Spit for Science: A Population-based Genetic Study of Childhood Attention Deficit Hyperactivity Disorder and Obsessive Compulsive Disorder

Spit for Science: A Population-based Genetic Study of Childhood Attention Deficit Hyperactivity Disorder and Obsessive Compulsive Disorder

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By: Laura Seohyun Park

“Would you like to spit for science?”

“SPIT! Why would I do THAT?” shouted the 10-year-old boy with both excitement and disgust. As I explained to him that his spit could contribute to science and help other people, the boy was quick to agree to participate. Our setup at the Ontario Science Centre (OSC) looked like an arcade with computers, game controllers, and toy prizes–but actually, it was the scene of cutting-edge research.

I had the pleasure of being a part of the Thoughts, Actions and Genes project (TAG), a ground-breaking study exploring the genetic basis of attention-deficit hyperactivity disorder (ADHD) (1,2) and obsessive-compulsive disorder (OCD) (3,4,5). Led by Dr. Russell Schachar, Dr. Jennifer Crosbie and Dr. Paul Arnold from the Department of Psychiatry at the Hospital for Sick Children, and in partnership with the OSC, over 17,000 children and adolescents (7-17 years of age) participated in TAG. Each participant completed a behavioural questionnaire, a cognitive task called the Stop Signal Task (SST), and donated a saliva sample. In a recent interview with the investigators behind TAG, the IMS Magazine learned about the project’s novel and creative approach to study complex psychiatric disorders.

What led you to conduct a research project like TAG?
Schachar: Psychiatric conditions are highly influenced by genetic risk factors as seen in twin and family studies of affected individuals. Thus far, candidate gene studies and genome-wide association studies (GWAS) have generated suggestive findings but either with difficulty to replicate, or nothing that is ‘significant genome-wide’, respectively. While global collaboration among scientists is a necessary strategy for collecting sufficiently large psychiatric patient samples for genetic analysis, they can introduce new problems such as the imprecision in measuring psychiatric “phenotypes”. It is not clear that ADHD or any other psychiatric disorder is assessed and diagnosed in exactly the same way in Brazil as it is in the Netherlands. Moreover, global studies collect DNA from very divergent ethnic groups. It is entirely possible that the genetic risks for a common disease may not be identical in every ethnic group. Based on these limitations, it was clear to us that novel methods were needed to break this impasse.

Crosbie: Endophenotypes6, which are objective, quantitative, and heritable “intermediate phenotypes” or “biological markers”, provide increased power to genetic studies by pointing to a more homogeneous genetic group of individuals and measuring a process that is closer to the underlying genetic mechanism. There is evidence that response inhibition, which refers to the ability to stop a speeded motor response and can be measured by the SST, is a valid endophenotype for ADHD based on the results of clinical, family, functional imaging and preliminary genetic investigations (response inhibition influenced by the genetic risk factors that influence ADHD). (2,7)

Arnold: The general population-based design of TAG provided a quick and cost-effective way to collect a large sample of children using a single and uniform assessment of behavioural (ADHD, OCD, and other conditions through questionnaire), cognitive (response inhibition measured by SST) and genetic (saliva DNA) traits. With this data, we are able to draw from the full range of variation in our traits of interest, and use an extreme trait approach8 to conduct a genome-wide association study comparing children in the upper and lower extremes of specific behavioural and cognitive traits.

What are the objectives of TAG?
Arnold: Once we have performed our GWAS and identified interesting risk variants, we intend to genotype these variants in our entire sample and clinical samples. By taking our results to clinical samples, we can test if the identified variants [in the general population] are also found in ADHD or OCD patients, and also look for associations with interesting phenotypes we can’t measure in the general population (e.g. neuroimaging). Another future direction is to look for other genetic variations beyond the common “single nucleotide polymorphisms” surveyed in GWAS. For example, we will analyze copy number variants and relatively rare but functional single nucleotide variants found in coding regions of genes.

Schachar: At that point, we will also generate animal models and learn more about the proteins that these genes play a role in.

How will this study contribute to the field of psychiatric genetics?
Schachar: There is a great deal of enthusiasm about the use of cognitive endophenotypes or biomarkers in psychiatric genetic research. Ours will be one of the first to be completed. If it proves to be useful in identifying genetic risks for inhibition and for these disorders, the field will move rapidly.

Crosbie: With this potential to point to new candidate genes of interest for ADHD and OCD, the study may provide us with novel information about the etiology and molecular pathways of these disorders, as well as further our understanding of other neuropsychiatric disorders.

Arnold: Our approach with TAG is consistent with previous work suggesting that we should be thinking of neuropsychiatric disorders as continuous rather than categorical traits. If we are successful in identifying risk variants for psychiatric disorders, others may want to adopt a similar strategy of studying large general population samples rather than focusing solely on clinic-based populations.

References
1. Neale BM, et al. Meta-analysis of Genome-wide Association Studies of Attention-Deficit/Hyperactivity Disorder. J Am Acad Child Adolesc Psychiatry. 2010;49:884-897.
2. Crosbie J, et al. Validating Psychiatric Endophenotypes: Inhibitory Control and Attention Deficit Hyperactivity Disorder. Neurosci Biobehav Rev. 2008;32:40-55.
3. Pauls DL. The Genetics of Obsessive Compulsive Disorder: A Review of the Evidence. Am J Med Genet C Semin Med Genet. 2008;148:133-139.
4. Boileau B. A Review of Obsessive-Compulsive Disorder in Children and Adolescents. Dialogues Clin Neurosci. 2011;13:401-411
5. Menzies L, et al. Neurocognitive Endophenotypes of Obsessive-Compulsive Disorder. Brain. 2007;130:3223-3236.
6. Gottesman II, Gould TD. The Endophenotype Concept in Psychiatry: Etymology and Strategic Intentions. Am J Psychiatry .2003;160:636-645.
7. Schachar RJ, et al. Heritability of response inhibition in children. J Int Neuropsychol Soc. 2011; 17(2):238-47.
8. Liu DJ, Leal SM. A Unified Framework for Detecting Rare Variant Quantitative Trait Associations in Pedigree and Unrelated Individuals via Sequence Data. Hum Hered. 2012;73:105-122.