Science /
Matthew Brown, Ph.D.
"We have been working with designs for GWAS approaches that are much more cost effective and provide more gene discoveries per dollar than just simple blanket cohort studies."
Matthew Brown, Ph.D.
Professor, Diamantina Institute, University of Queensland
Matthew Brown is a Professor of Immunogenetics at the University of Queensland, based at the Diamantina Institute and Institute of Molecular Biosciences, a position he has held since September 2005. His group's research focuses on evaluating the genetic architecture of common diseases, particularly musculoskeletal diseases.
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Q&A with Dr. Matthew Brown
Can speak you about your research interests?
I'm a clinician scientist, so I think an important part of my research interests is that I was trained as a clinical physician, particularly in rheumatology and bone and joint diseases. We have set up one of the first genotype and genomic array facilities in Australasia at the University of Queensland Diamantina Institute. The institute's major focuses are immunology and cancer biology research. It's great for me because it's part of a major teaching hospital, Princess Alexandra Hospital. So it's very easy to have close, clinical contact and to have really good clinical resources, which I think is essential if you're going to be an active disease gene mapper. My group works in predominantly two diseases: ankylosing spondylitis, which is an inflammatory arthritis, and osteoporosis. We initially had an Illumina BeadStation and more recently added an iScan and Tecan Robotics, and an Illumina GAII sequencer. So we are now a pretty high throughput laboratory and have a lot of experience with GWAS.
Please elaborate on your groups' work with ankylosing spondylitis
For many years people had thought that ankylosing spondylitis was actually a single-gene disease caused by the HLA-B27. As part of the Wellcome Trust Case Control Consortium, we completed one of the first non-synonymous SNP genome-wide association studies. That study identified the first two genes, other than actual HLA-B27, that are involved in the disease. Those two genes are ERAP1 and the other is Interleukin23 receptor—they have totally changed the field. Around the same time, the Interleukin-23 receptor association was replicated as being a gene associated with psoriasis and inflammatory bowel disease, so it partly explains why those diseases tend to occur together. More importantly, these findings showed that a particular part of the T-lymphocyte immunological pathway, called Th-17 lymphocytes, were important in disease pathogenesis. That has triggered quite a bit of research and even therapeutic development in blockading that pathway as a therapeutic for ankylosing spondylitis. There the inflammatory bowel disease and psoriasis communities are ahead of us, and targeted therapies based on that genetic finding are now actually licensed therapies for seronegative diseases.
So here is a situation where a gene finding that was first published in 2006/07 by 2010 has already been translated to a licensed, funded therapy in many countries around the world, which I think is an extraordinary rapid translation. Obviously that's not a general experience with genetics, but it does show that in some circumstances it can make real profound changes.
Describe some of your groups' approaches to GWAS
Working in a funding environment that doesn't have the huge levels of funding that some of the more nationalistic programs have, you have to do things that are a bit cleverer to provide more bang for the buck. We have been working with designs for GWAS approaches that are much more cost effective and provide more gene discoveries per dollar than just simple blanket cohort studies. Notably, at the moment we are just completing an osteoporosis GWAS where using just 2000 samples, we have confirmed 21 out of the 26 known osteoporosis genes and identified a further 5 completely novel osteoporosis genes, which makes the study roughly as predictive as all of the studies that have been done in osteoporosis to date, at a fraction of the cost. I think experimental designs like taking extremes of disease or extremes of quantitative traits are a potentially useful way forward for complex disease gene mapping, particularly in countries where there just isn't so much money to spend.
How does Illumina next-generation sequencing play into your research?
My interest in sequencing came about because of a genetics challenge of how to map genes for phenotypes that are so extreme they are effectively a monogenic trait, and where there was a high likelihood that there wouldn't be a common founder effect. We've been developing the bone exome and more recently whole-exome approaches for mapping bone genes in people who have extreme high bone density. That looks to be an extremely productive way forward of mapping those, even though they're all likely monogenic and couldn't be mapped by tag SNP approaches.
