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

International journal of epidemiology

Authors: Christina Dardani, Laurence J Howe, Nandita Mukhopadhyay, Evie Stergiakouli, Yvonne Wren, Kerry Humphries, Amy Davies, Karen Ho, Seth M Weinberg, Mary L Marazita, Elisabeth Mangold, Kerstin U Ludwig, Caroline L Relton, George Davey Smith, Sarah J Lewis, Jonathan Sandy, Neil M Davies, Gemma C Sharp

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 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.

METHODS: We 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.

RESULTS: There 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).

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.

© The Author(s) 2020. Published by Oxford University Press on behalf of the International Epidemiological Association.

PMID: 32373937

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