Abstract
Nonsyndromic cleft lip with or without cleft palate (nsCL/P) is among the most common human birth defects with multifactorial etiology. Here, we present results from a genome-wide imputation study of nsCL/P in which, after adding replication cohort data, four novel risk loci for nsCL/P are identified (at chromosomal regions 2p21, 14q22, 15q24 and 19p13). On a systematic level, we show that the association signals within this high-density dataset are enriched in functionally-relevant genomic regions that are active in both human neural crest cells (hNCC) and mouse embryonic craniofacial tissue. This enrichment is also detectable in hNCC regions primed for later activity. Using GCTA analyses, we suggest that 30% of the estimated variance in risk for nsCL/P in the European population can be attributed to common variants, with 25.5% contributed to by the 24 risk loci known to date. For each of these, we identify credible SNPs using a Bayesian refinement approach, with two loci harbouring only one probable causal variant. Finally, we demonstrate that there is no polygenic component of nsCL/P detectable that is shared with nonsyndromic cleft palate only (nsCPO). Our data suggest that, while common variants are strongly contributing to risk for nsCL/P, they do not seem to be involved in nsCPO which might be more often caused by rare deleterious variants. Our study generates novel insights into both nsCL/P and nsCPO etiology and provides a systematic framework for research into craniofacial development and malformation.
Highlights
Nonsyndromic cleft lip with or without cleft palate is among the most common of all human birth defects [1]
A total of 2556 SNPs showed P-values of at most 1Â10À05 in at least one of the analyses, 2002 of which mapped to 17 of the 20 nsCL/P risk loci that were known at the time of analysis
In the first wave of genome-wide association studies (GWAS), analysis of common variants was limited to a subset of $500 000 variants present on commercially available microarrays
Summary
Nonsyndromic cleft lip with or without cleft palate (nsCL/P) is among the most common of all human birth defects [1]. A substantial fraction of these loci confer their effects in diverse populations [10,11,12,13,14], the strength of the associations for single variants in different populations varies as a function of differences in risk allele frequencies and locus heterogeneity; reflected by different prevalence rates for nsCL/P observed in different populations [1,11,15] Despite these successes it remains unclear how much of the variance in nsCL/P risk can be explained by the risk loci identified to date or common genetic variation in general, and the identification of additional genetic factors contributing to nsCL/P is to be expected. It has remained unclear whether or not shared polygenic components might be involved in risk for both malformations
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