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Major Depressive Disorder Loci Discovered in Large GWAS Enabled by 23andMe Participants' Data

NEW YORK (GenomeWeb) – In a study published online today in Nature Genetics, researchers from Pfizer Global Research and Development, 23andMe, and Massachusetts General Hospital described 15 genetic loci linked to the risk of major depressive disorder in individuals of European descent.

Using data from hundreds of thousands of 23andMe customers who agreed to participate in research, coupled with data for participants in published MDD studies, the team narrowed in on MDD-associated variants at 15 sites in the genome, including loci already implicated in other psychiatric traits.

Those involved argued that the genetic results may ultimately prompt new approaches for treating MDD that are tailored to the biological processes that are altered in those with the condition.

"The neurotransmitter-based models we are currently using to treat depression are more than 40 years old, and we really need new treatment targets. We hope that finding these genes will point us toward novel treatment strategies," co-corresponding author Roy Perlis, a psychiatry and human genetics researcher at Massachusetts General Hospital, said in a statement.

The lack of genetic variants that have been identified in most past studies of MDD belies the apparent heritability of the psychiatric condition. In an effort to find genetic contributors to MDD in individuals with European ancestry, the team brought together genotyping data for a very large number of individuals with or without the condition.

For the first stage of their genome-wide association study, Perlis and colleagues considered array-based genotyping data for 75,607 23andMe participants with European ancestry and self-reported clinical diagnoses of MDD.

Compared with genotyping profiles in 231,747 unaffected 23andMe participants, the MDD group differed significantly in variants at two loci. One of these SNPs neighbored the brain-expressed gene OLFM4, they reported. The other fell near another gene that's expressed in the brain, TMEM161B, and a gene called MEF2C that's been implicated in intellectual disability, epilepsy, and other central nervous system-related conditions.

When they folded in data from nearly 19,000 more European cases and controls enrolled through the Psychiatric Genomics Consortium for a broader meta-analysis of depression, the researchers tallied up 17 suspicious SNPs at 15 loci — associations with MDD that they subsequently verified using data for another 45,800 23andMe participants with MDD and 106,000 without.

Almost four dozen more SNPs had shakier associations with MDD in the meta-analysis and discovery cohort alone. Of those, 41 showed apparent effects in the same direction in the validation cohort.

The team has already started searching for functional clues to the new associations, using gene set enrichment, expression data, and other types of information. It also attempted to put together a polygenic risk score for MDD based on the 17 significantly associated SNPs, demonstrating that a weighted risk score corresponded with reported depression symptoms, medical use, and so on in individuals from the discovery and replication groups.

"Identifying genes that affect risk for a disease is a first step towards understanding the disease biology itself, which gives us targets to aim for in developing new treatments," Perlis explained. "More generally, finding genes associated with depression should help make clear that this is a brain disease, which we hope will decrease the stigma still associated with these kinds of illnesses."

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