by Hakon Heimer Posted on
12 Jul 2017

On July 19, 2017, SRF held a webinar presentation and discussion with Mark Daly of the Broad Institute of MIT and Harvard. Daly discussed the current approaches that the Stanley Center for Psychiatric Research at the Broad is taking to determine how genes confer risk to psychiatric disorders. SRF advisor Francis McMahon of the US National Institute of Mental Health served as a discussant and moderator of the discussion with the audience.
Listen to the webinar.
Mark Daly's presentation
Comments
How important is clinical homogeneity in GWAS?
How important is clinical homogeneity in GWAS? Schizophrenia has many different subtypes/symptom domains that may be controlled by different pathways. Would grouping patients by these factors alter GWAS results?
Reply to E. Ovenden
I was an early enthusiast for splitting based on clinical subtypes, but I think this has not been a very successful approach. When sample sizes are large enough―larger than we probably have so far for most disorders―some clinical subtypes may emerge, but I suspect that clinical symptoms are just too far removed from the genes to have a benefit that outweighs the loss of power from reduced sample size.
Different psychiatric diseases
For different psychiatric diseases, should we focus more on de novo mutations/rare variants in autism and more on common variants in schizophrenia?
Reply to C. Chen
I think both play a role in each phenotype, and we need to invest more in analyses that span all types of variants. As they both have roughly 80 percent heritability, there is clearly a lot to learn from GWAS in autism, but to date the sample sizes have been much smaller than in schizophrenia. Conversely, with autism cases usually being children and collected with parents, the trio study design that enables de novo mutation discovery has been more deeply explored in autism but clearly has some signal also in schizophrenia (though seemingly a bit less, perhaps because most schizophrenia collections may not include children who were earlier diagnosed with a neurodevelopmental disorder such as developmental/intellectual disability or autism). As GWAS grows in autism and trio sequencing in schizophrenia, I would expect more discoveries and a better opportunity to draw insights from considering common and rare variations together.