Collective genomic segments with differential pleiotropic patterns between cognitive dimensions and psychopathology

Cognitive deficits are known to be related to most forms of psychopathology. Here, we perform local genetic correlation analysis as a means of identifying independent segments of the genome that show biologically interpretable pleiotropic associations between cognitive dimensions and psychopathology. We identify collective segments of the genome, which we call “meta-loci”, showing differential pleiotropic patterns for psychopathology relative to either cognitive task performance (CTP) or performance on a non-cognitive factor (NCF) derived from educational attainment. We observe that neurodevelopmental gene sets expressed during the prenatal-early childhood period predominate in CTP-relevant meta-loci, while post-natal gene sets are more involved in NCF-relevant meta-loci. Further, we demonstrate that neurodevelopmental gene sets are dissociable across CTP meta-loci with respect to their spatial distribution across the brain. Additionally, we find that GABA-ergic, cholinergic, and glutamatergic genes drive pleiotropic relationships within dissociable meta-loci.

decomposition; local_h2g = local heritability as estimated via HESS; var = estimated variance; p = two-sided p-values File Name: Supplementary Data 4 Description: Local genetic correlations estimated by HESS for 17 Cognitive Task Performance -Psychopathology trait pairs. Heritability indicated for each region was for Cognitive Task Performance -the strength of the heritability was colored in indigo. For each of the columns representing z-scores, each cell was colored based on their direction. Positive Z-scores were colored red, and negative Zscores were colored blue. Columns were defined as follows, Anxiety_QT b. Hierarchical Cluster Fit Indices for Cognitive Task Performance asw: Average Silouette Width; ch: Calinski and Harabasz index; dunn: minimum separation / maximum diameter. Dunn index; cvnnd: coefficient of variation of dissimilarities to nnkth nearest within-cluster neighbour, measuring uniformity of within-cluster densities, weighted over all clusters; correlation between distances and a 0-1-vector where 0 means same cluster, 1 means different clusters; avewithin: average distance within clusters; sindex: separation index; entropy: entropy of the distribution of cluster memberships; avstability: average clusterwise stability statistics by resampling. Indices highlighted in red = top ranked index, gold = second ranked index, orange = third ranked index.

c. Descriptive Statistics for CTP meta-locus
Overall heritability for the meta-locus, number of LD independent regions that were part of the meta-locus, cumulative length of the meta-locus and percentage of the heritability accounted for, and cumulative heritability accounted for by each meta-locus are displayed.
File Name: Supplementary Data 9 Description: a. Density Based Clustering Silhouette Scores for Non-Cognitive Factor Fit statistics for density-based clustering for local genetic correlation input. N umap dimensions: Number of UMAP dimensions used for density-based clustering, Epsilon: Nearest neighbor threshold, based on k-nearest neighbor distance; Unclassifiable: outlier LD segments not classified by density-based clustering; N db clusters: number of density-based clusters; Median: median silhouette scores, Mean: mean silhouette scores; 75th percentile: 3rd quarter silhouette scores; Max: maximum silhouette score.
b. Hierarchical Cluster Fit Indices for Non-Cognitive Factor asw: Average Silhouette Width; ch: Calinski and Harabasz index; dunn: minimum separation / maximum diameter. Dunn index; cvnnd: coefficient of variation of dissimilarities to nnkth nearest within-cluster neighbor, measuring uniformity of within-cluster densities, weighted over all clusters; correlation between distances and a 0-1-vector where 0 means same cluster, 1 means different clusters; avewithin: average distance within clusters; sindex: separation index; entropy: entropy of the distribution of cluster memberships; avstability: average clusterwise stability statistics by resampling. Indices highlighted in red = top ranked index, gold = second ranked index, orange = third ranked index.

c. Descriptive Statistics for NCF meta-loci
Overall heritability for the meta-locus, number of LD independent regions that were part of the meta-locus, cumulative length of the meta-locus and percentage of the heritability accounted for and cumulative heritability accounted for by each meta-locus are displayed. . CTP.meta.locus.ID: ID for CTP meta-locus; NCF.meta.locus.ID: ID for NCF meta-locus; PoPscore: gene prioritization score from PoPs algorithm; PoP.rank: ranking of gene from PoPscore; PoP.rank.norm; normalized rank score 0-1.
File Name: Supplementary Data 16 Description: a. Consolidated results of gene set analysis in long format SIZE: final gene set size; NES: normalized enrichment score, NOM p-value: nominal p-value, FDR q-value: False discovery rate, estimated probability that the normalized enrichment score represents a false positive finding; LEADING EDGE: Tags. The percentage of gene hits before the peak in the running enrichment score. This gives an indication of the percentage of genes contributing to the enrichment score, List. The percentage of genes in the ranked gene list before the peak in the running enrichment score. This gives an indication of where in the list the enrichment score is attained, Signal. The enrichment signal strength that combines the two previous statistics. If the gene set is entirely within the first Nth positions in the list, then the signal strength is maximal or 100%. If the gene set is spread throughout the list, then the signal strength decreases towards 0%; Method: gene set analysis method, GSEA, WG -WebGestalt or FUMA::GENE2FUNC (GENE2FUNC); Metalocus.ID: meta-locus ID for either CTP or NCF; Phenotype: Cognitive Task Performance (CTP) or Non-Cognitive Factor (NCF); Category: GO Ontology Biological Processes, Molecular Function, or Cellular Component Gene sets; Neural: Annotation for which the gene set implicates the brain/neurological component; Multi-Method: Annotation if the gene set was indexed by multiple gene-set analysis methodology; n.locus: number of meta-loci that the gene-set was implicated in. ".5" occurs where at least one of the gene sets were implicated in multiple meta-loci, and multiple methodologies; driver.genes: these are genes that are implicated within the gene sets in questions. However, only driver genes within the GSEA methodology were considered for downstream analysis.
b. Consolidated results for Drug based gene set analysis (WebGestalt only) SIZE: final gene set size, NES: normalized enrichment score, NOM p-value: nominal p-value, FDR q-value: False discovery rate, estimated probability that the normalized enrichment score represents a false positive finding; Phenotype: Cognitive Task Performance (CTP) or Non-Cognitive Factor (NCF); n.locus: number of meta-loci that the gene-set was implicated in. ".5" occurs where at least one of the gene sets were implicated in multiple meta-loci, and multiple methodologies; driver.genes: these are genes that are implicated within the gene sets in questions. However, only driver genes within the GSEA methodology were considered for downstream analysis.