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In a study published in Nature Genetics, researchers of Amsterdam UMC teamed up with colleagues from the Complex Trait Genetics department of VU Amsterdam and the Million Veteran Program to scrutinize the genetic similarity of twelve psychiatric disorders. The study shows that conducting a cross-trait meta-analysis with many traits does not yield joint genetic signal that is representative for all trait included; rather, this approach highly favours traits with large statistical power and particular genetic architecture.
To still gain insight into the genetic similarly between psychiatric disorders, the researchers took an alternative approach where they did pairwise comparisons between all twelve psychiatric disorders on multiple genetic levels. Through this, the researchers identified genetic variants, genes, and genomic regions common between pairs of psychiatric traits, and also found enrichment of genetic signal in conserved regions of the genome to be a feature shared between most (nine out of twelve) psychiatric disorders.
In the paper by Complex Trait Genetics researcher Cato Romero, genetic overlap was studied on different biological levels: from genetic variants, genes, and genomic regions, to overlapping biological processes, tissueand cell-types. Considerable overlap was observed, but mostly between pairs of psychiatric disorders. The largest overlap was observed between schizophrenia and bipolar disorder, which shared 117 genetic variants, 28 associated genes, and genetic signal in nine different genomic regions. Only genomic regions related to evolutionary conservation were associated to most of the twelve studied psychiatric disorders, which suggests genetic variation in essential biological processes as a common feature of psychiatric disorders.
While the degree of genetic overlap is often taken as an important determinant of the potential success of cross-trait genetic research, it is not the only deciding factor. The researchers showed that the twelve psychiatric disorders vary considerably with respect to statistical power (how many patients donated genetic data), polygenicity (the proportion of the genome that is causally involved in the disorder), and discoverability (the effect sizes and penetrance of these causally associated genetic variants). Variation between traits on these three dimensions crucially determines the potential success of future cross-trait genetic research.
Lessons for future cross-trait genetic research
Previous research has estimated significant overlap in genetic signal between multiple psychiatric disorders, but it remains challenging to identify which genes or genetic variants, and which biological processes, co-morbid disorders actually have in common. Pinpointing genetic variants and biological processes shared between psychiatric disorders is, however, essential to improve treatment of these debilitating disorders and can potentially even lead to genetically informed therapy (e.g., drug development, drug repurposing) and genetically informed adaptation of our diagnostic system. With novel methodologies and the ever-increasing, publicly available genetic datasets, we are beginning to see the potential of cross-trait genetic research.
