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Major Depression Risk Loci, Genes Identified in Multi-Ancestry Meta-Analysis


NEW YORK – New findings from an international research team are highlighting the importance of including individuals from diverse human populations and ancestry groups when searching for genetic contributors to major depression.

"The diversity, in combination with the large sample size, enabled a comparison of the causal genetic architecture across ancestry groups," corresponding author Karoline Kuchenbaecker, a professor of genetic epidemiology at University College London, and her colleagues wrote in Nature Genetics on Thursday.

The researchers searched for genetic factors linked to major depression within and across ancestry groups with a genome-wide association study and GWAS meta-analysis involving more than 88,300 cases and nearly 902,800 controls — including participants of African, East Asian, South Asian, and Hispanic/Latin American ancestry enrolled through several distinct research cohorts — before bringing in published data for 258,364 more cases and 571,252 controls of European descent.

From there, the team went on to perform fine-mapping analysis and gene prioritization. These were informed by 354 gene associations found in a transcriptome-wide association study done with expression data for major depression-related tissues. They also used "Multi-marker Analysis of Genomic Annotation" (MAGMA) methods with or without Hi-C and conducted analyses with the "functional mapping and annotation" (FUMA) platform.

All told, the investigators narrowed in on 190 genome-wide significant associations with major depression, falling at 160 distinct genetic loci, including 53 not described in the past.

While the results validated many of the associations reported in Europeans in the past, the authors pointed out that "a notable proportion of [major depression] loci are specific to samples of European ancestry." On the other hand, they explained, a subset of associations appeared to be specific to the multi-ancestry meta-analysis.

"We identified novel, biologically plausible associations that were missed in European ancestry analyses and demonstrated that large, diverse samples can be important for identifying target genes and putative mechanisms," the authors reported. "These findings suggest that for [major depression], a heterogeneous condition with highly complex etiology, increasing ancestral as well as global diversity in genetic studies may be particularly important to ensure discovery of core genes and to inform about transferability of findings across ancestry groups."

For example, the search led to a previously unappreciated association involving the chromosome 2 locus 2q24.2 in Hispanic/Latin American participants and a chromosome 6 locus linked to brain cortex expression of the melanin-concentrating hormone gene MCHR2 that showed more tenuous ties to major depression in African ancestry participants.

The team also went on to compare fine-mapping features in the multi-ancestry group and in Europeans, flagging 155 loci linked to major depression at a genome-wide significant level across ancestry groups, while prioritizing 43 genes of interest using TWAS, MAGMA, HiC-MAGMA, and FUMA approaches.

While the authors cautioned that "[i]t is possible that some of the 190 genome-wide significant loci we identified are linked to a more general susceptibility to mental illness instead of being specific to [major depression]," they suggested that "given the overlap between different psychiatric disorders, such findings are nevertheless of value for our understanding of the biology and for the development of new treatments for [major depression]."