Daniel Cromb1, Harriet Cullen1, Christiaan De Leeuw2, Madeleine Barnett1, Jonathan O'Muircheartaigh1, Serena Counsell1, and A. David Edwards1
1Centre for the Developing Brain, School of Biomedical Engineering and Imaging Sciences, King's College London, London, United Kingdom, 2Faculty of Science, Complex Trait Genetics, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
Synopsis
In a cohort of 185 infants born preterm we used linked MR imaging, genomic and neurodevelopmental data, to identify a significant association between common genetic variation in the IGFBP7 gene and cortical grey matter volumes as assessed at term-corrected age (p = 0.0057), as well as motor outcomes as assessed at 18-24 months of age (p = 0.044).
Introduction
Preterm birth is associated with abnormal grey matter development (1), as well as adverse neurodevelopmental outcomes (2, 3). Previous work has identified a single nucleotide polymorphism (SNP) (rs114518130), mapped to the gene IGFBP7, which achieved genome-wide significance for global grey matter volume (GMV) (4) in term-born infants, but the authors did not explore any association with developmental outcomes, and it is not known if this SNP is functional. We aimed to identify an association between variation on SNPs in IGFPB7 and grey matter volumes in an independent cohort of preterm infants; we hypothesised that there would be no association given the additional extreme environmental pressures preterm infants face. We also explored whether we could localise the effects of this gene within cerebral grey matter, and whether there was any association with developmental outcomes.Methods
We used paired MR imaging and whole genome (single nucleotide polymorphism) data obtained at term-corrected age as part of the ePRIME study (5) in a cohort of 185 of prematurely born infants (52% male), with a mean age at birth of 29+6 weeks, a mean birth weight of 1300g and a mean age at MR scan of 42+2 weeks. Total, cortical and deep grey matter tissues were automatically labelled using a neonatal-specific tissue segmentation algorithm (6) and volumes for each tissue type were derived from these. The MAGMA software package (7) was then used to compare genetic variation in 43 SNP’s mapped to IGFBP7 with each of these brain tissue volumes. Birth weight, sex, gestational age at birth, post-menstrual age at scan, total brain volume and three ancestry-related principal components were included as covariates in the analysis. We also compared variation in IGFBP7 with cognition, language and motor outcomes from the Bayley Scales of Infant Development III at 18-24 months of age, with gestational age at birth, sex, age at assessment and three ancestry-related principal components used as covariates in the analysis.Results
We identified significant associations between genetic variation in 43 SNP’s mapped to IGFBP7 with both total grey matter volume (p = 0.011) and cortical grey matter volume (p = 0.0057), but not deep grey matter volume (p = 0.54) in our cohort of preterm infants. No association between sequence variants and focal cortical change survived multiple comparison testing. We identified a significant association between genetic variation in SNP’s mapped to IGFBP7 and motor outcome at 18-24 months of age (P = 0.044), but not cognition (P = 0.11) or language skills (P = 0.42).Discussion
Our study offers a robust measure of association between common genetic variation in 43 SNPs mapped to IGFBP7 and both cortical grey matter volume and motor outcomes in a cohort of preterm born infants. The IGFBP7 gene acts through modulation of IGF binding (8), and is strongly expressed in nervous system tissue (9). IGF levels are also reduced in preterm infants (10). Our results suggest that IGFBP7 may be functionally associated with cortical grey matter volume, hinting at the biological mechanism by which IGFBP7 exerts its effects. Further work needs to be done to define whether this effect interacts with the stresses induced by preterm birth, and to define a mechanism of effect that encompasses wider interactions and gene networks. Conclusion
Our results provide evidence of a functional association between common genetic variation on IGFBP7 and grey matter volume, and localise the effects of IGFBP7 on grey matter development to the cerebral cortex.Acknowledgements
This work was partly funded by an NIHR Academic Clinical Fellowship for Dr. Cromb. The ePRIME study was partly funded by the NIHR grant RP-PG-0707-10154References
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