OS049. Exome sequencing identifies likely functional variantsinfluencing preeclampsia and CVD risk

Abstract

Introduction: Next-generation sequencing (NGS) in family-based study designs will be pivotal in unlocking the missing heritability of common complex diseases. Whilst our prior linkage- and association-based positional cloning studies in family- and population-based Australian cohorts, respectively, have discovered novel preeclampsia candidate genes (INHBB,ACVR2A,LCT,LRP1B,RND3,GCA,ERAP2,TNFSF13B), the full complement of causal genetic variation remains largely unknown. We have now sequenced the exomes of two Australian preeclampsia families in another step forward to unlocking preeclampsia's complex allelic architecture.

Objectives: Identify family-specific exon-centric loci segregating in preeclamptic women only.

Methods: The exomes of 18 women (7 preeclamptics,11 controls) from two Australian families contributing to our chromosome 5q (Family 1) and 13q (Family 2) susceptibility loci, respectively, were sequenced using Illumina's TruSeq Exome Enrichment assay and NGS technology. Sequence alignments, quality control assessment and variant calling were conducted on our 8000 parallel processor compute server, MEDUSA. As a first pass, we prioritized exome sequence data to non-synonymous variants within the 1-LOD drop intervals of our 5q and 13q loci. Prioritized exonic variants were also genotyped in the Western Australian Pregnancy (Raine) Cohort to assess their significance against a plethora of cardiovascular disease (CVD) related traits.

Results: In Family 1 we identified two missense SNPs and in Family 2 we identified one missense SNP to segregate in the preeclamptic women but not in the unaffected women. The first SNP in Family 1 (rs62375061) resides within the LYSMD3 gene, is predicted to "possibly" damage the focal protein and the only public record of this SNP is within the Watson genome. The second SNP in Family 1 (rs111033530) resides within the GPR98 gene, is predicted to "probably" damage the focal protein and is rare (1.7% population prevalence). The SNP in Family 2 (rs1805388) resides within the LIG4 gene, is predicted to be highly deleterious (F-SNP FSS=0.849) and is common (⩾17% population prevalence). In the Raine cohort the LIG4 SNP was also significantly associated with weight (p=0.0085), total cholesterol (p=0.0007), HDL cholesterol (p=0.0067) and LDL cholesterol (p=0.0324).

Conclusion: Our preliminary exome data documents the substantial potential to rapidly identify likely functional variants that influence preeclampsia risk. The GPR98 finding is of major interest to us as a recent genome-wide association study reported a significant association with diastolic blood pressure for a SNP at this same gene locus. Furthermore, our findings implicate LIG4 as a novel candidate susceptibility gene for CVD and add weight to the hypothesis of shared genetic risk factors for preeclampsia and CVD.