Polygenic prediction of major depressive disorder and related traits in African ancestries UK Biobank participants.

Genome-Wide Association Studies (GWAS) over-represent European ancestries, neglecting all other ancestry groups and low-income nations. Consequently, polygenic risk scores (PRS) more accurately predict complex traits in Europeans than African Ancestries groups. Very few studies have looked at the transferability of European-derived PRS for behavioural and mental health phenotypes to Africans. We assessed the comparative accuracy of depression PRS trained on European and African Ancestries GWAS studies to predict major depressive disorder (MDD) and related traits in African ancestry participants from the UK Biobank. UK Biobank participants were selected based on Principal component analysis clustering with an African genetic similarity reference population, MDD was assessed with the Composite International Diagnostic Interview (CIDI). PRS were computed using PRSice2 software using either European or African Ancestries GWAS summary statistics. PRS trained on European ancestry samples (246,363 cases) predicted case control status in Africans of the UK Biobank with similar accuracies (R2 = 2%, ß = 0.32, empirical p-value = 0.002) to PRS trained on far much smaller samples of African Ancestries participants from 23andMe, Inc. (5045 cases, R² = 1.8%, ß = 0.28, empirical p-value = 0.008). This suggests that prediction of MDD status from Africans to Africans had greater efficiency relative to discovery sample size than prediction of MDD from Europeans to Africans. Prediction of MDD status in African UK Biobank participants using GWAS findings of likely causal risk factors from European ancestries was non-significant. GWAS of MDD in European ancestries are inefficient for improving polygenic prediction in African samples; urgent MDD studies in Africa are needed.

Antidepressant Exposure and DNA Methylation: Insights from a Methylome-Wide Association Study.

Importance: Understanding antidepressant mechanisms could help design more effective and tolerated treatments. Objective: Identify DNA methylation (DNAm) changes associated with antidepressant exposure. Design: Case-control methylome-wide association studies (MWAS) of antidepressant exposure were performed from blood samples collected between 2006-2011 in Generation Scotland (GS). The summary statistics were tested for enrichment in specific tissues, gene ontologies and an independent MWAS in the Netherlands Study of Depression and Anxiety (NESDA). A methylation profile score (MPS) was derived and tested for its association with antidepressant exposure in eight independent cohorts, alongside prospective data from GS. Setting: Cohorts; GS, NESDA, FTC, SHIP-Trend, FOR2107, LBC1936, MARS-UniDep, ALSPAC, E-Risk, and NTR. Participants: Participants with DNAm data and self-report/prescription derived antidepressant exposure. Main Outcomes and Measures: Whole-blood DNAm levels were assayed by the EPIC/450K Illumina array (9 studies, N exposed = 661, N unexposed = 9,575) alongside MBD-Seq in NESDA (N exposed = 398, N unexposed = 414). Antidepressant exposure was measured by self- report and/or antidepressant prescriptions. Results: The self-report MWAS (N = 16,536, N exposed = 1,508, mean age = 48, 59% female) and the prescription-derived MWAS (N = 7,951, N exposed = 861, mean age = 47, 59% female), found hypermethylation at seven and four DNAm sites (p < 9.42x10 -8 ), respectively. The top locus was cg26277237 ( KANK1, p self-report = 9.3x10 -13 , p prescription = 6.1x10 -3 ). The self-report MWAS found a differentially methylated region, mapping to DGUOK-AS1 ( p adj = 5.0x10 -3 ) alongside significant enrichment for genes expressed in the amygdala, the "synaptic vesicle membrane" gene ontology and the top 1% of CpGs from the NESDA MWAS (OR = 1.39, p < 0.042). The MPS was associated with antidepressant exposure in meta-analysed data from external cohorts (N studies = 9, N = 10,236, N exposed = 661, f3 = 0.196, p < 1x10 -4 ). Conclusions and Relevance: Antidepressant exposure is associated with changes in DNAm across different cohorts. Further investigation into these changes could inform on new targets for antidepressant treatments. 3 Key Points: Question: Is antidepressant exposure associated with differential whole blood DNA methylation?Findings: In this methylome-wide association study of 16,536 adults across Scotland, antidepressant exposure was significantly associated with hypermethylation at CpGs mapping to KANK1 and DGUOK-AS1. A methylation profile score trained on this sample was significantly associated with antidepressant exposure (pooled f3 [95%CI]=0.196 [0.105, 0.288], p < 1x10 -4 ) in a meta-analysis of external datasets. Meaning: Antidepressant exposure is associated with hypermethylation at KANK1 and DGUOK-AS1 , which have roles in mitochondrial metabolism and neurite outgrowth. If replicated in future studies, targeting these genes could inform the design of more effective and better tolerated treatments for depression.

Polygenic prediction of major depressive disorder and related traits in African ancestries UK Biobank participants.

Introduction: Genome-Wide Association Studies (GWAS) over-represent European ancestries compared to the global population, neglecting all other ancestry groups and low-income nations. Consequently, polygenic risk scores (PRS) more accurately predict complex traits in Europeans than African Ancestries groups. Very few studies have looked at the transferability of European-derived PRS for behavioural and mental health phenotypes to non-Europeans. We assessed the comparative accuracy of PRS for Major Depressive Disorder (MDD) trained on European and African Ancestries GWAS studies to predict MDD and related traits in African Ancestries participants from the UK Biobank. Methods: UK Biobank participants were selected based on Principal component analysis (PCA) clustering with an African genetic similarity reference population and MDD was assessed with the Composite International Diagnostic Interview (CIDI). Polygenic Risk Scores (PRS) were computed using PRSice2 using either European or African Ancestries GWAS summary statistics. Results: PRS trained on European ancestry samples (246,363 cases) predicted case control status in Africans of the UK Biobank with similar accuracies (190 cases, R2=2%) to PRS trained on far much smaller samples of African Ancestries participants from 23andMe, Inc. (5045 cases, R2=1.8%). This suggests that prediction of MDD status from Africans to Africans had greater efficiency per unit increase in the discovery sample size than prediction of MDD from Europeans to Africans. Prediction of MDD status in African UK Biobank participants using GWAS findings of causal risk factors from European ancestries was non-significant. Conclusion: GWAS studies of MDD in European ancestries are an inefficient means of improving polygenic prediction accuracy in African samples.