ADAMTS18 as a candidate gene linking social stress and depression: a cross-species study in African wild dogs (Lycaon pictus) and humans.

Abstract

Background: Major depressive disorder (MDD) is a leading cause of disability; however, its neurogenetic mechanisms remain partially understood. Comparative genomic approaches reveal evolutionarily conserved risk factors, particularly when applied to ecologically valid models. Lycaon pictus is a social carnivore whose affiliative behavior has been shaped by natural selection. Since impaired social and affiliative function are a feature of depression, genes selected for social function in this species may serve as candidates for the social-affective dimension of MDD. Here, a comparative approach was integrated with human neuroimaging-genetic analysis, focusing on white matter phenotypes.

Methods: Whole-genome sequencing data from Lycaon pictus (n = 7) and Canis lupus (n = 36) were analyzed alongside a human cohort of 367 patients with MDD and 161 healthy controls using rare variant association tests. Across analyses, ADAMTS18 emerged as a convergent gene of interest. Whole-exome sequencing and diffusion tensor imaging (DTI) were conducted on 234 patients with MDD and 135 healthy controls. Eleven common SNPs within ADAMTS18 were examined for genotype-by-diagnosis and genotype-by-symptom interactions using tract-based DTI metrics.

Results: SNP rs11643211 showed a nominal genotype × diagnosis interaction on axial diffusivity in the bilateral uncinate fasciculus, with elevated values in A allele carriers with MDD. In symptom-based models, rs1948719 was nominally associated with depression severity in the left cingulum-cingulate gyrus. Although these associations did not survive false discovery rate correction, the nominal effects appeared to cluster within tracts implicated in affective integration and self-referential cognition.

Conclusion: The present study is hypothesis-generating and identifies ADAMTS18 as a gene worth further study in relation to white matter and depression. Cross-species neurogenomics may offer a useful framework for investigating links among social behavior, genetic variation and psychiatric vulnerability. However, given the small sample sizes and the absence of FDR-significant results, these findings should be interpreted as providing an exploratory framework for identifying candidate markers relevant to MDD.