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FRIMED2-FRIPRO forskerprosjekt, medisin og helse

POTENTIAL EARLY DIAGNOSTIC MOLECULAR MARKERS OF ADHD: Analysis of miRNA profiles and DNA methylation status in triads.

Alternative title: Tidlige molekylære markører for ADHD: Analyse av endringer i mikroRNA og DNA-metylering hos mor, far og barn.

Awarded: NOK 8.7 mill.

Project Manager:

Project Number:

240763

Application Type:

Project Period:

2015 - 2020

Partner countries:

Attention-deficit/hyperactivity disorder (ADHD) is the most common neuropsychiatric disorder in childhood affecting 5-6% of children, which often begins during childhood persisting into adulthood in the majority of patients, and is associated with poor academic and social outcomes. The core areas of difficulties for subjects with ADHD are hyperactivity, impulsivity, and inattention over time and across situations. The etiology of ADHD is still poorly understood, however; there are indications of genetic as well as environmental factors contributing to the development of the disorder, and epigenetic changes have been suggested to be involved. It also shares genetic risk factors in common with other neurodevelopmental disorders like autism, schizophrenia and epilepsy. Family studies have shown that ADHD runs in families, and twin studies indicate that the heritability of ADHD in children is 70-80%. However, findings from molecular genetic studies thus far can only explain a small fraction of the heritability, indicating that ADHD risk variants will be of very small effect size and include multiple rare variants. The disorder is associated with impaired social functioning, lower academic achievement, substance abuse and criminality. In addition, ADHD is associated with increased healthcare costs for patients and their family members. The disorder is thus of great societal concern, and increased knowledge of the etiology may lead to earlier diagnosis and improved treatment and health. Epigenetic changes have been studied intensely in recent years. Altered epigenetic markers can provide information on early life exposures. Dysregulation of epigenetic mechanisms are linked to many human diseases such as cancer, asthma, and neuropsychological defects. Identifying the epigenetic mechanism involved in ADHD will allow the development of interventions to alter or reduce deleterious genes expression level or to increase the expression level of protective genes. The main aim of POEMA is to study whether the epigenetic status at birth is important for ADHD which appears in childhood. By studying epigenetic factors, we hope to understand more about the causes of ADHD. POEMA will explore the interplay between pre- and peri-natal moderate exposures of fathers or mothers to environmental factors, and their relation to epigenetic modifications (DNA methylation status and miRNA profiles) in the offspring. POEMA is based on a linkage between the MoBa, with biological material and extensive information on lifestyle and environmental exposures, and the Norwegian Patient Registry (NPR), with a clinical valid phenotype and registry recorded diagnosis of ADHD. Modification in the DNA methylation status or miRNA profiles of the ADHD children (and their parents, who also gave much information to MoBa on their diet, life-style etc.) will be compared with the same types of factors in other children in MoBa for which there is no indication of ADHD. We hope to find clear differences between the ADHD and other children; if we succeed in this, we have established good tools to understand ADHD and possibly even its treatment and prevention. Recently, we identified a set of miRNAs regulating the ADHD associated candidate genes, and the predictive value of these miRNAs is now been analyzed in plasma samples from cord blood of ADHD cases and matched controls. These miRNAs can be used to assist in the prediction and maybe early diagnosis of ADHD. Identification of miRNA-regulated ADHD candidate genes can be used to develop blood-based molecular markers to be investigated in future studies of ADHD patients.

Måle for prosjektet er å identifisere tidlige molekylære-markører for ADHD. Prosjektet vil karakterisere mikroRNA og DNA-metylering endringer som er assosiert med ADHD. Vi har identifiserte et sett av miRNA-er som regulerer ADHD-assosierte kandidatgener, og disse miRNA-ene kan benyttes til prediksjon av ADHD og muligens til utviklingen av blod-baserte markører som kan benyttes i fremtidige ADHD studier. Vi analyserer nå DNA-metylering ved Ilumina EPIC-array, og resultatene forventes å bli ferdig i vår 2021. Den enorme data som genereres fra DNA metylering analysen kommer til å være også tilgjengelige for framtidig prosjekter. Den epigenetisk-analyse plattformen som er etablert via POEMA-prosjektet har allerede resultert at vi er nå med et H2020-prosjekt (2020-2024: EXIMIOUS: grantNo 874707), og videre samarbeider med et annet H2020-finansiert prosjekt som skal undersøke sammenhengen mellom miljøeksponering og neurologiske utfall (inkludert ADHD).

ADHD is a serious neurological disorder affecting 5-6 % of children in Norway and is a major global health concern which seems to increase in magnitude. There are indications of genetic as well as environmental factors contributing to the development of the disorder, and epigenetic changes have been suggested to be involved. The main aim of this project is to investigate whether the epigenetic status at birth is important for neurodevelopmental disorders appearing in childhood and persisting into adulthood. A specific aim is to identify early diagnostic biomarkers of ADHD. The biomarkers will be important for early identification and intervention of affected individuals, and may contribute to a better mechanistic understanding of ADHD. Using molecular methods, the project will characterise epigenetic markers associated with ADHD. The biological samples to be analysed are cord blood samples already collected and stored in the MoBa biobank. A triade case-control study within MoBa will be designed, and data will be linked with the Norwegian Patient Registry (NPR). A clinically validated ADHD diagnosis in NPR will define the case group. Controls matched by age and gender, negative for ADHD family history and ADHD symptoms, will be randomly drawn from the MoBa cohort. MiRNA and DNA methylation, as markers of epigenetic status, will be characterised for cases and controls. Analysis of the biological relevance of epigenetic changes for ADHD will be performed.

Funding scheme:

FRIMED2-FRIPRO forskerprosjekt, medisin og helse

Funding Sources