While reading a recent publication in the American Journal of Human Genetics Part B entitled DISC1 in Adult ADHD Patients: An Association Study in Two European Samples ^[1], I was immediately intrigued by the first sentence of the abstract: “The DISC1 gene was named after its discovery in a Scottish pedigree with schizophrenia (SCZ) patients.” ^[1] This inspired me to do a little background reading regarding the discovery of the DISC1 gene and, as it turns out, it’s a pretty interesting story. Therefore, for the third blog in our Genetics and Mental Health Series, I would like to tell you how this curious gene came to be associated with ADHD.

In 1968, while collecting cytogenetic data from residents at a Scottish young offender’s institute, Professor Patricia Jacobs (who you may recognize as the first scientist to describe a chromosomal abnormality in humans) noticed a balanced translocation between chromosomes 1 and 11 in the karyotype of an 18 year old boy with “adolescent conduct disorder”. ^[2] A balanced translocation occurs when a piece of one chromosome is swapped with a piece of another chromosome without any loss of DNA.  In this case, Jacobs observed that chromosome 1 had a piece of chromosome 11 and chromosome 11 had a piece of chromosome 1. Jacobs went on to examine the chromosomes of the boy’s family and discovered that many of them also carried the translocation. Over the next 20 years, psychiatrists diagnosed many members of the boy’s extended family with schizophrenia, major depressive disorder and other mental and behavioural disorders.  Notably all members of the family with major mental illnesses also carried the translocation discovered by Professor Jacobs. ^[3]

While there was a growing body of evidence that the translocation was associated with mental and behavioural disorders, the question remained whether the translocation disrupted a gene or genes which could be implicated in the high incidence of mental illness in the translocation carriers. In 2000, once the technology was available to clone genes, researchers at the University of Edinburgh reported that they cloned a gene located at the break point caused by the translocation on chromosome 1. They named the gene Disrupted-In-Schizophrenia 1, DISC1. ^[4]

Presently, 45 years after the translocation was initially discovered, and 13 years after the gene was cloned, Kaya Jacobsen, a PhD Candidate at the University of Bergen, and her colleagues have proposed that DISC1 variants may also play a role in attention-deficit/hyperactivity disorder (ADHD) in adults. ^[1] Patients with ADHD are commonly identified because they have a persistent pattern of symptoms related to inattention, hyperactivity and impulsiveness.  This disorder is predominantly diagnosed and studied in children but at least one-third of childhood ADHD patients continue to exhibit an array of frustrating symptoms in adulthood that impair everything from their relationships to their career.

From a Norwegian sample of 561 adults with ADHD and 713 adult controls, Jacobsen collected DNA from blood using standard methods or collected DNA from saliva using Oragene  self collection kits.  Because Oragene self collection kits are non-invasive and pain free, they are a great option for research studies for which participants are reluctant to give a blood sample  increasing study compliance rates. Jacobsen and colleagues compiled a list of single nucleotide polymorphisms (SNPs) throughout the DISC1 gene that were reported to be associated with schizophrenia, bipolar disorder and depression.  After analysis, they found a single DISC1 SNP that was associated with ADHD diagnosis and were able to replicate this finding in a similar sample population from Spain.  And so, many decades after its discovery in a Scottish family with a high incidence of schizophrenia, a DISC1 SNP has been linked to ADHD in adults. Do you have a favourite gene discovery story? I’d love to hear about it in the comments below!

I also think the story of DISC1, from the discovery of the translocation to the cloning of the gene to the study of DISC1 SNPs, is a great example of how genetic research relies on new technological advances. Our genomic service experts can help you determine which technologies and which assays may be best for your research study. 

You can find past articles in the Genetics and Mental Health series here. Be sure to subscribe to our blog so you can be notified of new articles.

References:

[1] Jacobsen KK et al. DISC1 in Adult ADHD Patients: An Association Study in Two European Samples.  Am J Med Genet Part B.  162B:227-234 (2013).

[2] Jacobs PS et al. Studies on a family with three cytogenetic markers.  Ann. Hum. Genet.  33:325-336 (1970).

[3] St Clair D et al. Association within a family of a balanced autosomal translocation with major mental illness.  Lancet.  336:13-16 (1990).

[4] Millar JK et al. Disruption of two novel genes by a translocation co-segregating with schizophrenia.  Human Molecular Genetics.  9(9):1415-1423 (2000).