Analyses of GWAS and Sub‐Threshold Loci Lead to the Discovery of Dendrite Development and Morphology Dysfunction Underlying Schizophrenia Genetic Risk
Year: 2025
Type: article
Abstract: Schizophrenia (SCZ) is highly polygenic, and thousands of genes contribute to its risk. The 145 GWAS loci identified to date do not fully reveal SCZ genetic risk pathways. In this study, we explore a cost-effective strategy to increase power of inference of novel pathways, by expanding the analysis to include sub-threshold GWAS (subGWAS) loci. We identify 180 subGWAS loci (e.g., 5 x10-8 < P ≤ 10-6) based on SCZ summary statistics of 40,675 cases and 64,643 controls from CLOZUK and PGC datasets, and show that subGWAS loci contain substantial true genetic association signals. We merge GWAS (sigGWAS) and subGWAS loci and identify in total 304 high-confidence risk genes (HRGs) by jointly modeling the expanded set of loci. We identify dendrite development and morphogenesis (DDM, GO:0016358 and GO:0048813) as a novel category of biological processes implicated in SCZ genetic risk. SigGWAS loci fail to detect DDM, which is predominantly enriched in subGWAS loci. Further, DDM genes are significantly enriched for heritability of SCZ, as well as bipolar disorder and major depression. Genes in this functional process show cell type specificity in neurons in both fetal and adult brains, and their involvement in SCZ risk is further supported by eQTL analysis of SCZ risk alleles. We derived induced pluripotent stem cell (iPSC) lines from sporadic SCZ patients and normal controls and observe increased neurite lengths and soma sizes in patient-derived iPSC lines along multiple time points during neuronal development, further validating the genetic findings. We also find that the implicated genes are enriched in FDA-approved drug targets, suggesting a therapeutic potential for targeting the implicated biological processes for prevention and treatment. Our results showcase that expanding the analysis to include subGWAS loci is a valuable strategy for enhancing power of uncovering disease mechanisms, especially those of weak effect size, for SCZ and other complex diseases.
Source: Advanced Science
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,730
Awards: G2663813066, Analysis, Validation and Resource Creation for Genome Sequencing of Complex Diseases, Genetic variants affect brain gene expression and risks of psychiatric disorders, Towards a better understanding of genetic architecture of Alzheimer's disease with human iPSC models, Discovering Biology for Neuropsychiatric Diseases Through Omics Studies on Comorbidities, 1/3 High-resolution mapping of cell type-specific DNA (hydroxy)methylation in the human brain during postnatal development and in psychiatric disease., NHGRI Genome Sequencing Program Coordinating Center, Genetics-informed dissection of human brain cell-cell communication in Alzheimer's disease progression, Drug repositioning for Alzheimer's disease via genetics, electronic health records, and human iPSC models, Gene Expression Regulation in Brains of East Asian, African, and European Descent Explains Schizophrenia GWAS Across Populations
OpenAlex ID: W4413833607