FEATURE 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 genomewide association study comparing children in the upper and lower extremes of specific behavioural and cognitive traits.
Investigator photos by Brett Jones
Q 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
Schachar: At that point, we will also generate animal models and learn more about the proteins that these genes play a role in.
Q
How will this study contribute to the field of psychiatric genetics?
Paul Arnold, MD, PhD
Russell Schachar, MD, FRCP(C)
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;32:4055. 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.
Jennifer Crosbie, PhD, CPsych
4. Boileau B. A Review of Obsessive-Compulsive Disorder in Children and Adolescents. Dialogues Clin Neurosci. 2011;13:401-411
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.
5. Menzies L, et al. Neurocognitive Endophenotypes of Obsessive-Compulsive Disorder. Brain. 2007;130:32233236. 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.
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