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ADAMTS18 as a candidate gene linking social stress and depression: a cross-species study in African wild dogs (Lycaon pictus) and humans
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DOI：10.3389/fnbeh.2026.1878769.png)
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Abstract
En 中文
BackgroundMajor 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.MethodsWhole-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.ResultsSNP 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.ConclusionThe 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.
Keywords:
major depressive disorder
diffusion tensor imaging
Lycaon pictus
white matter connectivity
ADAMTS18
cross-species genomics
neuroimaging genetics
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