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

Christina Dardani*, Laurence J M S Howe, Nandita Mukhopadhyay, Evangelia Stergiakouli, Yvonne E Wren, Kerry J Humphries, Amy J V Davies, Karen M Ho, Seth Weinberg, Mary Marazita, Elizabeth Mangold, Kerstin Ludwig, Caroline L Relton, George Davey Smith, Sarah J Lewis, Jonathan R Sandy, Neil M Davies, Gemma C Sharp

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

20 Citations (Scopus)
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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.
Original languageEnglish
Article numberdyaa047
Number of pages12
JournalInternational Journal of Epidemiology
Publication statusPublished - 6 May 2020


  • non-syndromic cleft
  • educational attainment
  • Mendelian Randomization
  • IQ
  • orofacial cleft
  • cleft lip and palate
  • intelligence


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