by Cynthia M. Bulik, PhD
This is the third in a series of four posts on results of the Anorexia Nervosa Genetics Initiative (ANGI) published in Nature Genetics. Read about the results of ANGI in Part 1, the process in Part 2, and personal reflections and information for patients, clinicians, and family in Part 4.
In this blog, we tackle the question of what next. The Psychiatric Genomics Consortium (PGC) has set forth an ambitious goal of achieving sample sizes of 100,000 for all major psychiatric disorders, and anorexia nervosa is no exception. As the Eating Disorders Working Group of the PGC, or work is even more extensive as we need to ascertain sample sizes this large for anorexia nervosa, bulimia nervosa, and binge-eating disorder. In addition, members of the PGC-ED are in the beginning stages of also planning a GWAS for avoidant/restrictive food intake disorder (ARFID) and once we more fully understand the clinical phenomenon of atypical anorexia nervosa (all of the symptoms of anorexia nervosa but in the absence of low body weight), we will also explore the genetics of that condition.
But our work is not just about collecting large samples and identifying loci on the genome that are associated with various disease states. The real question is how do you go from a GWAS to functional biology and ultimately translating your science for use in the clinic? To answer this question, I conducted an interview with Patrick Sullivan, MD, FRANZCP, the co-founder and chair of the Coordinating Committee of the PGC. Full disclosure, Dr. Sullivan is both my collaborator and my husband (not in that order!).
Dr. Bulik: “As you know the PGC-ED and ANGI just published a paper (on which you are author) in Nature Genetics that identified 8 loci significantly associated with anorexia nervosa and an intriguing panel of genetic correlations suggesting metabo-psychiatric origins. From your perspective, what are the key findings of this paper?”
Dr. Sullivan: “Big picture—the key thing is that this method (GWAS) works and will help us understand this disorder whose cause has been impossible for us to understand through other methods. Physicians have wondered about the etiology of anorexia nervosa for generations and here we have the first clear-cut insights into its cause.”
Dr. Bulik: “We always hear that a large sample size is critical to the success of GWAS. Where does anorexia nervosa sit in terms of progress with the other psychiatric disorders that the PGC studies?”
Dr. Sullivan: “This GWAS sits in the middle. Schizophrenia, bipolar disorder, and major depression are ahead, but work in those areas started earlier. The PGC was founded in 2007. ANGI only started in 2013. The anorexia nervosa GWAS is somewhere in the middle of all of the disorders we study at this point.”
Dr. Bulik: “You are often heard to say that the point of GWAS is to elucidate biology. What does this study tell us about the biology of anorexia nervosa?”
Dr. Sullivan: “We have intriguing hints in this paper. We were able to preliminarily identify some cell types and biological pathways, but the signal to noise ratio is not good enough yet. In schizophrenia, so many things become incredibly clear when you get a large enough sample size. This is a great start but there is so much more we have to do. Unlike conditions like inflammatory bowel disease or prostate cancer for example, we have been unable to sample a tissue or even know what tissue we should sample in anorexia nervosa in order to investigate the biology—is it brain, is it adipose tissue—we simply do not know where the ‘seat’ of anorexia nervosa is. The work in this paper began that process, that but we need a larger sample size to pin it down.”
Dr. Bulik: “A lot of our readers are interested in the basic question of ‘So what?’ What does it matter that we identified 8 loci and how does that benefit us in terms of understanding and therapeutics?”
Dr. Sullivan: “I have two answers to that question. First, from work like this, we are able to calculate an individual’s genetic risk score. Basically this tells us how high their individual genetic risk for an illness like anorexia nervosa is. We are extremely interested in applying genetic risk scores in the clinic to see if we can predict at the outset of illness, who is at risk for poor outcome. If we can do this, then we can implement specific strategies to mitigate the development of a chronic or severe course. It is an important component of personalized medicine. Second, if with increased sample size, our neuroscientist collaborators can home in on cell types and identify the network or networks that are perturbed or dysfunctional in AN, then with clear pathways to target, we can leverage modern combination high-throughput drug screening to identify or develop therapeutics that target the biology of the illness directly. That is especially important for anorexia nervosa, because there are no medications that are effective in treating the illness.”
Dr. Bulik: “Thank you for your time and for all of the work that you do to advance the field of psychiatric genetics.”
Dr. Sullivan: “My pleasure!”