Preterm birth and neuropsychiatric genetic risks: a pilot investigation

Lead Research Organisation: Cardiff University
Department Name: School of Medicine

Abstract

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.

Technical Summary

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.

Planned Impact

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).

Publications

10 25 50
 
Description BLISS -the preterm birth charity 
Organisation Bliss
PI Contribution WE are working with BLISS as we will do the science and they will conduct focus groups with parents
Collaborator Contribution They will conduct two focus groups
Impact None yet
Start Year 2017
 
Description Rutter text book 
Organisation National Institutes of Health (NIH)
Department National Institute of Mental Health (NIMH)
Country United States 
Sector Public 
PI Contribution Lead editor of the Rutter text book
Collaborator Contribution co lead editor of the Rutter text book
Impact The Rutter text book was published in 2015
Start Year 2012
 
Description Cardiff Univeristy Lab Talk - 26 January 2016 - Attention Deficit Hyperactivity Disorder: a developmental journey 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact Talk to the Cardiff University MRC Centre staff and students - approximately 70 people attended with discussion time.
Year(s) Of Engagement Activity 2016
 
Description Cardiff University ADHD Day held on 28.10.2016 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Approximately 60 people attended an afternoon of talks and workshops to provide information and support to individuals and families with ADHD.
Year(s) Of Engagement Activity 2016
URL http://www.ncmh.info/2016/11/07/adhd-open-day-for-families-a-success/
 
Description Giving talk on "ADHD: What next?" at the Royal College of Psychiatrists in Wales Faculty of Child & Adolescent Psychiatry meeting in Wales on 29 April 2016 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Talk to clinical practitioner members of the Royal College of Psychiatrists in Wales Faculty of Child & Adolescent Psychiatry to discuss research into ADHD
Year(s) Of Engagement Activity 2016
 
Description Talk at ADHD event organised by Cardiff and Vale Parents' Federation, 24 February 2016 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Talk entitled "What do we know about ADHD" given by Sharifah Syed to inform and educate
Year(s) Of Engagement Activity 2016
 
Description Talk at Cardiff University Summer School on 12 July 2016 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Talk by Prof Thapar to 60 delegates of the Cardiff University Summer School on Developmental Disorders/Child & Adolescent Psychiatry
Year(s) Of Engagement Activity 2016
 
Description Talk at D'Or Institute for Research and Education (IDOR), Rio de Janeiro, Brazil on 24.11.2016 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Talk on the subject of ADHD: a developmental journey. A talk given to physicians (neurologists, psychiatrists and other specialities), psychologists, speech therapists and some PhD students from all areas. Followed by a discussion with the audience.
Year(s) Of Engagement Activity 2016
 
Description Talk at the XIV ProDAH Meeting at the University of Rio Grande Do Sul in Porto Alegre, Brazil on 25.11.2016 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Talk on ADHD: a developmental journey given to a mix of mater degree, doctoral degree and post-doc students, Professors and clinical instructors of psychiatry and genetics, including students of genetics.
Joint grant (Wellcome Trust) and joint paper.
Year(s) Of Engagement Activity 2016