Identification of a Novel Functional Non-synonymous Single Nucleotide Polymorphism in Frizzled Class Receptor 6 Gene for Involvement in Depressive Symptoms

Abstract

Although numerous susceptibility loci for depression have been identified in recent years, their biological function and molecular mechanism remain largely unknown. By using an exome-wide association study for depressive symptoms assessed by the Center for Epidemiological Studies Depression (CES-D) score, we discovered a novel missense single nucleotide polymorphism (SNP), rs61753730 (Q152E), located in the fourth exon of the frizzled class receptor 6 gene (FZD6), which is a potential causal variant and is significantly associated with the CES-D score. Computer-based in silico analysis revealed that the protein configuration and stability, as well as the secondary structure of FZD6 differed greatly between the wild-type (WT) and Q152E mutant. We further found that rs61753730 significantly affected the luciferase activity and expression of FZD6 in an allele-specific way. Finally, we generated Fzd6-knockin (Fzd6-KI) mice with rs61753730 mutation using the CRISPR/Cas9 genome editing system and found that these mice presented greater immobility in the forced swimming test, less preference for sucrose in the sucrose preference test, as well as decreased center entries, center time, and distance traveled in the open filed test compared with WT mice after exposed to chronic social defeat stress. These results indicate the involvement of rs61753730 in depression. Taken together, our findings demonstrate that SNP rs61753730 is a novel functional variant and plays an important role in depressive symptoms.

CRISPR/Cas9 based gene editing of Frizzled class receptor 6 (FZD6) reveals its role in depressive symptoms through disrupting Wnt/β-catenin signaling pathway

“…All these studies strongly demonstrated a significant role of this family in depression [17] . Very recently, we found a SNP rs61753730 located in FZD6 was linked to depression and allele specifically affected the expression of FZD6 [18] .…”

“…Voleti et al showed that virus-mediated inhibition of Fzd6 in the brain resulted in depressive-like behaviors in a rodent model [17] . Very recently, we found a missense single nucleotide polymorphism (SNP) located in FZD6 associated significantly with depressive symptoms [18] , but the underlying mechanism of such an association was not addressed.…”

Debiased Lasso After Sample Splitting for Estimation and Inference in High Dimensional Generalized Linear Models

“…We apply the proposed method to a dataset of single nucleotide polymorphisms (SNPs) from a sample of African-American participants in the Mid-South Tobacco Case-Control study population (Jiang et al, 2019;Xu et al, 2020;Han et al, 2022) to assess genetic risk factors for nicotine dependence. The dataset is publicly available with GEO accession GSE148375.…”