Genome-wide investigation identifies a rare copy-number variant burden associated with human spina bifida

Paul Wolujewicz,Vanessa Aguiar-Pulido,Alice Abdelaleem,Vidya Nair,Gaurav Thareja,Karsten Suhre,Gary M Shaw,Richard H Finnell,Olivier Elemento,M Elizabeth Ross

doi:10.1038/s41436-021-01126-9

Abstract

PurposeNext-generation sequencing has implicated some risk variants for human spina bifida (SB), but the genome-wide contribution of structural variation to this complex genetic disorder remains largely unknown. We examined copy-number variant (CNV) participation in the genetic architecture underlying SB risk. MethodsA high-confidence ensemble approach to genome sequences (GS) was benchmarked and employed for systematic detection of common and rare CNVs in two separate ancestry-matched SB case–control cohorts. ResultsSB cases were enriched with exon disruptive rare CNVs, 44% of which were under 10 kb, in both ancestral populations (P = 6.75 × 10−7; P = 7.59 × 10−4). Genes containing these disruptive CNVs fall into molecular pathways, supporting a role for these genes in SB. Our results expand the catalog of variants and genes with potential contribution to genetic and gene–environment interactions that interfere with neurulation, useful for further functional characterization. ConclusionThis study underscores the need for genome-wide investigation and extends our previous threshold model of exonic, single-nucleotide variation toward human SB risk to include structural variation. Since GS data afford detection of CNVs with greater resolution than microarray methods, our results have important implications toward a more comprehensive understanding of the genetic risk and mechanisms underlying neural tube defect pathogenesis.

Highlights

Neural tube defects (NTDs) are anomalies of the central nervous system (CNS) present at birth that manifest with varying subtypes and severity and are among the most common structural birth defects
Principal component analysis (PCA) of the population admixtures for each cohort show that the cases and controls are comprised of similar ancestral backgrounds (Fig. 1a)
We found rare coding copy-number variant (CNV) in genes serving several cellular and mitochondrial processes, including choline transport and catabolism, which are closely associated with NTD formation (Fig. 5b)

Summary

Introduction

Neural tube defects (NTDs) are anomalies of the central nervous system (CNS) present at birth that manifest with varying subtypes and severity and are among the most common structural birth defects. The successes of folic acid supplementation for prevention has led to an emphasis in genetic and epidemiological NTD research on the disease association with candidate genes involved in folate metabolic pathways. It has prompted numerous studies in animals of genes involved in one-carbon metabolism and their link with structural birth defects. There remains a translational challenge to reconcile mouse and human NTD data in order to pinpoint genes, pathways, and eventually discern patterns of genetic variation that pose NTD risk in humans

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