The NeuroIMAGE project

Attention-deficit / Hyperactivity Disorder (ADHD) is a neuropsychiatric disorder which involves substantial involvement of genetic factors as indicated by adoption and twin studies. In the context of the International Multisite ADHD Genetics (IMAGE) project, an ongoing genetic initiative funded by the National Institute of Mental Health in 2002, extensive phenotypic, endophenotypic (neuropsychological) and genotypic information of about 5758 subjects from 1401 ADHD families in 8 countries in Europe has been collected.

A substantial subsample (1625 subjects from 388 families) of this database has been collected in the Netherlands by research groups in Nijmegen, Amsterdam and Groningen. The Dutch database also includes phenotypic and endophenotypic data from 301 healthy control children from 271 families. In 2006 the Genetic Association Information Network (GAIN) initiative of the National Institute of Health granted the IMAGE consortium the genotyping of 600,000 single nucleotide polymorphisms (SNPs) to perform a genome-wide association scan (GWAS) in 958 (315 from the Netherlands) trios of ADHD-affected children and their parents from the IMAGE cohort.

General aims

The overall aim of this investment proposal is to enrich the database of the Dutch IMAGE samples with (i) structural magnetic resonance imaging (sMRI) and functional MRI (fMRI) data; (ii) follow-up data of clinical status (ADHD symptoms and relevant comorbidities) using questionnaires and a semi-structured interview, and (iii) neuropsychological endophenotypes of both probands and siblings of ADHD families and controls; in addition, (iv) comparable phenotypic and neuropsychological endophenotypic data of the parents of children with ADHD and of control children will be collected.

This resource will be made publicly available. By having access to the genotypes of the GWAS, this will allow us and other investigators to clarify the consequences of ADHD risk alleles at the level of both brain function and structure, to increase our understanding of the pathophysiology of ADHD, and to examine the role of genes in the persistence and outcome of ADHD over time.

Specific aims

We will enrich the Dutch IMAGE database and make it publicly available: Adding sMRI, fMRI and neuropsychological data to the Dutch IMAGE database will allow us and other investigators to address many important research questions:

1) Examine the familiality of structural and functional brain abnormalities.
2) Test hypothesis that previously known risk alleles for ADHD will predict sMRI.and fMRI endophenotypes.
3) Carry out a GWAS of structural brain abnormalities.
4) Carry out a GWAS of functional brain abnormalities.
5) Investigate the longitudinal aspect of neuropsychological performance and ADHD symptom severity in children with ADHD and their siblings.
6) Contrast GWAS data of persistent versus remitted cases of ADHD, and of stable versus unstable neuropsychological performance.
7) Investigate neuropsychological performance and severity of ADHD in parents of children with ADHD and control children.
8) Incorporate parental neuropsychological deficits and parental ADHD symptom levels into family-based association tests. Secondary or exploratory analyses may include:
9) Assessment of structural and functional brain connectivity and GWAS,
10) Assessment of parent-of-origin effects.
11) Tests for epistasis and gene-gene interactions.
12) GWAS of genetic copy number variants and the (endo)phenotypic measures.

This project was funded by: