Matching genotype to phenotype in a detailed assessment of lip morphology

Background:Craniofacial morphology has been reported to be highly heritable, but prior to this research,little was known as to which genetic variants influence normal lip phenotypes. Much of theprevious genetic research involved assigning rare genetic mutations to craniofacial abnormalities,giving little insight as to what causes normal variation. More recent studies have attempted to assign genetic variants to facial genotypes using landmarking methods, however,thesemarkers are sparse in the lip region. Considerable variation of lip morphology exists, which is not amenable to landmarking methods. The aim of this study was to investigate the biological basis of lip phenotypes. Objectives • Develop a robust,reproducible classification system of lip phenotypes • Measure the prevalence of lip phenotypes within a population sample of 4,747 • Assess for associations of lip phenotypes with other lip phenotypes • Assess if there were any sex variations of lip phenotypes •Assess the reproducibility of the classification system with other acquisition methods •Perform a nomeMwide association study(GWAS)of lip phenotypes • Assess for"associations of nonMsyndromic cleft"lip/palate(NSCL/P)SNPs to lip phenotypes • Perform a case/control study to assess the prevalence of lip phenotypes amongst unaffected biological parents of cleft and nonMcleft children" • Assess the predictive capability of lip phenotypes as a precursor of cleft risk Methods: ThreeMdimensional laser scanned facial images were obtained of 4,747 subjects recruited from the AvonLongitudinalStudyof Parents"and"Children"(ALSPAC)." A"total"of"102"individuals"were"recruited"from"the"University"Dental"Hospital,"Cardiff"to" assess"the"reproducibility"of"the"classification"system"with"other"acquisition"methods." Genetic"data"was"available"for"3,687"ALSPAC"subjects"for"the"discovery"phase"of"GWAS," and"3,215"digital"photographs"of"Australian"twins"for"the"replication"phase."Images"of" 597"3dMD"caseMparent"trios"and"controls"were"obtained"through"FaceBase,"to"assess" the"prevalence"of" lip"phenotypes"amongst"unaffected"biological"parents"of" cleft" and" nonMcleft"children."" Results:" TwentyMfive" reproducible" lip" phenotypes" have" been" described." Most" phenotypes"occur"in"combinations,"except"mentolabial"fold"and"chin"dimple,"which"are" distinct."Prevalence"of"features"and"sex"dimorphism"are"also"explained."A"modification" of"the"lip"scale"is"required"for"facial"shells"with"reduced"surface"resolution"taken"with" 3dMD"or"digital"photographs."" A"discovery"GWAS"of"3,687"ALSPAC"subjects"revealed"two"new"GWAS"significant"hits:" chin" dimple" and" DOCK1* (P=2x10M8)* and"mentolabial" fold" and" CDH4* (P=1x10M8)." Both" genes"have"been"reported"to"play"a"role"in"tumour"pathways"(Du,"C.*et*al,"2011,"Laurin," M.*et*al,"2013),"and"CDH4"may"have"a"role"to"play"in"muscle"development"(Nogueira," J.M.* et* al," 2015)." In" addition," 29" nearMhit" associations" were" found" with" 18" lip" phenotypes"(P