples that had been surgically removed from 122 patients undergoing temporal lobectomy for epilepsy. Conservation of modules was then tested using distinct expression datasets from non-diseased post-mortem hippocampus samples (n=63) and healthy mouse hippocampus samples (n=100). From this, we identified 4 cross-species conserved hippocampal gene co- expression modules whose co-expression relationships are unrelated to epilepsy (M1, M3, M11 and M19). We then used independent gene expression datasets to show that these modules were conserved widely across the human cortex and expressed under tight developmental regulation during brain development. The modules were then integrated with GWAS data relating to four cognitive abilities (general fluid cognitive ability, processing speed, crystalized cognitive ability and verbal delayed recall) in two independent community cohorts (GS:SFHS and LBC1936), and de novo mutation data from parent-offspring trios across five neurodevelopmental disorders (ASD, SCZ, ID, EE, DDD) to reveal convergent gene co-expression modules for healthy human cognitive abilities and neurodevelopmental disease. Full details relating to datasets, experimental methods and references are provided in the manuscript. TLE=temporal lobe epilepsy; ASD=autism spectrum disorder; SCZ=schizophrenia; ID=intellectual disability; DDD=Deciphering Development Disorders Cohort (http://www.ddduk.org). UKBEC=UK Brain Expression Consortium (http://www.braineac.org). WES= whole-exome sequencing.
Supplementary Figure 1 (PDF 838 kb)
Values in the table are actual numbers with percentages indicated in brackets. Genome-wide expression data were generated from snap frozen (liquid nitrogen) whole human hippocampus samples surgically resected en bloc. All samples were resected at a single neurosurgical centre. Clinical data recorded for each patient included; date of birth, gender handedness, age at epilepsy onset, laterality of TLE as determined by imaging and ictal EEG criteria, operation date, age at operation, pre-operative seizure type/s and frequency, antiepilepsy drug (AED) therapy and pathology. All patients underwent detailed neuropsychological testing prior to surgery (see text for details). (XLSX 10 kb)
Supplementary Table 2: Probe annotations and gene lists for the WGCNA-inferred human surgical hippocampus gene co-expression modules.
Clusters are arranged by name. Probes that are not part of any cluster are listed at the end. See Methods for details relating to data generation and network construction. (XLSX 1079 kb)
Supplementary Table 3: Summary statistics for each of the 24 human hippocampal co-expression networks.
*, average of pairwise biweight correlations between expression of all genes in the module. **, proportion of genes from the module represented in replication dataset (for mouse brain expression, only one-to-one orthologues were considered). ***, P-values for the significance of the co-expression relationships in post-mortem human hippocampus and healthy mouse hippocampus were calculated by comparing the average topological overlap for network genes to the average connectivity in 10,000 randomly sampled networks with the same size (see Methods for details). Bold, significant after Bonferroni correction for the number of modules (24) (P=0.002). Boxed modules are preserved across all three hippocampus datasets (i.e., human surgical, human post-mortem and mouse). (XLSX 48 kb)
Supplementary Table 4: Conservation of co-expression for M1 and M3 genes in occipital cortex, cerebellum, temporal cortex, frontal cortex.
Expression data from UK Brain Expression Consortium (Ramasamy, A., Trabzuni, D., Guelfi, S., Varghese, V., Smith, C., Walker, R., … Weale, M. E. (2014). Genetic variability in the regulation of gene expression in ten regions of the human brain. Nature Neuroscience, 17(10), 1418–1428. doi:10.1038/nn.3801). Significance of conservation of co-expression relationships was assessed by empirical P-values, which were calculated by comparing the strength of gene co-expression between the module genes and 10,000 randomly sampled networks of the same size. P-values passing Bonferroni correction for the number of modules and brain regions analyzed are highlighted in bold. (XLSX 48 kb)
For each module (M1-M24) identified by WGCNA in human hippocampus the functional enrichment statistics were calculated with respect to a background set of 11,837 microarray- expressed probes (representing 9,616 protein coding genes, see Methods) used to infer the networks. The WebGestalt tool (Wang et al. Nucleic Acids Res. 2013 41, W77–83) was used to test the enrichment for (GO) categories (biological processes, cellular components and molecular functions) and pathways (“KEGG” and “Pathway common” databases) in module genes. In all cases, only significant enrichments are reported (Benjamini-Hochberg (BH) corrected P<0.05); colours represent the significance of the enrichment. (XLSX 127 kb)
Supplementary Table 6: Detailed annotation of Module 3 genes from UNIPROT function and Entrez gene summary.
