Fig 1.
Liability threshold model for nsCL/P.
Shown is an illustration of a liability threshold model for nsCL/P. Every individual has a normally distributed liability to nsCL/P, determined by genes, environment and chance. Individuals over the liability threshold develop nsCL/P, with the area under the curve past the threshold equal to the trait incidence. We are hypothesising that liability to nsCL/P, specifically genetic liability to nsCL/P, may be associated with differences in facial morphology across the general population.
Fig 2.
Flowchart detailing primary analyses.
This figure outlines the primary analyses and data-sets in the study: 1) the meta-analysis GWAS for nsCL/P, 2) testing the association of nsCL/P PRS with facial phenotypes in ALSPAC, 3) attempted replication of PRS analyses in 3DFN for implicated facial phenotypes, 4) the meta-analysis GWAS for implicated facial phenotypes and 5) bidirectional MR analyses for nsCL/P and implicated facial phenotypes.
Fig 3.
Facial morphological distances of interest.
This figure shows the 12 facial landmarks that were used to generate the facial phenotypes tested for association with the nsCL/P PRS. Facial phenotypes were defined as the 3D Euclidean distance between the following landmarks (Nasal width: 1–2, Nasal-lip distance: 3–7, Lip width: 4–5, Philtrum width: 6–8, Lip height: 7–9, Lip-chin distance: 9–10 and inter-palpebrale width: 11–12).
Table 1.
Association of nsCL/P PRS with facial phenotypes in ALSPAC children.
Table 2.
Causal estimates of genetic liability for nsCL/P on philtrum width using mendelian randomization.
Fig 4.
Interpretation of bidirectional MR.
(A) SNPs associated with nsCL/P have a homogeneous effect on the facial phenotype with weak evidence for the reverse direction MR. We would conclude that genetic liability to nsCL/P causes both increased liability to nsCL/P (in conjunction with the environment and chance) and changes in the facial phenotype. (B) SNPs associated with nsCL/P have a heterogeneous effect on the facial phenotype. In this instance, there is weak evidence for genetic liability to nsCL/P causing changes in the facial phenotype because liability assumes a consistent effect. We would conclude that an unknown confounder Y affects the facial phenotype and liability to nsCL/P independently. (C) SNPs associated with nsCL/P have a homogeneous effect on the facial phenotype AND SNPs associated with the facial phenotype cause increased liability to nsCL/P. In this instance, there are two possibilities. The first possibility is that the genetic instruments for the facial phenotype are weak (e.g. only one SNP) and so the causal effect estimate of the facial phenotype on liability to nsCL/P is imprecise. The second possibility is that nsCL/P and the facial phenotype have a substantial genetic correlation, which would require further investigation. Here, the results of the Steiger test are useful, as they can infer the most likely direction of effect between nsCL/P and implicated facial phenotypes.