In the last several years, the frequency of genetic findings impacting human health has grown steadily. With this, the public is inundated with headlines like, “Schizophrenia has clear genetic ties, new study finds.” But how do scientists discern these ties? At this point in time, it would be expensive, time-consuming, and arduous to examine entire genomes of diseased patients and compare them to entire genomes of healthy patients. After all, a human genome is comprised by the entirety of DNA contained within the chromosome, a whopping 3 billion base pairs (A,C,G,T!)
GWAS whittle down the vast 3 billion nucleotide haystack to a manageable million!
GWAS (Genome-Wide Association Studies), made possible by the completion of the Human Genome Project in ’03 and the International HapMap Project in ’05, allow researchers to use data to find genetic markers correlated with disease. Rather than having to examine all 3 billion base pairs in each patient, researchers examine 500,000 to a million SNPs across a large sample size of individuals with a given disease compared to a control group to find markers more common in the disease group than the control. SNPs (pronounced “snips” and standing for Single Nucleotide Polymorhphisms) are individual locations across a genome where nucleotide variations can occur (more than 99% of all humans’ genomes are the same!) Because of a phenomenon known as “linkage,” researchers do not even have to examine the 10 million SNPs across genomes, but only about a million.
These million SNPs are so much more manageable than 3 billion base pairs! Importantly, SNPs found to be significant in a GWAS are not necessarily the causative variation of a disease; rather they are strongly correlated with the disease sample. Essentially, when there is a heavy variation at particular SNP loci as compared to reference data, researchers know this is meaningful, and this can lead to clinically actionable information.
Why is this significant?
Human disease can broadly be classified in two ways: Complex/multifactorial or single gene/Mendelian disorders. Mendelian disorders occur more rarely than complex disease, but inheritance patterns and causes are more readily understood because they are caused by genetic variation in a single locus in one single gene. To a large extent, clinicians and researchers can predict whether a child will inherit diseases like Tay-Sachs, cystic fibrosis, or sickle-cell anemia. There are some instances when this doesn’t hold 100 percent true, but for the most part, they are the better understood of disorders.
Conversely complex diseases are, as their name suggests, complicated to understand. They are caused not only by interactions between variations at multiple loci in multiple genes, but are heavily influenced by multiple environmental factors. GWAS have been the prevalent tool used over the last few years by researchers of complex diseases. Because complex diseases, like heart disease and many cancers are affected by several factors including environment, lifestyle, and genetics, they are harder to understand than the more rarely occurring but predictably inherited Mendelian disorders, like Cystic Fibrosis and Sickle-cell anemia. GWA studies have been making significant inroads into comprehending and treating these diseases.
Mental illness falls under the complex disease umbrella
In the past into today, mental illness drugs are prescribed in a hit or miss fashion. Furthermore, mental illnesses are mainly studied through clinical presentation as opposed to genotype. Genotype refers strictly to any individual’s genetic code, whereas phenotype is what is expressed (visible) in their bodies and behavior. So when it comes to psychiatry (and other non-mental illnesses,) diagnoses and treatment decisions are made by outward symptoms exhibited by patients. This is less than ideal because how an individual’s illnesses are expressed, and how they interact with drugs are both heavily influenced by genotype. These potential reactions are mostly unknowable unless we know genotype. As this NIMH resource explains, some mental health patients suffer side effects from certain medications, while others don’t. Some medications are efficacious for some patients while not for others. The exercise of finding the right medication(s) and the right dosage is often wrought with frustration. With the help of GWAS, the genomic era is poised to change this.
What are some recent breakthroughs in mental health?
You may have seen headlines about a very recent paper published in Nature that found 108 loci, over 80 percent of which are novel, associated with schizophrenia. Schizophrenia is a chronic brain disorder affecting a whopping 1 percent of the population, and is characterized by hallucinations, delusions, movement disorders, and more. The Schizophrenia Working Group used over 36,000 genotyped patient samples and compared to an even larger number of controls. The GWAS findings indicate that most likely, much of what causes schizophrenia occurs with gene expression in the brain itself, some of which affect pathways including learning and memory, and synaptic connections.
Another recent paper is about findings on Obsessive-Compulsive Disorder (OCD). Johns Hopkins researchers recently found genetic markers linked to OCD in a GWAS study. A mental disorder, OCD is characterized by disturbing thoughts and images (obsessions), and repetitive actions or thoughts (compulsions) performed to neutralize or make the obsessive thoughts disappear. These compulsions only serve their purpose temporarily, and must be repeated in a vicious cycle. In this GWAS study, a strong link was identified in OCD patients near a gene called protein tyrosine phosphokinase (PTPRD). This genetic region is known to influence memory and learning.
How might these findings help patients suffering from these and other mental health issues?
The hope is that findings from such studies will lead to clinical applications. These and future studies could greatly transform outcomes for those with OCD, one of the lesser understood psychological disorders. Scientists may use the information to develop new drugs, as only 60 to 70 percent of OCD patients respond to present-day medications. It’s also possible that when personalized medicine becomes the norm, measures can be taken in childhood to minimize the effects of the disease.
Currently, diagnosis of schizophrenia in teenagers is difficult, as behaviors like irritability, isolation, and change in friends and academic performance tend to mimic typical teenage angst. Thus, earlier diagnosis and therapy should be enabled by the results of GWA studies. Furthermore, development of more effective drugs is one of the goals of understanding the underlying genetic bases of schizophrenia. Patient response to anti-psychotic drugs is currently unpredictable. Pharmacogenomic approaches (tailoring drug choice and dosage based on a patient’s genotype) to treating mental illnesses like OCD and schizophrenia are on their way to reality. With an ever-advancing grasp of the genetic pathways that lead to these disorders, treatment and diagnosis of mental illness should transform before our eyes in this amazing era of genomic medicine.
- Largest-ever genetic study of schizophrenia cements genetic links, Genetic Literacy Project
- What role will genetics play in a biology-based approach to psychiatry? Genetic Literacy Project
- Blazing trails in brain science, New York Times