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Research

ADHD Genetics Group

The ADHD Genetics Group is a research group within the SGDP whose main aim is to identify the genes involved in ADHD and related behavioural traits, and investigate how such genes work together and with environment to influence behaviour. For further information on any of these projects please contact Lena Johansson (Professor Phil Asherson’s office).

 

MAPPING GENES FOR ADHD – INTRODUCTION

ADHD, hyperactivity and related problems are very common, affecting the lives of many children and adults. The disorder is recognised as one of the most important cause of problems that some children have with their schoolwork and relationships with friends and family. These problems often have long-term consequences so that about two thirds of children diagnosed with ADHD have persistent problems that effect them as adults. By investigating the causes and finding out much more about how genes and environments – nature and nurture – combine together to bring about ADHD, we will be in a far better position to develop the best and most effective approaches to help individuals with ADHD. Finding the genes involved in an important step in this direction since we know that genetic influences on ADHD are particularly important. Molecular genetic methods have been highly successful in identifying genes of major effect that co-segregate with single gene disorders. As a result huge strides have been made in our understanding of conditions such as Huntington’s Disease, fragile-X syndrome, familial Alzheimer’s disease and rare familial epilepsies, among many others. Progress in identifying genetic risk factors for more common and complex disorders has however proved to be far more difficult since in most cases the genetic influences result from multiple genetic variants, each conferring only a small additional risk to disease susceptibility. This is the case for attention deficit hyperactivity disorder (ADHD) where familial risks are relatively low, with an estimated sibling risk ratio (risk to siblings of ADHD probands/population risk) for broadly defined ADHD of around 3-4 fold.

Twin studies support the view that genetic factors are the major influence on familial risk with heritability estimates for ADHD symptom scores consistently reported to be in the region of 60-90%. These studies find no role for shared environmental influences on familiarity, although the role of environment may still be pivotal acting through mechanisms of gene-environment interaction. Progress in identifying some of the genes involved in ADHD susceptibility has been relatively fruitful over the past decade by screening genetic variants that lie within or close to genes that regulate neurotransmitter systems, particularly dopamine pathways. The genes that have already been identified as risk factors for ADHD include the dopamine D4 receptor gene (DRD4), the dopamine transporter gene (DAT1), the dopamine D5 receptor gene (DRD5) and synaptosomal associated protein (SNAP-25). It is important to note that all of these genes confer only a small additional risk to ADHD on their own (odds ratio range from 1.2 – 2).

 

Below are some of the studies that our research group is working on.

 

1) THE INTERNATIONAL ADHD GENE PROJECT

FUNDED BY THE US NATIONAL INSTITUTE OF MENTAL HEALTH
UK principle investigator: Prof. Philip Asherson

The IMAGE project, funded by the US National Institute of Mental Health, is a major genetic initiative designed to map the genes that influence risk for ADHD and provide an understanding of the function of such genes. The International project, coordinated by Steve Faraone in Boston and Philip Asherson in London is an international project involving ten European clinical centres based in the UK, Ireland, Holland, Germany, Spain, Switzerland and Israel.

The main aim of this project to create a permanent clinical and DNA resource that can be used both now and in the future to find the genes involved. This is an exciting opportunity since the resource will then be available to some of the best scientists in the world who wish to find out what genes are involved and how they increase risk for ADHD. The first phase of this project started in 2002 and will take five years, during which DNA and clinical data will be gathered from around 1400 school age children with ADHD as well as their brothers, sisters and parents. At the same time we will begin the search for the genes involved by screening the human genome - the entire set of human genes - for genes that are linked to ADHD.

2) CANDIDATE GENE STUDIES OF ADHD
FUNDED BY THE MEDICAL RESEARCH COUNCIL AND THE WELLCOME TRUST

UK principle investigator: Prof. Philip Asherson

The Medical Research Council (MRC) and the Wellcome Trust have funded candidate gene studies that investigate whether specific genes increase the risk for ADHD. In the first project we collected a series of 200 individual with a DSM-IV diagnosis of ADHD (mainly combined type) and have been using this sample to investigate associations with dopamine system genes.

In addition, we have taken another approach by looking for genetic variants that correlate with ADHD-symptoms within population samples unselected for ADHD or other phenotypes. This approach assumes that ADHD represents the extreme of a continuously distributed trait, with genes correlating with different levels of ADHD symptoms across the entire population. To date this approach has not been as fruitful as the investigation of clinical cases of ADHD. We have however found some evidence that two genes, the dopamine transporter gene (DAT1) and synaptosomal protein (SNAP-25), influence levels of ADHD symptoms in the general population.

3) THE GENETIC INVESTIGATION OF ACTIVITY LEVELS
FUNDED BY THE US NATIONAL INSTITUTE OF MENTAL HEALTH

Local principle investigator: Prof. Philip Asherson

This project headed by Dr. Kimberly Saudino in the University of Boston is funded for 5-years by the US NIMH. A core dimension of nearly every temperament theory, activity level (AL) is a highly salient feature of child behavior that has been linked to various facets of child health and development. Twin studies of temperament in infancy and early childhood have yielded considerable evidence that AL is genetically influenced, however, little is known about the role that genetic factors play in the continuity and change in AL across age or situations.

The goal of this project is to use mechanical motion recorders to examine (a) long-term developmental change in AL from 2 to 3 years of age; and (b) short-term changes in AL across situations within each age. We will measure the AL of 300 twin pairs between the ages of 2 and 3 years of age. At each age, twins will wear mechanical motion recorders in the home for a 48-hour period. In addition to the home measure of AL, motion recorders will be used to assess the AL of each twin in a series of laboratory-based activity episodes. Traditional observational ratings of AL will be obtained for each of the laboratory episodes. Parents will complete rating measures of AL and behavior problems. Cheek scrapings will be collected from both twins and parents.

This investigation will enable us to answer the following questions: (1) Investigate the role of genetic influences on developmental change in AL from age 2 to 3. (2) Investigate genetic influences on contextual or situational change on AL within each age (3) Determine the extent to which the agreement between mechanically-assessed AL and parent and observer ratings of AL within the home and laboratory situations is genetically mediated (4) Examine the relation between mechanically-assessed AL and behavior problems. (5) Identify genes associated with AL.

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