Cleft lip/palate and educational attainment:cause, consequence, or correlation? A Mendelian randomization study

Background: Previous 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 stigmatisation, 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.Methods: We performed a genome-wide association study (GWAS) meta-analysis of nsCL/P with 1,692 nsCL/P cases and 4,259 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 causal effects of genetic liability to nsCL/P on educational attainment and intelligence.Results: There was limited evidence for shared genetic aetiology or causal relationships between nsCL/P and educational attainment (rg -0·05, 95% CI -0·12 to 0·01, P 0·13; 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).Conclusions: Common 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.