Bold highlights genes with function potentially relating to neural activity. (XLSX 72 kb)
Waist-hip ratio (n=15,234 subjects), fasting glucose homeostasis (n=69,395 subjects), glucose challenge homeostasis (n=242,530 subjects), systolic blood pressure (n=46,186 subjects) and diastolic blood pressure (n=69,395 subjects). *, Number of genes in the module with ≥1 genotyped SNP within the transcription start and end positions of the gene (NCBI36, hg18). **, P-value for enrichment of association. (XLSX 51 kb)
Supplementary Table 8: Results of RVIS analysis for the 24 modules identified in the human hippocampus.
RVIS, Residual Variation Intolerance Score (Petrovski et al. PLoS Genet 2013) was assessed as described in Supplementary Methods. Grey, modules preserved in the mammalian hippocampus and unrelated to epilepsy (Fig. 1a). The Mann-Whitney U test (2-tailed) was used to compare the distribution of genic RVIS scores for each module to the distribution from the rest of the protein-coding genes outside the 24 modules and expressed in the human hippocampus (n=8,414 with CCDS) (see Methods for additional details). Sample estimate (difference in medians) represents the direction of enrichment, where negative values reflect enrichment for intolerant genes (and vice versa positive values reflect enrichment for tolerant genes). Bold, significant overrepresentation of genes intolerant to genetic variation (alpha adjusted for 24 modules, p<0.002). The four cross-species conserved hippocampal modules are highlighted in grey. (XLSX 11 kb)
Enrichment for each module is tested in two ways. Firstly, we adopt a binomial exact test, BET (two-tail) to assess whether there is excess single variant de novo mutations among cases as compared with what is expected based on the protein-coding real-estate that the collection of genes in a module takes up from the entire CCDS release 17 exome and on a length model in which DNMs occur randomly in all genes, proportional to length. The Ratio Obs/Exp is the ratio between the number of observed DNMs overlapping with the module and the expected number based on this model. Subsequently, we adopt a Fisher's exact test, FET (two-tail) to empirically compare the rates of overlap between case- and control-ascertained de novo mutations for the module. See Methods for additional details. Significant P-values are highlighted in bold. Empirical P-values of enrichment test for reported single nucleotide variant (SNV) DNMs reflecting loss-of-function DNM (only nonsense and splice-site mutations), predicted deleterious DNM (loss-of-function DNM and missense DNM with SIFT score < or = 0.05 and Polyphen2 score > or = 0.5), non synonymous DNM (all missense, nonsense and splice-site mutations), and synonymous DNM. *Subset of module genes that are CCDS release 17 genes, as filtered for DNM comparisons. Autism spectrum disorder (ASD), epileptic encephalopathy (EE), intellectual disability (ID), schizophrenia (SCZ), Combined = ASD+EE+ID+SCZ combined, Deciphering Developmental Disorders (DDD). The DNMs of the DDD study were not combined with the other neurospychiatric disorders as some of the patients of the DDD study present with congenital abnormalies without neuropsychiatric features. Background genes are all expressed genes in the surgical hippocampus (n=9,616), including those genes that contribute to the individual modules. (XLSX 60 kb)
Supplementary Table 10: Enrichment of association of M1 and M3 with phenotypes relating to the Psychiatric Genomics Consortium (PGC) traits.
Attention deficit-hyperactivity disorder (ADHD), bipolar disorder (BP), major depressive disorder (MDD) and schizophrenia (SCZ), as well as GWAS data relating to common forms of epilepsy (EPI) from the International League Against Epilepsy (ILAE) Consortium on Complex Epilepsies and Alzheimer's disease (AD) from the GenADA study (see manuscript for details and GWAS references). Bold, significant GWAS enrichment after Bonferroni correction for the number of modules and phenotypes tested. * Genes in the module with ≥1 genotyped SNP within the transcription start and end positions of the gene (NCBI36, hg18). ** Empirical P-value for enrichment of association determined by 100,000 bootstrap samples. (XLSX 56 kb)
R code for the main analytical functions. (TXT 8 kb)
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Johnson, M., Shkura, K., Langley, S. et al. Systems genetics identifies a convergent gene network for cognition and neurodevelopmental disease. Nat Neurosci 19, 223–232 (2016). https://doi.org/10.1038/nn.4205
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