Multi-ancestry genome-wide association study of major depression aids locus discovery, fine mapping, gene prioritization and causal inference

Abstract

Most genome-wide association studies (GWAS) of major depression (MD) have been conducted in samples of European ancestry. Here we report a multi-ancestry GWAS of MD, adding data from 21 cohorts with 88,316 MD cases and 902,757 controls to previously reported data. This analysis used a range of measures to define MD and included samples of African (36% of effective sample size), East Asian (26%) and South Asian (6%) ancestry and Hispanic/Latin American participants (32%). The multi-ancestry GWAS identified 53 significantly associated novel loci. For loci from GWAS in European ancestry samples, fewer than expected were transferable to other ancestry groups. Fine mapping benefited from additional sample diversity. A transcriptome-wide association study identified 205 significantly associated novel genes. These findings suggest that, for MD, increasing ancestral and global diversity in genetic studies may be particularly important to ensure discovery of core genes and inform about transferability of findings.

The causal role of adiposity in mental illness: A systematic review and meta-analysis of Mendelian randomization studies

“…Twenty-eight studies reported 98 estimates of the association between adiposity and depression 25,32–35,37,40,42–45,47,48,50,53,55–59,62–64,66–70 , three studies reported 9 estimates for anxiety 25,41,67 , three studies reported 8 estimates for anorexia nervosa 61,67,68 , five studies reported 13 estimates for bipolar disorder 31,53,55,65,67 , three studies reported 7 estimates for OCD 61,67,68 , three studies reported 23 estimates for PTSD 49,60,67 , and twelve studies reported 26 estimates for schizophrenia 36,38,39,46,51,52,54,55,61,65,67,68 . One-sample MR design was conducted in six studies 33,34,43,56,57,62 , two-sample MR design was conducted in thirty-two studies 31,32,35–42,44–55,58,60,61,63–69 , both one-sample MR and two-sample MR were conducted in three studies 25,59,70 . Thirty unique MR estimates out of 184 total estimates were included in meta-analyses (details as shown in “Yes” under “For meta-analysis” collum in Appendix).…”

“…We repeated the main analyses estimating the association of genetically predicted adiposity with depression including only studies that reported results with binary outcomes. In Appendix , nine studies with 15 estimates provided results with binary outcomes (OR 1.06, 95% CI 1.00-1.13) 33,50,57,58,63,64,67,69,70 . The findings were similar to the main analysis which included binary and continuous outcomes ( Figure 5 ).…”

An integrative single-cell atlas to explore the cellular and temporal specificity of neurological disorder genes during human brain development

“…Genes significantly enriched for PTVs or damaging missense variants (p-value <0.01) in cases were subset from the summary statistics (https://bipex.broadinstitute.org). We obtained 450 major depression-associated genes from a GWAS analysis of 88,316 cases and 902,757 controls 23 . Schizophrenia-related genes were sourced from exome and GWAS analysis.…”

Human pluripotent stem cells as a translational toolkit in psychedelic research in vitro

“… 84 Furthermore, genome-wide significant variants associated with the risk factors or symptomatic features of psychiatric disorders such as depression, SUDs, and PTSD are continually being identified, offering unprecedented insights for identifying novel therapeutic targets, repurposing existing drugs, and establishing target-based systems that also model relevant phenotype rescues. 85 , 86 , 87 Analyzing editing revertants in PSCs from donors with disease-linked variations allows for scrutinizing their genotype-phenotype relationship, whose functional implications are still unknown and could influence the clinical response to psychedelics.…”