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Professor Michael Gill

red line Professor Michael Gill
Figure 1 The 10 repeat allele at the Dopamine Transporter (DAT1) gene is associated with Attention Deficit Hyperactivity disorder. We have shown that it is also associated with an enhanced response to methylphenidate. We have shown that spatial bias in ADHD is largely determined by DAT1 genotype. Finally we have used a simple test for spatial bias as a predictor of response.
Figure 1 The 10 repeat allele at the Dopamine Transporter (DAT1) gene is associated with Attention Deficit Hyperactivity disorder. We have shown that it is also associated with an enhanced response to methylphenidate. We have shown that spatial bias in ADHD is largely determined by DAT1 genotype. Finally we have used a simple test for spatial bias as a predictor of response.

The overall strategy of Prof Gill’s research is to study the relationships between phenotype and genotype in three key neuropsychiatric disorders; Psychoses, Autism and ADHD. Step one, gene hunting, is highly multidisciplinary and involves ascertaining large family and individual case samples and measuring clinical, neuropsychological, neurophysiological and neuroimaging phenotypes, and relating these to genotype at candidate genes and regions. We have developed a series of large and highly valuable family and individual case resources over the last ten years. Whole genome association approaches are underway or are planned. Step two, functional genomics, involves the focused examination of the function of demonstrated candidate genes, and their specific involvement in disease aetiology.

Figure 2 Diagram showing the molecular characterization of a deletion on chromosome 2 in a boy with Autism
Figure 2 Diagram showing the molecular characterization of a deletion on chromosome 2 in a boy with Autism
Autism:- Recent work examines pathways of molecular interaction, on which at any of several points a breakdown in normal functioning can lead to the development of autism. Several risk genes have been identified and some confirmed. Functional studies include examination of enzyme function using stored serum. We are participants in the Autism Genome Project which has recently been funded (€15M) by a consortium of funding agencies including Department of Health and the HRB (€3M to TCD) and as lead applicants for the AGP have been awarded a grant (€2.5M) from Autism Speaks to develop and make available a sample of 2000 parent-child trios. Since the genetic basis of autism is expected to involve several genes that interact in as-yet unknown ways, we will be applying novel statistical techniques to tease out any underlying interaction pathways. This will involve the construction of extended, multi-gene genotypes, and the exploration of clustering, or cooccurrence of particular variants in affected individuals.

Schizophrenia and other psychoses:- We have conducted a series of targeted case control studies and have identified or confirmed several risk genes. For example, Dysbindin is associated with schizophrenia in our patient sample. We have found epistatic interaction with Muted, another BLOC1 protein. Using pathway gene analyses we found evidence that BloS3 and ART1 also associated with schizophrenia. In a functional analysis comparing schizophrenic individuals with and without the dysbindin risk variants we found that those with the risk variants showed decreased excitability symptoms, deficits in the early stages of visual information processing (Dysbindin risk haplotype carriers show significantly attenuated P1 responses. Difference not associated with age, medication type), and deficits in later stages of visual information processing (Spatial Working Memory).

Figure 3 The aim of the Neuropsychiatric Genetics Research group is to bridge from genetics and genomics information to disease pathophysiology using in vivo and in vitro functional studies.
Figure 3 The aim of the Neuropsychiatric Genetics Research group is to bridge from genetics and genomics information to disease pathophysiology using in vivo and in vitro functional studies.
We are nearly two years into the clinical collection phase of Resource for Psychoses Genomics Ireland (RPGI) a Wellcome Trust funded (€1.8M) Biological Collections study in collaboration with colleagues in RCSI, UCD, UCC, and QUB. This sample is already the subject of collaborative NIMH and EU Whole Genome Association grant applications.

Attention Deficit Hyperactivity Disorder:- We are working with three trio based samples in several distinct but overlapping projects. Our genetic studies have identified dopaminergic and serotonergic risk genes. We are examining genes that may predict response to medications. In association with our colleagues in TCIN, we are examining the genetic correlates of neuropsychological endophenotypes. We have interesting findings in relation to special attention, DAT1 genotype and response to medication. We are translating these finding to the normal population attempting to understand the genetic of aspects of neurocognitive function. We are lead members of the IMAGE consortium, a ten centre neuropsychological and genetic study of ADHD and related disorders (€1.2M from NIMH over 5 years).

Key Publications
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Dopaminergic genotype biases spatial attention in healthy children.
Molecular Psychiatry 1-7, 2007.
Bellgrove MA, Chambers CD, Johnson KA, Daibhis A, Daly M, Hawi Z, Lambert D, Gill M, Robertson IH.

Dissociation in performance of children with ADHD and highfunctioning autism on a task of sustained attention. Neuropsychologia 45:2234-2245, 2007.
Johnson K, Robertson I, Kelly S, Silk T, Barry E, Daibhis A, Watchorn A, Keavey M, Fitzgerald M, Gallagher L, Gill M, Bellgrove M.

Dopaminergic genotype biases spatial attention in healthy children.
Molecular Psychiatry 1-7, 2007.
Bellgrove MA, Chambers CD, Johnson KA, Daibhis A, Daly M, Hawi Z, Lambert D, Gill M, Robertson IH.

Preferential Transmission of Paternal Alleles at Risk Genes in Attention Deficit/Hyperactivity Disorder.
Am. J. Hum. Genet. 77:958-965, 2005.
Hawi Z, Segurado R, Conroy J, Sheehan K, Lowe N, Kirley A, Shields D, Fitzgerald M, Gallagher L, Gill M.

Tryptophan hydroxylase 2 (TPH2) gene variants associated with ADHD.
Mol Psychiatry. 11(2):221, Feb 2006.
Sheehan K, Lowe N, Kirley A, Jullins C, Fitzgerald M. Gill M, Hawi M.

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Last updated: May 9, 2008.
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