Attention deficit hyperactivity disorder (ADHD) is one of the most common and most heritable childhood onset psychiatric conditions. Children with ADHD are at high risk of developing antisocial behavior, substance abuse and other psychiatric disorders, consequently presenting difficulties in their education and social integration.
ADHD does not obey the classical laws of Mendelian inheritance, making it difficult to pinpoint the genes involved. Despite the early advances of candidate gene approaches, subsequent progress in unraveling genetics of ADHD has been rather slow. So far, association studies of ADHD yielded risk variants that (1) generally tend to have small effect sizes or be rare, (2) often refer to co-occurring conditions and (3) lack consistent replication. Even the most comprehensive genome-wide scans available with thousands of patients still appear to result in variants accounting for a relatively small proportion of disorder expression. Thus, there is a growing need for pursuing approaches alternative to dominating association studies.
This project proposes the examination of epigenetic factors in ADHD. Epigenetics concerns alterations in gene expression caused by mechanisms other than changes in DNA sequence. These modifications have been shown to be dynamic and may be reversible throughout life, even in fully differentiated brain cells. As epigenetic mechanisms contribute to several neuropsychiatric disorders, we suggest the investigation a well-known process: parent-of-origin effect (POE).
POE is an umbrella term for a range of genetic and epigenetic phenomena inflecting the development of complex traits. POE have already been implicated in psychiatric health, with documented evidence in schizophrenia, autism and bipolar disorder. Nonetheless, little is known about POE in ADHD, with conflicting results dominating the field.
The hypothesis of POE in ADHD may be supported by several previous studies. The variability in ADHD phenotype was shown to vary depending on parental ADHD history and syndromes with ADHD symptomatology exhibit clinical evidence of POE. Furthermore, it is well-established that the expression of growth-enhancing genes such as IGF2 (insulin-like growth factor 2) is regulated through imprinting, while suboptimal prenatal environment resulting in low birth weight or preterm birth can increase the risk for adverse neurobehavioral outcomes, including ADHD.
Currently, there is no methodology to properly investigate POE (especially for continuous phenotypes), meaning that all previous studies on POE in ADHD are subject of much debate and little replication. This project will be performed in collaboration with BROAD Institute of Harvard and MIT (Boston, MA, USA), where we will be working on the development of new methodology as well as the analyses of the data.