Abstract
BackgroundPrevious studies have found that children born with a non-syndromic orofacial cleft have lower-than-average educational attainment. Differences could be due to a genetic predisposition to low intelligence and academic performance, factors arising due to the cleft phenotype (such as social stigmatization, impaired speech/language development) or confounding by the prenatal environment. A clearer understanding of this mechanism will inform interventions to improve educational attainment in individuals born with a cleft, which could substantially improve their quality of life. We assessed evidence for the hypothesis that common variant genetic liability to non-syndromic cleft lip with or without cleft palate (nsCL/P) influences educational attainment.MethodsWe performed a genome-wide association study (GWAS) meta-analysis of nsCL/P with 1692 nsCL/P cases and 4259 parental and unrelated controls. Using GWAS summary statistics, we performed Linkage Disequilibrium (LD)-score regression to estimate the genetic correlation between nsCL/P, educational attainment (GWAS n = 766 345) and intelligence (GWAS n = 257 828). We used two-sample Mendelian randomization to evaluate the causal effects of genetic liability to nsCL/P on educational attainment and intelligence.ResultsThere was limited evidence for shared genetic aetiology or causal relationships between nsCL/P and educational attainment [genetic correlation (rg) −0.05, 95% confidence interval (CI) −0.12 to 0.01, P 0.13; MR estimate (βMR) −0.002, 95% CI −0.009 to 0.006, P 0.679) or intelligence (rg −0.04, 95% CI −0.13 to 0.04, P 0.34; βMR −0.009, 95% CI −0.02 to 0.002, P 0.11).ConclusionsCommon variants are unlikely to predispose individuals born with nsCL/P to low educational attainment or intelligence. This is an important first step towards understanding the aetiology of low educational attainment in this group.
Highlights
Worldwide, orofacial clefts affect around one in 600–700 live births.[1]
We used Linkage Disequilibrium (LD)-score regression and Mendelian randomization (MR) to assess whether the association of nonsyndromic cleft lip with or without palate (nsCL/P) and low educational attainment relates to genetic predisposition to low educational attainment or low intelligence
Using LD-score regression, we found little evidence of a substantial genetic correlation between liability to nsCL/P and educational attainment [genetic correlation coefficient À0.05, 95% confidence interval (CI) À0.12 to 0.01, P 0.13] or intelligence
Summary
Some evidence suggests that children born with orofacial clefts are at higher risk of low educational attainment, even when there are no other major birth defects or known syndromes. In a data-linkage study in Atlanta, children with isolated clefts were two times more likely to use special-education services than children with no major birth defects, whereas the broader group of children with any orofacial cleft (i.e. isolated or occurring with another condition) were three times more likely to use these services.[10] A Swedish population-based registry study showed that children with cleft lip and palate were less likely to receive high grades compared with over 1.2 million controls.[11] Children with cleft palate only were even less likely to receive high grades. Using GWAS summary statistics, we performed Linkage Disequilibrium (LD)-score regression to estimate the genetic correlation between nsCL/P, educational attainment
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