Preterm birth and neuropsychiatric genetic risks: a pilot investigation

Around 1 in 7 babies are born too early. Although survival has greatly improved, we now know that many children who are born very early (less than 32 weeks of pregnancy -known as very preterm birth), develop neuropsychiatric disorders such as ADHD, Autism Spectrum Disorder as well as later mood and psychotic disorders. These same neuropsychiatric disorders also are strongly influenced by genetic inheritance. However we do not know how these risks work together. Although at least 1 in 4 of those born preterm develop an impairing psychiatric disorder by childhood, many remain healthy. Genetic differences between people might be one explanation.

Some preterm birth studies suggest having biological relatives with a history of psychiatric disorder further adds risk, others suggest it might not. Other research indicates babies who are born preterm birth might have a pre-existing genetic anomaly. These possibilities can now be directly tested using lab genetics. Why do we need to address these questions now? It is because preterm birth rates not only have risen sharply in the last few decades but survival has improved to over 90%.

Here, we propose to begin answering one question and finding out how to set up a future, much larger study that will address these questions. First, we examine in a sample of 500, if those born very preterm show an increase in rare genetic deletions and duplications (copy number variants) already implicated as neuropsychiatric genetic risks. We will also conduct an investigation with families, UK neonatal units and a broad range of scientific advisors, that will provide information needed to carry out a future, much larger genetic study of those born very preterm that can be linked to later health outcomes.

Preterm birth and genetic inheritance are two potent, very early risk factors for neuropsychiatric disorders. Our aim is to utilise a large, on-going UK database that includes very preterm births (<32 weeks gestation) to resolve important questions about the relationships between these risk factors and later neuropsychiatric disorder. Why do we need to address these questions now? It is because preterm birth rates have risen sharply in the last few decades to around 10-15%, survival has improved to over 90% and at least 1 in 4 of those born preterm develop an impairing psychiatric disorder by childhood. However, not all do and the reasons for variation in mental health outcomes are uncertain. Some preterm birth studies suggest a family history of psychiatric disorder further contributes to risk, others suggest it might not. Alternative investigations indicate preterm birth is a marker of pre-existing fetal genetic or developmental anomaly which could overlap with neuropsychiatric genetic risks.

For this proposal, we will capitalise on the existence of the UK Neonatal Collaborative which involves all neonatal units in England, Scotland and Wales (n=200) and the National Neonatal Research Database (NNRD) that holds rich clinical and demographic data on all babies admitted to these NHS neonatal units (~6,000 very preterm births per year).
The first aim involves testing one genetic hypothesis, that one class of neuropsychiatric genetic risk, namely rare (<1%) CNVs, is enriched in a very preterm birth sample of n=500. The second aim is to examine, in partnership with families, clinicians, researchers and the national newborn charity and parent advocacy organisation, Bliss, the processes that will enable us to conduct a future, prospectively phenotyped, whole-population genetic study. This would include electronically-linking anonymised genetic data to UK health outcome information and creating a "consent-to-contact" sample to permit future direct phenotyping.

The main impact of this pilot study will be generated via a future, definitive large scale investigation informed by the pilot results.

1. One future impact is to inform scientists, clinicians and families as to the potential value of screening for large, rare copy number variants in preterm birth neonates.
The time line for this impact is 5 to 7 years (after a full scale investigation)

2. A second potential impact is to provide information that could eventually aid stratifying preterm neonates with regards to likely future risk of neuropsychiatric impairments.
The time line for impact 2 would be 5 to 7 years (after a full scale investigation).

4. The post doc research assistant will acquire statistical genetics and analytic skills by working on the pilot CNV data. They will also gain experience across research areas-psychiatric genetics, neonatology and statistics. We have an excellent track record in developing research capacity at post-doctoral levels and beyond.
The timeline for this is 3 years (after the present pilot study).