BY: Zeynep Yilmaz, PhD

DATE: November 14, 2016

In continuation with Parts 1 and 2 of this blog series, we will now present you with an overview of what we have learned from the genetic studies of other psychiatric disorders, and most importantly, what these findings mean for the future of eating disorder genetic studies. If you haven’t had a chance to read the previous blog posts in this series, you can find them here: (Part 1: Overview of Genetics and Genetic Research Methods and Part 2: The Genetics of Eating Disorders).

The Era of Genome-Wide Association Studies

With the advances in technology and genome-wide association studies becoming increasingly cost-effective, we have started gaining important insights into the genetics of psychiatric disorders. As summarized in Part 1 of the series, a genome-wide association study (or GWAS for short) comprises the scan of millions of sites across the genome for differences in base-pairs (i.e., letters A, T, C, and G) at the exact same location among individuals with the disorder (“cases”) and individuals without the disorder (“controls”). This scan is done in a hypothesis-free manner, meaning that the researchers do not make any prior assumptions about where they think these base-pair differences will reside in the genome. Because we study millions of spots in the genome, we need a very large number of individuals in order to determine statistically whether certain base-pairs in certain genes are more common in individuals with an illness than individuals without an illness.

Psychiatric Genomics Consortium

Alongside the recent advances in genotyping technologies, formation of the Psychiatric Genomics Consortium (or PGC for short) in 2007 has been a key milestone for psychiatric genetic research. Chaired by Dr. Patrick Sullivan at UNC, the PGC currently includes working groups for schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorder, attention deficit/hyperactivity disorder, eating disorders, obsessive-compulsive disorder/Tourette’s syndrome, post-traumatic stress disorder, and substance use disorders. With 800+ investigators from 36 countries and DNA samples from over 600,000 individuals. PGC is truly an international effort that brings world-renowned and junior researchers and clinicians together to understand the genetic underpinnings of psychiatric disorders using modern genomic techniques. The Eating Disorders Working Group of PGC is chaired by Dr. Cynthia Bulik from UNC CEED and Dr. Gerome Breen from King’s College London. PGC has led to the publication of over 35 scientific articles to date, and this number is steadily increasing as sample sizes become bigger.

Success of GWAS: Schizophrenia

Among psychiatric disorders, schizophrenia is a perfect example of a GWAS success story. Schizophrenia is a serious and chronic psychiatric disorder characterized by the presence of psychotic symptoms such as delusions or hallucinations. Schizophrenia was one of the first psychiatric disorders in which a GWAS was conducted. It took a while for the state of schizophrenia genomics to get to where it is today, as large sample sizes are crucial for GWAS. The first PGC schizophrenia GWAS paper was published in 2009 with 1,600 cases with schizophrenia and fewer than 3,500 controls. In that first analysis, no genes were identified that were associated with schizophrenia risk. But undeterred, the researchers continued to collect samples and in 2011, once they reached around 10,000 cases and 12,000 controls, they identified five genetic risk variants for schizophrenia. In 2013, reaching over 25,000 cases and close to 30,000 controls, yielded 62 variants identified for schizophrenia risk. The most recent publication from the PGC Schizophrenia group was published in 2014, and in a sample of over 35,000 cases and around 47,000 controls, the researchers identified over 108 risk loci for schizophrenia.

Examining the schizophrenia findings more closely, one of the significant genes is a dopamine receptor gene. Dopamine is a key neurotransmitter in the brain. This finding makes sense since current medications used to treat schizophrenia act on dopamine receptors in the brain, thus providing confirmation for the role of dopamine in the biology of schizophrenia. So right off the bat, you can see how GWAS findings relate to treatment and how they potentially could tell us about the biological pathways involved in eating disorders.

Other findings may suggest new avenues for medication development. For example, other genes that have emerged from schizophrenia GWAS are related to glutamate (a neurotransmitter in the brain) and calcium channels (which regulate the flow of calcium and sodium in and out of the cell). Although there are currently not any medications for schizophrenia that target glutamate or calcium channels, these results suggest that developing or repurposing of existing medications which act on glutamate or calcium channels may be a wise next step.

