# Analyses of GWAS and Sub‐Threshold Loci Lead to the Discovery of Dendrite Development and Morphology Dysfunction Underlying Schizophrenia Genetic Risk

## TL;DR

This study finds that genetic risk for schizophrenia involves impaired dendrite development and morphogenesis, highlighting new biological pathways and mechanisms.

## Contribution

A cost-effective method using sub-threshold GWAS loci reveals a novel pathway in schizophrenia involving dendrite development and morphogenesis.

## Key findings

- 180 sub-threshold GWAS loci and 304 high-confidence risk genes were identified for schizophrenia.
- Dendrite development and morphogenesis (DDM) is a novel biological process linked to schizophrenia risk.
- Upregulation of DDM genes CUL7 and DCC reduces neurite length and disrupts key neural regulators.

## Abstract

Schizophrenia (SCZ) is highly polygenic, and its biological underpinnings remain unclear. In this study, a cost‐effective strategy of including sub‐threshold GWAS (subGWAS) loci (i.e., 5 × 10−8 < P ≤ 10−6) in analysis is explored to increase the inference power of novel pathways. A total of 180 subGWAS loci are identified from SCZ GWAS studies and are shown to contain substantial true genetic association signals. By jointly modeling GWAS (sigGWAS) and subGWAS loci, 304 high‐confidence risk genes (HRGs) are identified, as well as a novel category of biological processes detected only in subGWAS loci, i.e., dendrite development and morphogenesis (DDM). Two candidate DDM genes (CUL7 and DCC), whose risk alleles in GWAS are associated with increased expression, are examined, and it is observed that upregulation of these genes leads to reduced neurite length. It is further revealed that the DDM genes lead to disrupted regulatory programs of the transcription factors CUX1/2 and NEUROD1. Collectively, the study identifies DDM as a novel biological process in SCZ susceptibility, with particular implications for DCC‐ and CUL7‐mediated alterations in neurite development and reveals regulatory programs involved in perturbation of the two candidate genes.

A cost‐effective strategy is developed analyzing sub‐threshold GWAS loci (5 × 10−8 < P ≤ 10−6), identifying 180 risk loci and 304 high‐confidence genes through combined GWAS/subGWAS analysis. This approach reveals dendrite development and morphogenesis (DDM) as a novel SCZ pathway. Functional validation shows DDM genes CUL7 and DCC impair neurite growth and disrupt neural regulators (CUX1/2, NEUROD1), uncovering new SCZ mechanisms.