Major depressive disorder (MDD) is the leading cause of disability globally, with moderate heritability and well-established socio-environmental risk factors. Genetic studies have been mostly restricted to European settings, with polygenic scores (PGS) demonstrating low portability across diverse global populations.

This study examines genetic architecture, polygenic prediction, and socio-environmental correlates of MDD in a family-based sample of 10 032 individuals from Nepal with array genotyping data. We used genome-based restricted maximum likelihood to estimate heritability, applied S-LDXR to estimate the cross-ancestry genetic correlation between Nepalese and European samples, and modeled PGS trained on a GWAS meta-analysis of European and East Asian ancestry samples.

We estimated the narrow-sense heritability of lifetime MDD in Nepal to be 0.26 (95% CI 0.18–0.34, p = 8.5 × 10−6). Our analysis was underpowered to estimate the cross-ancestry genetic correlation (rg = 0.26, 95% CI −0.29 to 0.81). MDD risk was associated with higher age (beta = 0.071, 95% CI 0.06–0.08), female sex (beta = 0.160, 95% CI 0.15–0.17), and childhood exposure to potentially traumatic events (beta = 0.050, 95% CI 0.03–0.07), while neither the depression PGS (beta = 0.004, 95% CI −0.004 to 0.01) or its interaction with childhood trauma (beta = 0.007, 95% CI −0.01 to 0.03) were strongly associated with MDD.

Estimates of lifetime MDD heritability in this Nepalese sample were similar to previous European ancestry samples, but PGS trained on European data did not predict MDD in this sample. This may be due to differences in ancestry-linked causal variants, differences in depression phenotyping between the training and target data, or setting-specific environmental factors that modulate genetic effects. Additional research among under-represented global populations will ensure equitable translation of genomic findings.

Adverse childhood experiences (ACEs) and genetic liability are important risk factors for depression and inflammation. However, little is known about the gene−environment (G × E) mechanisms underlying their aetiology. For the first time, we tested the independent and interactive associations of ACEs and polygenic scores of major depressive disorder (MDD-PGS) and C-reactive protein (CRP-PGS) with longitudinal trajectories of depression and chronic inflammation in older adults.

Data were drawn from the English longitudinal study of ageing (N~3400). Retrospective information on ACEs was collected in wave3 (2006/07). We calculated a cumulative risk score of ACEs and also assessed distinct dimensions separately. Depressive symptoms were ascertained on eight occasions, from wave1 (2002/03) to wave8 (2016/17). CRP was measured in wave2 (2004/05), wave4 (2008/09), and wave6 (2012/13). The associations of the risk factors with group-based depressive-symptom trajectories and repeated exposure to high CRP (i.e. ⩾3 mg/L) were tested using multinomial and ordinal logistic regression.

All types of ACEs were independently associated with high depressive-symptom trajectories (OR 1.44, 95% CI 1.30–1.60) and inflammation (OR 1.08, 95% CI 1.07–1.09). The risk of high depressive-symptom trajectories (OR 1.47, 95% CI 1.28–1.70) and inflammation (OR 1.03, 95% CI 1.01–1.04) was also higher for participants with higher MDD-PGS. G×E analyses revealed that the associations between ACEs and depressive symptoms were larger among participants with higher MDD-PGS (OR 1.13, 95% CI 1.04–1.23). ACEs were also more strongly related to inflammation in participants with higher CRP-PGS (OR 1.02, 95% CI 1.01–1.03).

ACEs and polygenic susceptibility were independently and interactively associated with elevated depressive symptoms and chronic inflammation, highlighting the clinical importance of assessing both ACEs and genetic risk factors to design more targeted interventions.

Though cognitive abilities in adulthood are largely influenced by individual genetic background, they have also been shown to be importantly influenced by environmental factors. Some of these influences are mediated by epigenetic mechanisms. Accordingly, polymorphic variants in the epigenetic gene DNMT3B have been linked to neurocognitive performance. Since monozygotic (MZ) twins may show larger or smaller intrapair phenotypic differences depending on whether their genetic background is more or less sensitive to environmental factors, a twin design was implemented to determine if particular polymorphisms in the DNMT3B gene may be linked to a better (worse) response to enriched (deprived) environmental factors.

Applying the variability gene methodology in a sample of 54 healthy MZ twin pairs (108 individuals) with no lifetime history of psychopathology, two DNMT3B polymorphisms were analyzed in relation to their intrapair differences for either intellectual quotient (IQ) or working memory performance.

MZ twin pairs with the CC genotype for rs406193 SNP showed statistically significant larger intrapair differences in IQ than CT pairs.

Results suggest that DNMT3B polymorphisms may explain variability in the IQ response to either enriched or impoverished environmental conditions. Accordingly, the applied methodology is shown as a potentially valuable tool for determining genetic markers of cognitive plasticity. Further research is needed to confirm this specific result and to expand on other putative genetic markers of environmental sensitivity.