Extensions of GWAS can also allow us to identify biological pathways (a set of genes that regulate similar functional processes) that are related to schizophrenia risk. These include pathways involved in immune system, brain development, and neuronal density. These associations are being further studied, but they have already made enormous contributions to how we think of schizophrenia risk, opening many new lines of research.

In addition to the resounding success in schizophrenia genetics, similar successes are also emerging for bipolar disorder, major depressive disorder, autism spectrum disorders, and attention deficit/hyperactivity disorder. As more cases and controls are added to analyses, the number of risk genes identified for each disorder will also increase, thus opening doors to new biological pathways to be examined to understand the etiology these psychiatric disorders.

The story of schizophrenia is an encouraging one for eating disorders. Early on, with smaller sample sizes, we also had no significant GWAS results; however, as we have increased our sample size, out work is now bearing fruit. At a recent conference in Jerusalem, Dr. Bulik reported on the first genome-wide significant finding for anorexia nervosa. If we follow in the footsteps of schizophrenia and the other psychiatric disorders, we expect that we have reached that critical inflection point after which increases in sample sizes start to yield greater insight into the genes and pathways involved with anorexia nervosa and the other eating disorders.

One of the main goals we hope to accomplish with genetic studies is to help de-stigmatize eating disorders through understanding their biological causes. For instance, autism genomic research has once and for all dispelled the myth of the “refrigerator mother” and provided strong evidence for the involvement of genetic risk factors in autism risk. As for eating disorders, it is unacceptable that there are still people out there thinking that having an eating disorders is a personal choice. While we know that it couldn’t be further from the truth, showing that eating disorders have biological roots may make an important shift in how people see individuals who suffer from an eating disorder. Identifying the genes that increase risk for eating disorders could down the road lead to more tangible developments toward early detection, effective interventions, and more accurate risk detection for prevention.

As indicated in the other blog posts in this series, the interplay between the genes and environment is the basis of many behaviors, and psychiatric disorders are no exception. Like most things, genetic influence exists on a spectrum. On one end, we have traits that are 100% determined by your genes, such as your eye color, or certain medical conditions such as Huntington’s Disease. On the other extreme, we have things that are 100% environmental, such as your favorite sports team. Most of the human traits and risk for medical conditions lie somewhere between these two extremes, therefore most human traits, including eating disorders, are partially inherited. As a neurogeneticist, I cannot emphasize enough the importance of environmental risk factors; having risk genes alone does not determine whether an individual will develop an eating disorder. Likewise, genetic risk alone does not make eating disorders inevitable, and it is very important to take environment into consideration. However, unlike the environmental risk factors, the genome is finite and therefore much easier for us to study and a valuable starting point. Genetic research does much more than focus on the genes alone; on the contrary, gaining an initial understanding of the genes could provide us with invaluable information about how genetic risk may interplay with environmental risk by making certain individuals more vulnerable to environmental risk factors, which could then lead to eating disorders.

References cited:

1. BoraskaV, Franklin CS, Floyd JA, Thornton LM, Huckins LM, et al. A genome-wide association study of anorexia nervosa. Mol Psychiatry. 2014 Oct;19(10):1085-94. doi: 1038/mp.2013.187.
2. Bulik CM, Kleiman SC, Yilmaz Z. Genetic epidemiology of eating disorders. Curr Opin Psychiatry. 2016 Nov;29(6):383-8. doi: 10.1097/YCO.0000000000000275.
3. International Schizophrenia Consortium, Purcell SM, Wray NR, Stone JL, Visscher PM, et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature. 2009 Aug 6;460(7256):748-52. doi: 10.1038/nature08185.
4. Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium. Genome-wide association study identifies five new schizophrenia loci. Nat Genet. 2011 Sep 18;43(10):969-76. doi: 10.1038/ng.940.
5. Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014 Jul 24;511(7510):421-7. doi: 10.1038/nature13595.
6. Ripke S, O’Dushlaine C, Chambert K, Moran JL, Kähler AK, Akterin S, et al. Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat Genet. 2013 Oct;45(10):1150-9. doi: 10.1038/ng.2742.
7. Yilmaz Z, Hardaway JA, Bulik CM. Genetics and Epigenetics of Eating Disorders. Adv Genomics Genet. 2015;5:131-150 (read full article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4803116/)

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