106. Identification Of Genetic Variants Associated With Intraventricular Hemorrhage Of Prematurity

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Authors: Aaron Michael Yengo-Kahn, MD; Michael Feldman, MD; Andrew Hale, MS; Jing He, MS; Janey Wang, MS; Chevis Shannon; Robert Naftel, MD; John Wellons, MD, MPH; Lisa Bastarache, PhD (Nashville, TN)


Intraventricular hemorrhage of prematurity (IVH) affects around 20% of preterm infants. IVH pathophysiology involves fragile vasculature of the germinal matrix susceptible to aberrant cerebral blood flow. However, at least 80% of preterm infants do not suffer IVH, suggesting genetic susceptibility. We used whole-genome genotyping (WGG) linked to deidentified medical records (BioVU) to identify genetic-variants associated with IVH.


Using BioVU, we identified 196 premature (<38 weeks gestational age) infants diagnosed with grade I-IV IVH on head ultrasound and 295 premature infants without evidence of intracranial hemorrhage. Subjects had WGG using the MEGA array, containing 679,902 single-nucleotide polymorphisms (SNPs), minor allele frequency (MAF) > 0.05. Genome-wide association analysis (GWAS) was performed was performed using PLINK v1.90b6.7 and ANNOVAR. Logistic regression determined IVH-associated SNPs. Covariates included gestational-age, sex, ethnicity. Independent replication was performed using the UK Biobank.


Our cohort was 58% male and 66% Caucasian with a median gestational age of 34 (IQR: 32-36) weeks. We identified 33,334 SNPs nominally (p< 0.05) associated with IVH, and report the top 3 genetic-variants here: rs2030998 (intergenic, MAF=0.29, OR=2.10, p=1.57x10-6), rs1484684 (intergenic, MAF= 0.34, OR= 0.49, p=3.57x10-6), and rs7740467 (intergenic, MAF= 0.37, OR=1.94, p=6.67x10-6). Intriguingly, rs7740467 is within the intergenic (i.e. regulatory) region of TBC1D32, a gene required for Sonic-Hedgehog (Shh) signaling in the neural tube and blood vessel formation, while rs2030998 has a pleiotropic association with cerebral cysts in the UK Biobank. The function of rs1484684 is unknown.


To our knowledge, we performed the first GWAS of IVH, suggesting a role for Shh signaling and vascular development in IVH pathophysiology. Identification of high-risk genetic variants will aid in our understanding of IVH and may lead to earlier identification of, and interventions for at-risk fetuses.