Expert commentary in Nature Neuroscience

21 November 2016

Commentary on translating genome-wide association findings into new therapeutics for psychiatry, in this months Nature Neuroscience issue by Danielle Posthuma et al.

The 2016 November issues of Nature Neuroscience and Nature Medicine are jointly focused on psychiatric research, providing a collection of Commentaries, Perspectives, and Reviews from leaders in the field that address current challenges and provide an authoritative overview of basic and clinical sciences advancing mental health research. Together with several lead investigators from the Psychiatric Genomics Consortium (PGC), Danielle Posthuma from the Dept. Complex Trait Genetics published a commentary on translating genome-wide association findings into new therapeutics for psychiatry, in this months Nature Neuroscience issue.

The PGC is the largest consortium in the history of medicine and currently includes > 400 researchers from all over the world. The main strength of the PGC is its access to enormous sample sizes of clinically defined psychiatric patients and controls, as well as genetic data. Research output from the PGC includes the 2014 breakthrough in gene-finding for schizophrenia, using a large scale Genome-wide association study (GWAS) design.

Results from the PGC have shown that GWAS in psychiatry, once they reach sufficient sample size and power, have been enormously successful. The PGC aims for mega-analyses with sample sizes that will grow to >1 million individuals in the next 5 years. This should lead to hundreds of new findings for common genetic variants across nine psychiatric disorders studied by the PGC. The new targets discovered by GWAS have the potential to restart largely stalled psychiatric drug development pipelines, and the translation of GWAS findings into the clinic is a key aim of the recently funded phase 3 of the PGC. This is not without considerable technical challenges. This paper outlines the motivations, technical and analytical issues, and the plans for translating PGC phase 3 findings into new therapeutics.

One of the biggest challenges of current research in psychiatry genetics is to translate statistical association findings into actionable variants, that can be functionally tested, and subsequently provide direct target for pharmaceutical intervention. “GWAS hits typically are not directly actionable. However, by studying GWAS hits in biological context, combining multiple levels of -omics data for example and applying smart methods, we can potentially turn them into actionable genetic variants.” says Danielle Posthuma. It will only be through collaborative work to fulfill the translational potential of GWAS beyond polygenic risk score and prediction, with the identification of new biology and eventually clearing the blockages in psychiatric drug discovery.

The commentary appeared online Oct 26 2016: Translating genome-wide association findings into new therapeutics for psychiatry. Breen G, Li Q, Roth BL, O’Donnell P, Didriksen M, Dolmetsch R, O’Reilly PF, Gaspar HA, Manji H, Huebel C, Kelsoe JR, Malhotra D, Bertolino A, Posthuma D, Sklar P, Kapur S, Sullivan PF, Collier DA, Edenberg HJ.

Nat Neurosci. 2016 Oct 26;19(11):1392-1396. doi: 10.1038/nn.4411.