In the latest episode of The Genetics Podcast, host Patrick Short is joined by Dr. Hilary Martin, Group Leader in Human Genetics at the Wellcome Sanger Institute, to discuss her research in neurodevelopmental disorders, consanguinity, and genetic complexity. With a career spanning studies in population genomics and developmental disorders, Hilary offers a unique perspective on the interplay between rare and common genetic variants, as well as the ethical and scientific considerations surrounding her work.
Understanding neurodevelopmental disorders
A major focus of Hilary’s research is neurodevelopmental disorders, where her team investigates the contributions of both rare and common genetic variants. In a recent Nature paper, her group highlighted how polygenic risk factors—common variants associated with traits like educational attainment—interact with rare monogenic mutations to influence the development of neurodevelomental disorders.
While the field has traditionally focused on rare, ultra-damaging mutations, Hilary’s findings reveal a more nuanced picture. Her team showed that children without monogenic diagnoses had significantly lower polygenic scores for educational attainment compared to controls, suggesting a broader genetic liability threshold model at play.
Surprisingly, even children with a monogenic diagnosis showed reduced polygenic scores when accounting for parental effects, prompting further exploration into the roles of indirect genetic effects. Hilary's work highlights the need to better understand how parents’ genetics and behaviors may influence their child’s development.
Communicating complex results
Hilary’s work touches on sensitive topics like cognition, education, and neurodevelopment, which can be prone to misinterpretation. Recognizing this, her team collaborated with patient advocates to create a lay summary and an FAQ document to ensure their findings are accessible and correctly understood. Now, Hilary’s team has a 20-page FAQ and a simplified “easy-read” version, designed to meet the needs of diverse audiences.
Rare variants and population genomics
Hilary’s other major area of focus is genetic research in populations with high rates of consanguinity. Her work with the Genes and Health study, which focuses on British Pakistani and Bangladeshi communities, aims to uncover novel genetic insights by analyzing rare gene knockouts and their links to complex diseases.
With over 55,000 participants and whole-genome sequencing completed, the Genes and Health study is a powerful resource for studying recessive disorders and autozygosity. Hilary’s team explores how homozygous rare variants affect complex traits and diseases, providing unique opportunities for drug target discovery.
Future directions in genetic research
Hilary is particularly excited about follow-up studies on common and rare variants in neurodevelopmental disorders. Her team is working to separate the influence of parental genetics on a child’s development from other factors, such as parents choosing partners with similar traits. Understanding these relationships could lead to practical ways to improve outcomes for children with neurodevelopmental conditions.
Collaboration and data sharing
As a final note, Hilary and Patrick discuss the importance of collaboration, especially as data availability continues to be a limiting factor for many studies. Her group is eager to work with researchers who have access to multi-generational cohorts or unique datasets that could shed light on genetic mechanisms in neurodevelopmental conditions.
If you’re interested in collaborating or learning more about her research, Hilary welcomes inquiries from fellow researchers, particularly those with access to family-based cohorts.
Listen now:
.png)
