Genetic variations in extracellular matrix degradation pathways linking to major depressive disorder: Evidence from a large-scale genetic association study

Abstract

Dysregulation of extracellular matrix (ECM) degradation pathways has been increasingly implicated in major depressive disorder (MDD), yet its genetic basis remains unclear. This study investigated the relationship between ECM-related genetic polymorphisms and MDD susceptibility. In a case-control study, we analyzed 317 MDD patients and 1268 sexmatched controls from the Taiwan Biobank (TWB). Genomic DNA was analyzed using the Affymetrix TWB array, targeting single nucleotide polymorphisms (SNPs) in 140 ECM degradation genes (Reactome database). Full-model association tests identified significant SNPs, validated with 5000 max(T) permutations and adjusted via logistic regression for age, body mass index, education level, and marital status. We identified 12 SNPs across 10 ECMrelated genes significantly associated with MDD, including ADAM metallopeptidase domain 17 (ADAM17, rs55820761), brevican (BCAN, rs11264511), CD44 molecule (CD44, rs12270356), collagen type XVII alpha 1 chain (COL17A1; rs2282436 and rs10883962), collagen type III alpha 1 chain (COL3A1; rs16830979 and rs10883962), collagen type VI alpha 6 chain (COL6A6, rs16830219), cathepsin L (CTSL, rs2274611), Kallikrein-related peptidase 2 (KLK2, rs2664156), matrix metallopeptidase 11 (MMP11, rs738791), and nicastrin (NCSTN, rs3753391). This study provides the first genetic evidence linking ECM degradation pathways to MDD susceptibility, identifying novel biomarkers for early diagnosis and precision therapy. Further research and cross-population studies are needed to confirm these findings.

Keywords: Blood-brain barrier; Extracellular matrix; Genome-wide association study; Major depressive disorder; Single nucleotide polymorphisms.